I-Neuroinflammation ne-Psychiatric Illness

Neuroinflammation:

Abstract

Imigca emininzi yobungqina ixhasa indima ye-pathogenic ye-neuroinflammation kwisifo sengqondo. Ngelixa izifo ze-systemic autoimmune zibhalwe kakuhle ngoonobangela bokuphazamiseka kwe-neuropsychiatric, i-synaptic autoimmune encephalitides eneempawu zengqondo zihlala zingaqondwa kakuhle. Ngokuhambelana nekhonkco phakathi kweempawu zengqondo kunye nokuzimela ngokuzenzekelayo kwizifo ezizimelayo, ukuphazamiseka kwe-neuroimmunological kwenzeka kwi-classical psychiatric disorders (umzekelo, ukudakumba okukhulu, i-bipolar, i-schizophrenia, kunye ne-obsessive-compulsive disorders). Uphando kwi-pathophysiology yezi meko ngokwesiko lugxininisa ukungasebenzi kakuhle kwe-glutamatergic kunye ne-monoaminergic systems, kodwa iindlela ezibangela oku kungahambi kakuhle kwe-neurotransmitter zisahleli zinzima. Siphonononga ikhonkco phakathi kwe-autoimmunity kunye ne-neuropsychiatric disorders, kunye nobungqina bomntu kunye novavanyo oluxhasa indima ye-pathogenic ye-neuroinflammation kwiingxaki ezikhethiweyo zengqondo zengqondo. Ukuqonda indlela i-psychosocial, genetic, immunological kunye ne-neurotransmitter iinkqubo ezisebenzisana ngayo kunokutyhila imikhondo ye-pathogenic kwaye incede ekujolise kuyo olutsha lothintelo kunye nonyango lweempawu.

Internet:

• Neuroinflammation,
• I-Psychoneuroimmunology,
• IAstrocyte,
• Microglia,
• IiCytokines,
• Uxinzelelo lwe-oxidative,
• Ukuxinezeleka,
• Ubume obungalunganga obuphambanisayo,
• Ingxaki yeBipolar, iSchizophrenia

intshayelelo

Njengoko izinto ezingaqhelekanga zebhayoloji zichongwa ngakumbi phakathi kwezigulana ezinezigulo zengqondo, umahluko phakathi kwemithambo-luvo kunye nesifo sengqondo uyaphela. Ukongeza kwizifo ze-autoimmune ze-systemic ezinxulumene nokubonakaliswa kwengqondo (umzekelo, i-lupus) [1], ngoku kutshanje, izigulane ezine-psychosis ezizimeleyo zichongiwe nge-synaptic autoimmune encephalitides (Itheyibhile 1) [2-6]. Ezi zigulana zihlala zifunyaniswa ngempazamo ukuba zineengxaki ezisisiseko zengqondo, ukulibazisa ukuqaliswa konyango olusebenzayo lwe-immune (Itheyibhile 1). Ukongezelela, ubungqina obukhulayo buxhasa indima ye-pathogenic ye-anti-neuronal antibodies kwi-neuropsychiatric disorders [7].

Ukwahlulwa kokuphazamiseka kwemithambo-luvo kunye nengqondo, exhaswa yingcamango kaDescartes "yengqondo" njengento eyahlukileyo ye-ontologically kunye nokuphindaphinda kwe-neuropathological abnormalities, amayeza alawulayo.kwinkulungwane ye-19 nasekuqaleni kwe-20 [8]. Ukusukela ngoko, ingqokelela eyandayo yezizathu zebhayoloji ezinokuphinda ziphindaphindeke, ukusuka kwi-neurosyphilis, ukwenzakala entloko, isifo sohlangothi, ithumba, ukuqhawuka kwemyelination kunye nezinye ezininzi kubangele iimpawu ezihambelana nokuphazamiseka kwengqondo okuqhelekileyo [9-11]. Kutshanje, i-neuroinflammatory kunye ne-immunological abnormalities ziye zabhalwa kwizigulana ezine-classical psychiatric disorders.

I-peripheral immune modulators inokubangela iimpawu zengqondo kwiimodeli zezilwanyana kunye nabantu [12-19]. Izilwanyana eziphilileyo zitofwe nge-pro-inflammatory IL-1? kunye ne-tumor necrosis factor alpha (TNF-?) iicytokines zibonisa �ukuziphatha kokugula� okuhambelana nokurhoxa kwezentlalo [12]. Ebantwini, iinaliti zedosi ephantsi ye-endotoxin yenza ukuba i-ventral striatum isebenze, ummandla obaluleke kakhulu ekusebenzeni komvuzo, uvelisa i-anhedonia uphawu oludakumba oludakumba [14]. Phantse i-45% ye-hepatitis C engaxinzekanga kunye nezigulane zomhlaza eziphathwa nge-IFN-? ukuphuhlisa iimpawu ezixinzelelekileyo ezinxulumene nokunyuka kwe-serum IL-6 amanqanaba [12,15,17,18].

Iimeko zonyango ezinxulumene nokuvuvukala okungapheliyo kunye nokungahambi kakuhle kwe-immunological, kubandakanywa ukukhuluphala, isifo sikashukela, i-malignancies, i-rheumatoid arthritis, kunye ne-multiple sclerosis, yimiba yengozi yokudakumba kunye ne-bipolar disorder [10,12,13,15,17,18]. Okulungileyo�Ulungelelwaniso phakathi kwezi meko zonyango kunye nesifo sengqondo sibonisa ubukho benkqubo exhaphakileyo yokuvuvukala echaphazela ingqondo phakathi kwezinye izitho [10,19,20]. Uphononongo lweminyaka engama-30 olusekwe kubemi lubonise ukuba ukuba ne- isifo okanye ukulaliswa kwangaphambili esibhedlele ngenxa yosulelo olubi kwandisa umngcipheko wokuphuhlisa i-schizophrenia nge-29% kunye ne-60%, ngokulandelanayo [16]. Ngaphezu koko, i-herpes simplex virus, i-Toxoplasma gondii, i-cytomegalovirus, kunye nomkhuhlane ngexesha lokukhulelwa zonyusa umngcipheko wokuphuhlisa i-schizophrenia [16].

I-Peripheral cellular [21,22] (Itheyibhile 2), kunye ne-humoral immunological abnormalities [13,21-23] ixhaphake kakhulu kwizigulane zengqondo ezinxulumene nolawulo olunempilo. Kuzo zombini i-pilot (n = izigulane ze-34 ezine-depressive disorder enkulu (MDD), n = 43 ulawulo olunempilo) kunye nezifundo zokuphindaphinda (n = 36 MDD, n = 43 ulawulo olunempilo), uvavanyo lwe-serum olubandakanya i-serum biomarkers ezisithoba zahlula izifundo ze-MDD ezivela kwimpilo. ulawulo olunobuntununtunu obungama-91.7% kunye ne-81.3% yobuchule; i-biomarkers ephakamileyo ephakanyisiweyo yeempawu ze-neuropsychiatric yayiyi-molecule ye-immunological alpha 1 antitrypsin, i-myeloperoxidase, kunye ne-TNF-enyibilikayo? receptor II [23].

Siqale sihlolisise umbutho phakathi kwe-autoimmunity kunye ne-neuropsychiatric disorders, kubandakanywa: 1) i-systemic lupus erythematosus (SLE) njenge-prototype ye-systemic auto-immune disease; I-2) i-encephalitides ye-autoimmune ehambelana ne-serum anti-synaptic kunye ne-glutamic acid decarboxylase (GAD) i-autoantibodies; kunye ne-3) iingxaki ze-neuropsychiatric autoimmune zabantwana ezinxulumene ne-streptococcal infections (PANDAS) kunye ne-pure obsessive-compulsive dis- order (OCD) ehambelana ne-anti-basal ganglia / i-thalamic autoantibodies. Emva koko sixoxa ngendima yokuvuvukala okungaphakathi / ukuzimela ngokuzenzekelayo kwiingxaki zengqondo zakudala, kuquka i-MDD, i-bipolar disorder (BPD), i-schizophrenia, kunye ne-OCD.

I-Neuropsychiatric Disorders eNxulunyaniswe ne-Autoimmunity

Lupus Erythematosus

Phakathi kwe-25% ukuya kwi-75% yezigulane ze-SLE zinenkqubo ye-nervous central (CNS) ukubandakanyeka, kunye neempawu zengqondo ezihlala zivela kwiminyaka emibini yokuqala yesifo. Iimpawu zengqondo zinokubandakanya ukuxhalaba, imo kunye nokuphazamiseka kwengqondo [97]. I-Brain magnetic resonance imaging (MRI) iqhelekile malunga ne-42% yeemeko ze-SLE ze-neuropsychiatric [97]. Ukuqhekeka kweMicroangiopathy kunye nesithintelo segazi (BBB) ​​kunokuvumela ukungena kwee-autoantibodies kwingqondo [97]. Ezi zithinteli zibandakanya i-anti-ribosomal P (i-positive kwi-90% yezigulane ze-psychotic SLE) [1], i-cell anti-endothelial, i-anti-ganglioside, i-anti-dsDNA, i-anti-2A / 2B i-subunits ye-N-methyl-D-aspartate receptors ( NMDAR) kunye ne-anti-phospholipid antibodies [97]. I-pro-inflammatory cytokines, ikakhulu i-IL-6 [97], S100B�[97], i-molecule ye-intra-cellular adhesion 1 [97] kunye ne-matrix- metalloproteinase-9 [98] nayo iphakanyisiwe kwi-SLE. Ukubonakaliswa kwengqondo ye-SLE, isifo sika-Sjo?gren's, i-Susac's syndrome, i-CNS vasculitis, isifo se-CNS Whipple, kunye nesifo sika-Behc?et sanda kujongwa [1].

I-Neuropsychiatric Autoimmune Encephalitides eNxulunyaniswe neSerum Anti-Synaptic kunye neGlutamic Acid Decarboxylase

Autoantibodies

I-encephalitides ye-Autoimmune ibonakala ngokuqala ngokukhawuleza kwe-lobe yesikhashana, iimpawu zengqondo, kunye nokusilela kwengqondo [2,3,99-108]. I-pathophysiology ngokuqhelekileyo ixutyushwa zi-autoantibodies ezijolise kwi-synaptic okanye i-intracellular autoantigens ngokubambisana neplastiki yeparaneo okanye imvelaphi ye-nonparaneoplastic [3]. I-Anti-synaptic autoantibodies ijolise kwi-NR1 subunits ye-NMDAR [100,108,109], i-voltage-gated potassium channel (VGKC) complexes (i-Kv1 subunit, i-leucine-rich glioma inactivated (LGI1) kunye ne-contactin protein 2 (CASPR2)) [101,102,106] kunye ne-GluR1 I-GluR2 subunits ye-amino-3-hydroxy-5-methyl-l-4-isoxazolepropionic acid receptor (AMPAR) [6,110,111] kunye ne-B1 subunits ye-?-aminobu-tyric acid B receptors (GABABR) [3,99,103]. I-Autoantibodies ye-Anti-intracellular ijolise kwi-onconeuronal kunye ne-GAD-65 autoantigens [2,3].

Ukukrala okunxulunyaniswa ne-anti-synaptic autoantibodies, ngakumbi i-NMDAR-autoantibodies, idla ngokuba buthathaka kakhulu kuneyayanyaniswa ne-GAD-autoantibodies okanye i-anti-neuronal autoantibodies ezinxulumene ne-systemic auto-immune disorders okanye i-paraneoplastic syndromes [2,107].

Nangona iimpawu ze-neurological ekugqibeleni zivela, ukubonakaliswa kwengqondo, ukusuka kwixhala [2,3] ukuya kwi-psychosis elinganisa i-schizophrenia [2-6], inokuqala ilawula okanye ilandele iimpawu ze-neurological. Ukuya kuthi ga kwisibini kwisithathu sezigulana ezine-anti-NMDAR autoimmune encephalitis, ekuqaleni zikhoyo kwiinkonzo zengqondo [5]. I-anti-synaptic antibodies-mediated autoimmune encephalitides kufuneka ithathelwe ingqalelo ngokwahlukileyo kwi-psychosis ebukhali [2-6]. Iintetho zengqondo zingabandakanya i-MRI yengqondo eqhelekileyo kunye ne-cerebrospinal fluid (CSF) uhlalutyo, ngaphandle kwe-encephalopathy okanye i-seizures [2,3,5,6,107]. Sichaze imeko ye-GAD ye-seropositive autoantibodies ehambelana ne-biopsy-proven neuroinflammation, nangona i-MRI yengqondo eqhelekileyo kunye nohlalutyo lwe-CSF, apho isigulane sibonisa i-psychosis eyedwa efunyenwe njenge-schizophrenia nge-Diagnostic kunye ne-Statistical Manual ye-Mental Disorders, i-4th Edition (DSM-IV) imigaqo [2]. Ngapha koko, i-seronegative autoimmune encephalitides inokuphinda ibonise ngokuphazamiseka okubonakalayo kwe-neuropsychiatric, okwenza ukuxilongwa kube nzima ngakumbi [107,112,113]. Iimpawu zengqondo kunye ne-neurological ezinxulumene ne-anti-synaptic kunye ne-GAD autoantibodies zishwankathelwe kwiThebhile 1 [1-6,99-108,114].

I-Serum anti-synaptic kunye ne-GAD autoantibodies inokuthi yenzeke kwizigulane ezinezifo zengqondo ezicocekileyo [2,4,5,112,115-121]. Kwiqela elilindelekileyo lezifundo ze-29 eziye zadibana neendlela ze-DSM-IV ze-schizophrenia, i-serum anti-NMDAR autoantibodies ifunyenwe kwizifundo ezintathu, kunye ne-anti-VGKC-complex autoantibodies zifunyenwe kwisifundo esinye [5]. Ukusebenzisa ubuchule obunobuthathaka bokubona i-immunoglobulin G (IgG) i-NR1 i-auto-antibodies kwizigulane ze-100 ezine-schizophrenia ecacileyo, akukho zi-autoantibodies zichongiwe [122]. Nangona kunjalo, olu phononongo aluzange luvavanye ii-autoantibodies ezijolise kwi-NR2 subunit ye-NMDAR. Olunye uphando luchaze ngokuphawulekayo ukwanda kweengxaki eziphakamileyo (?90th percentile non-psychiatric control levels) NR2 amanqanaba e-antibody (OR) 2.78, i-95% yexesha lokuzithemba (CI) 1.26 ukuya kwi-6.14, P = 0.012) phakathi kwabantu abane-mania enzima ( n = 43), kodwa kungekhona kwi-mania engapheliyo okanye i-schizophrenia [116].

I-PANDAS kunye ne-Pure Obsessive-Compulsive Disorder eNxulunyaniswe ne-Anti-Basal Ganglia/Thalamic Autoantibodies

I-OCD ihlala yenza nzima ukuphazamiseka kwemithambo-luvo okubandakanya i-basal ganglia kubandakanya i-Sydenham chorea, isifo sikaHuntington kunye nesifo sikaParkinson. I-Anti-basal ganglia antibodies iyabandakanyeka kwi-chorea ye-Sydenham [123]. I-PANDAS ibonakaliswe ngokugqithisileyo kweempawu ze-OCD kunye / okanye i-motor / phonic tics elandela iqela le-prodromal A ?-hemolytic streptococcal infection. I-pathophysiology icingelwa ukuba ibandakanya ukuphinda kusebenze phakathi kwe-anti-streptococcal antibodies kunye ne-basal ganglia proteins [124]. Ukugqithwa kweklinikhi phakathi kwe-PANDAS kunye ne-OCD ecocekileyo ibonisa indlela eqhelekileyo ye-etiological [125].

Phakathi kweqela elingenamkhethe le-21 yezigulane ezicocekileyo ze-OCD, i-91.3% ine-CSF ye-anti-basal ganglia (P <0.05) kunye ne-anti-thalamic autoantibodies (P <0.005) kwi-43 kDa [88], ukungahambi kakuhle okusebenzayo kwi-cortico-striatal-thalamo. -i-cortico circuitry yezifundo ze-OCD [84]. Olunye uphando lubhalwe ukuba i-42% (n = 21) yezifundo ze-OCD zabantwana kunye nabafikisayo babene-serum anti-basal ganglia autoantibodies kwi-40, 45, kunye ne-60 kDa xa kuthelekiswa ne-2% ukuya kwi-10% yolawulo (P = 0.001) [7]. I-Anti�basal ganglia autoantibodies yafunyanwa kwi-sera ye-64% yezifundo ze-PANDAS (n = 14), xa kuthelekiswa ne-9% kuphela (n = 2) ye-streptococcal-positive / OCD-negative controls (P <0.001) [126]. Olunye uphando alufumananga mmahluko phakathi kokuxhaphaka kwe-anti-basal ganglia autoantibodies kwi-OCD (5.4%, n = 4) ngokubhekiselele kulawulo lwe-MDD (0%) [127]; nangona kunjalo, umda ibikukusetyenziswa ngokungakhethiyo kwe-rat cortex kunye ne-bovine basal ganglia kunye ne-cortex enokuthi ithintele ukuchongwa kweemeko ze-seropositive.

I-basal ganglia autoantigens yi-aldolase C (40 kDa), i-neuronal-specific/non-neuronal enolase (45 kDa doublet) kunye ne-pyruvate kinase M1 (60 kDa) � i-neuronal glycolytic enzymes ebandakanyeka kwi-neurotransmission, neuronal metabolism.

Iphepha le-3 le-24 kunye nomqondiso weseli [128]. Ezi enzymes zibonisa i-homology enkulu yesakhiwo kwiiprotheni ze-streptococcal [129]. Uphononongo lwamva nje (96 OCD, 33 MDD, 17 schizophrenia subjects) luvavanye i-serum yesigulana ngokuchasene ne-pyruvate kinase, i-aldolase C kunye ne-enolase, ngokukodwa; Inxalenye enkulu yezifundo ze-OCD zazine-sero-positive ngokumalunga nolawulo (19.8% (n = 19) ngokuchasene ne-4% [n = 2], P = 0.012) [130].

Nangona kunjalo, kuphononongo olunye kuphela kwezifundo ze-OCD ezili-19 ezine-sero-positive ezine-anti-streptolysin O antibody titers, ezibonisa ukuba kwi-OCD ecocekileyo i-anti-streptolysin O antibody seronegativity ayibandakanyi ubukho be-anti-basal ganglia autoantibodies. .

Kwi-OCD ecocekileyo, i-sero-positivity ye-anti-basal ganglia / i-thalamic antibodies idibaniswa namanqanaba okwanda kwe-CSF glycine (P = 0.03) [88], ebonisa ukuba ezi zichasayo zinegalelo kwi-hyperglutamatergia ebonwe kwi-OCD [84,88,131]. Ukuphuculwa kwe-OCD exhokonxwa yintsholongwane kunye nonyango lwe-immune luxhasa i-pathogenicity yezi autoantibodies [132]. Ulingo olukhulu lwe-NIH oluvavanya ukuphumelela kwe-immunoglobulin (IVIG) kubantwana abane-OCD enzima kunye ne-anti-streptococcal antibodies iyaqhubeka (ClinicalTrials.gov: NCT01281969). Nangona kunjalo, ukufunyaniswa kwamanqanaba aphezulu e-CSF e-glutamate kwizigulana ze-OCD ezine-CSF engalunganga ye-anti-basal ganglia / i-thalamic anti-body xa kuthelekiswa nezo zine-antibodies ze-CSF zibonisa ukuba iindlela ezingezo-immunological zinokudlala indima kwi-OCD [84]. Ezinye iindlela, ezibandakanya ukuvuvukala kwe-cytokine-mediated (Itheyibhile 2), nazo ziqikelelwa.

Iziphazamiso zengqondo eziNxulunyaniswe nokudumba okuNgazalwayo

Ukuphazamiseka kokudumba okungaphakathi / ukuzimela ngokuzenzekelayo kwenzeka kwezinye izigulana ezineengxaki zengqondo zakudala. Sixoxa ngezinto ezingaqhelekanga ze-CNS ezinxulumene nokudumba-kubandakanya i-glial pathology, amanqanaba aphezulu e-cytokines, ukusebenza kwe-cyclo-oxygenase, i-glutamate dysregulation, ukwanda kwamanqanaba e-S100B, ukonyuka koxinzelelo lwe-oxidative, kunye nokungasebenzi kakuhle kwe-BBB kwi-MDD, BPD, schizophrenia, kunye ne-OCD. Sikwachaza ukuba ukudumba okungaphakathi kunokunxulunyaniswa njani nesiqhelo se-monoaminergic kunye ne-glutamatergic abnormalities echazwe kwezi ngxaki (Amanani 1 kunye ne-2). Indima yonyango ye-anti-inflammatory agents kwi-psychiatric disorders iphinda ihlaziywe.

I-Astroglial kunye ne-Oligodendroglial Histopathology

I-Astroglia kunye ne-oligodendroglia zibalulekile kwi-neural nguqulo i-homeostasis, ukuziphatha kunye nemisebenzi ephezulu yokuqonda [54-56,133-136]. I-astroglia eqhelekileyo epholileyo inika amandla kunye nenkxaso ye-trophic kwi-neurons, ilawula i-synaptic neurotransmission (Umfanekiso 2), i-synaptogenesis, ukuhamba kwegazi lobuchopho, kunye nokugcina ingqibelelo ye-BBB [134,136,137]. I-oligodendroglia eqolileyo ibonelela ngamandla kunye nenkxaso yetrophic kwii-neuron kwaye igcine ingqibelelo ye-BBB, kwaye ilawule ukulungiswa kwe-axonal.kunye ne-myelination yamaphecana ezinto ezimhlophe ezibonelela ngoqhagamshelwano phakathi kunye ne-intra-hemispheric [54-56]. Zombini i-astroglia kunye ne-oligodendroglia zivelisa i-cytokines ezichasayo ezinokuthi zinciphise-ukulawula ukuvuvukala okuyingozi [52,55].

Kwi-MDD, ukulahleka kwe-astroglial kukufumana okuhambelanayo kwe-post-mortem kwiindawo ezifanelekileyo ezisebenzayo, kubandakanywa ne-anterior cingulate cortex, i-prefrontal cortex, i-amygdala, kunye ne-white matter [35-38,42-46,55,138-147], ngaphandle kokumbalwa [42,43] , 37,38]. Uphononongo lwe-Post-mortem lubonakalise ukuncitshiswa kweprotein ye-glial fibrillary acidic (GFAP) -positive astroglial density ikakhulu kwi-prefrontal cortex [36] kunye ne-amygdala [39]. Uhlalutyo olukhulu lweproteomic lwe-cortices yangaphambili evela kwizigulane ezidandathekileyo lubonise ukunciphisa okubonakalayo kwii-isoform ezintathu ze-GFAP [75]. Nangona kuphononongo olunye oluthe akukho lahleko ibalulekileyo ye-glial, uhlalutyo lweqela elingaphantsi lubonise ukuhla okukhulu (45%) kwi-GFAP-positive astroglial density phakathi kwezifundo ezingaphantsi kweminyaka eyi-35 [148]. Uphononongo lwe-morphometric ngokufanayo alubonisi lutshintsho kuxinzelelo lwe-glial kubuchopho be-MDD yobomi kade [35]. Sicinga ukuba ukungabikho okubonakalayo kwelahleko ye-astroglial phakathi kwezigulane ze-MDD ezindala kunokubonakalisa i-astrogliosis yesibini [42,50] ehambelana nobudala obudala [XNUMX] kunokuba i-negative yokwenyani.

Izifundo zezilwanyana ziyahambelana nezifundo zabantu ezibonisa ilahleko ye-astroglial kwi-MDD. Iimpuku ze-Wistar-Kyoto� ezaziwa ngokubonisa ukuziphatha okunxunguphalisayo-zibonise ukunciphisa ukuxinana kweenkwenkwezi kwiindawo ezifanayo njengoko zibonwa ebantwini [40]. Ulawulo lwe-astroglial-toxic agent, i-L-alpha-aminoadipic acid, ibangela iimpawu ezidakumbisayo kwiimpuku, iphakamisa ukuba ilahleko ye-astroglial yi-pathogenic kwi-MDD [41].

Izifundo ze-Post-mortem zezifundo ze-MDD ezibhalwe zanciphisa ubuninzi be-oligodendroglial kwi-prefrontal cortex kunye ne-amygdala [54-57,66], enokuthi ihambelane ne-brain MRI egxile kwimiba emhlophe eguquguqukayo ngamaxesha athile kwizigulane ze-MDD [57]. Nangona kunjalo, i-microvascular abnormalities inokuba negalelo kolu tshintsho [57].

Kwi-BPD, ezinye izifundo zibonisa ukulahleka okukhulu kwe-glial [138,143,149,150], ngelixa abanye bengenayo [37,44-46]. Ezi ziphumo ezingahambelaniyo zingabangela ukungabikho kokulawula: i-1) unyango kunye ne-mood stabilizers, kuba uhlalutyo lwe-post-hoc oluchazwe ngolunye uphando lubonise ukunciphisa okukhulu kwilahleko ye-glial kuphela emva kokulawula unyango nge-lithium kunye ne-valproic acid [46]; I-2) iintlobo zeentsapho ze-BPD, njengoko ukulahleka kwe-glial kuvelele ngokukodwa phakathi kwezigulane ze-BPD ezinembali yentsapho eqinile [143]; kunye / okanye, i-3) imeko ephambili yokudakumba ngokuchasene ne-mania, njengoko ukulahleka kwe-glial kuqhelekileyo kwi-MDD [35-38,42-46,55,138-147]. Ingaba i-astroglia okanye i-oligodendroglia i-akhawunti yobuninzi belahleko ye-glial ayicacanga; ngelixa uhlalutyo lweproteomic lubonakalise ukuhla okubonakalayo kwi-isoform ye-astroglial GFAP [39], ezinye izifundo ezininzi emva kokufa zifunyenwe zingatshintshanga [36,37] okanye zinciphise i-GFAP-positive astroglial expression kwi-cortex ye-orbitrofrontal [47], okanye ukunciphisa ubuninzi be-oligodendroglial [ 54-56,58,59].

Kwi-schizophrenia, ukulahleka kwe-astroglial kukufumanisa okungahambelaniyo [48,150]. Nangona ezinye izifundo zibonise ukulahlekelwa okukhulu kwe-astroglial [42,50,51], abanye abaninzi bafumene ukunciphisa ukuxinana kweenkwenkwezi [37,38,43,44,48,49,151] kunye nokunciphisa okubalulekileyo kwi-isoforms ezimbini ze-GFAP [39]. Ukufunyaniswa okungahambelaniyo kunokubangelwa: 1) i-MDD comorbidity, ehlala ihambelana nokulahlekelwa kwe-glial; I-2) ukuhluka kweminyaka, njengoko izigulane ezindala ziye zanda i-GFAP-positive astroglia [35,42,50]; 3) ingingqi [150] kunye ne-cortical layer variability [48]; I-4) unyango ngamachiza okulwa ne-antipsychotic, njengoko izifundo zokulinga zibonisa zombini zincitshisiwe [152] kwaye zanda [153] i-astroglial-density enxulumene nonyango olungapheliyo lwe-antipsychotic [70]; kunye ne-5) imeko yesifo (umzekelo, ukuzibulala ngokuchasene nokuziphatha okungazibulali) [154]. Izifundo ze-post-mortem zibhalwe ukulahleka kwe-oligodendroglial [54,56,60-65,148,155,156], ngokukodwa kwi-cortex yangaphambili, i-cortex yangaphambili ye-cingulate, kunye ne-hippocampus [148]. Ukuhlolwa kwe-Ultrastructural yommandla we-prefrontal kubonise imicu ye-myelinated ngokungaqhelekanga kwimiba engwevu kunye nemhlophe; zombini ubudala kunye nobude bexesha lokugula zihambelana ngokuqinisekileyo kunye nokungahambi kakuhle kwezinto ezimhlophe [157].

Ngokuchaseneyo nokuphazamiseka kwe-neurodeergenerative okuxhaphake ukunxulunyaniswa nokunyuka kweenkwenkwezi [136], ukuphazamiseka kwengqondo endaweni yoko kunxulunyaniswa nokuncitshiswa okanye ukungaguquki kwe-astroglial density [138]. Ukungabikho kokunyuka koxinzelelo lwe-glial ekuqaliseni ukuphazamiseka kwengqondo [44,138] kunokubonakalisa izinga eliphantsi lokuqhubela phambili okuwohlokayo kwizifo zengqondo [138].

Sichaza ukuba utshintsho oluguquguqukayo olunxulumene nokuphazamiseka kwengqondo luncinci kwaye alunzima ngokwaneleyo ukuvusa izinto ze-astroglial intracellular transcription ezilawula kakuhle i-astrogliosis, kubandakanywa i-activator ye-transducer yesignali ye-transcription 3 kunye ne-nuclear factor kappa B (NF-?B) [136].

Ngelixa uninzi lwezifundo zasemva kokufa zijolise ekuguqulweni koxinzelelo lweglial kwi-MDD, BPD, kunye ne-schizophrenia, abanye bachaze ukuguqulwa kwe-glial cell morphology, kunye neziphumo ezixubeneyo. Kwi-MDD kunye ne-BPD, ubungakanani beglial bunonyuswa okanye bungatshintshwa [55]. Olunye uphando lufumene ubungakanani obuncitshisiweyo be-glial kwi-BPD kunye ne-schizophrenia kodwa kungekhona kwi-MDD [43]. Uphononongo lwangemva kokufa kwezigulana ezidakumbileyo ezizibuleleyo zafumana ukwanda kobungakanani beenkwenkwezi kwi-anterior cingulate white matter kodwa hayi kwi-cortex [158]. Olunye uphononongo kwizifundo ze-schizophrenic lufunyenwe ngokuphawulekayo ukuncipha kwesayizi ye-astroglial kumaleko we-V we-dorsolateral prefrontal cortex, nangona ubuninzi be-astroglial buphindwe kabini kulawulo olufanayo [48]. Iziphumo ezixubileyo zingabonakalisa ngokuyinxenye izifundo zangaphambili zokuguqulwa kweglial kwizigulo zengqondo ezingakhange zichaze i-astroglia ngokuchasene ne-oligodendroglia [148].

Ukulahleka kweGlial kwizigulo zengqondo kunokufaka isandla kwi-neuroinflammation ngeendlela ezininzi, kubandakanya amanqanaba e-cytokine angaqhelekanga (jonga icandelo le-Cytokine), i-dysregulated glutamate metabolism (jonga icandelo le-Glutamate), iprotheni ephezulu ye-S100B (jonga icandelo le-S100B),kunye nokuguqulwa komsebenzi we-BBB (jonga icandelo lokuthintela ubuchopho beGazi), okubangela ukungakwazi ukuqonda kunye nokuziphatha [44,45,54,133,159].

I-Microglial Histopathology

I-Microglia ziiseli zomzimba ezihlala kwi-CNS. Banikezela ngovavanyo oluqhubekayo lwe-immune kwaye balawule ukuthenwa kwe-synaptic yophuhliso [160,161]. Ukulimala kwe-CNS kuguqula i-ramified resting microglia ibe yi-activated elongated-shaped-shaped and macrophage-like phagocytic amoeboid cells ezikhula kwaye zifudukele kwindawo yokulimala kunye ne-chemotactic gradients (oko kukuthi, i-micro-glial activation kunye nokwanda (MAP)) [161]. Iiseli ze-microglial zomntu zivakalisa ii-NMDAR ezinokuthi zidibanise i-MAP ekhokelela kukwenzakala kwe-neuronal [162].

Kwi-MDD, BPD kunye ne-schizophrenia, iziphumo zezifundo zasemva kokufa eziphanda ubukho be-MAP zixutywe. Uphononongo lwe-Post-mortem luveze i-MAP ephakamileyo kwisifundo esinye kwisihlanu se-MDD [67]. Kwezinye izigulana zokuphazamiseka kwe-BPD, ukonyuka kwe-leukocyte yabantu i-antigen-DR-positive microglia ebonisa iinkqubo ezityebileyo zibhalwe kwi-cortex yangaphambili [69]. Kwi-schizophrenia, ngelixa ezinye izifundo zichaza i-MAP ephakamileyo ngokumalunga nolawulo, abanye babonisa ukuba akukho mahluko phakathi kwamaqela [22,67,70]. Kuphononongo lwe-post-mortem lokuvavanya i-MAP kwi-MDD kunye ne-BPD; I-quinolinic acid-positive microglial cell density yandiswe kwi-subgenual anterior cingulate cortex kunye ne-anterior midcingulate cortex ye-MDD kunye nezigulane ze-BPD ezizibulele ngokumalunga nolawulo [53]. Uhlalutyo lwe-Post-hoc lubonakalise oku kwanda kwe-MAP kwakubangelwa kuphela kwi-MDD kwaye kungekhona i-BPD, ekubeni i-microglial immuno-staining kwizifundo ze-MDD yayinkulu kakhulu kuneqela le-BPD kuzo zombini i-cingulate yangaphambili kunye ne-middlecingulate cortices, kwaye ukususela ngoko. Uxinaniso lwe-microglia lwalufana kuzo zombini i-BPD kunye namaqela olawulo [53]. Uphononongo oluthelekisa zonke iziphazamiso ezithathu (i-MDD esithoba, i-BPD emihlanu, i-schizophrenia elishumi elinesine, ulawulo olusempilweni olulishumi) alubonakalisi mahluko ubalulekileyo kuxinzelelo lwe-microglial kuwo onke amaqela amane [68].

Ezi ziphumo ezixubileyo zinokuthi zifakwe kwiimpawu eziguquguqukayo ze-microglial immunological markers ezisetyenziswe phakathi kwezifundo ezahlukeneyo [70] kunye / okanye ukungaphumeleli ukulawula ubunzima besifo [22,53,68]. Ngokucacileyo, izifundo ezintathu zasemva kokufa kwe-MDD kunye nezifundo ze-schizophrenic zibonise ulungelelwaniso oluqinileyo phakathi kwe-MAP kunye nokuzibulala kwi-anterior cingulate cortex kunye ne-mediodorsal thalamus, exhomekeke ekuxilongweni kwengqondo [22,53,68]. Ke, i-MAP inokuba ngurhulumente endaweni ye-trait marker ye-MDD kunye ne-schizophrenia.

Kwi-OCD, imifuziselo yezilwanyana icebisa ukuba ukungasebenzi kunye nokuncipha kwezinto ezithile ze-microglial phenotypes, ezifana nezo zichaza i-Hoxb8 gene, efaka i-homeobox transcription factor, inokubangela ukuziphatha okufana ne-OCD [71,72].

Iimpuku ze-Hoxb8 zokunkqonkqoza zibonisa ukuziphatha okugqithisileyo kunye nokuxhalaba ngokubambisana nokuncipha kwe-microglial density [71,72]. Oku kuzilungisa ngokugqithisileyo kufana neempawu zokuziphatha ze-OCD yomntu. Inaliti ye-Hoxb8 kumntu omdala we-Hoxb8 wokunkqonkqoza iimpuku ubuyisela umva ilahleko ye-microglial kwaye ibuyisela indlela yokuziphatha eqhelekileyo [71,72]. Indima yezi phenotypes ezithile ze-microglial kwi-OCD yomntu ayicacanga.

Idatha yovavanyo iphakamisa ukuba i-MAP iquka i-phenotypes eyingozi kunye neuroprotective eyahlukileyo (Umfanekiso 2). I-microglia enobungozi ayibonakalisi i-histocompatibility complex II (MHC-II) kwaye, ngoko ke, ayikwazi ukwenza njengeeseli ezibonisa i-antigen (APC) [163,164]; bakhuthaza imiphumo ephazamisayo [17,69,165] ngokuveliswa kwe-cytokine ye-proinflammatory, i-nitric oxide synthase signaling [17,166], ukukhuthaza i-glial kunye ne-BBB-pericyte / endothelial cyclooxygenase-2 (COX-2) intetho [167], i-astroglial secretion100Bsee S100 icandelo), kunye ne-microglial glutamate release [17,136,168,169]. I-microglia enobungozi iphinda ikhuphe i-prostaglandin E-2 (PGE-2) ekhuthaza ukuveliswa kwe-cytokines ye-proinflammatory, leyo eyandisa amanqanaba e-PGE-2 kumjikelezo wokutya [29]. Ukuqhubela phambili, i-PGE-2 ivuselela i-COX-2 inkcazo, edibanisa ukuguqulwa kwe-arachidonic acid kwi-PGE-2, ukuseka omnye umjikelezo we-feed-forward [29].

I-neuroprotective microglia ngokungafaniyo inokuthi: 1) ibonise i-MHC-II kwi-vivo kunye ne-vitro [163,166] kwaye isebenze njenge-APC ye-cognate (Umfanekiso 2) [163,164,166]; I-2) iququzelele ukuphilisa kunye nokunciphisa ukulimala kwe-neuronal ngokukhuthaza ukukhuselwa kwe-cytokines ye-antiinflammatory [17], i-brain-derived neurotrophic factor [17], kunye ne-insulin-like growth factor-1 [166]; kunye ne-3) i-excitatory amino acid transporter-2 (EAAT2) ekhupha i-glutamate engaphezulu kwe-extracellular [163,166], kwaye ikhuthaza i-neuroprotective T lymphocytic autoimmunity (Figure 2) [163,164]. Nangona kunjalo, uphando oluninzi luyafuneka ukuze kuqinisekiswe indima yegalelo le-neuroprotective microglia kwiziphazamiso ze-neuropsychiatric ebantwini.

 

I-In vitro Izifundo zezilwanyana zibonisa ukuba umlinganiselo we-microglia enobungozi ngokuchasene ne-neuroprotective inokuphenjelelwa yimpembelelo yenetha yeendlela zokulawula ukuvuvukala [15,74,164,166]. Ezi ndlela ziquka inani le-neuroprotective CD4 + CD25 + FOXP3 + T iiseli ezilawulayo ((T regs) Umfanekiso 1) [15,74,164,166] kunye namanqanaba e-cytokine yobuchopho; ephantsi IFN-? amanqanaba anokukhuthaza i-neuroprotective microglia (Umfanekiso 2) [166], kanti amanqanaba aphezulu anokukhuthaza i-phenotype eyingozi [166].

Indima yeeCytokines

I-proinflammatory cytokines ziquka i-IL-1 ?, IL-2, IL-6, TNF-? kunye IFN-?. Ziye zifihliwe ngokuyinhloko nge-micro-glia, i-lymphocytes ye-Th1 kunye ne-M1 phenotype monocytes / macrophages (Umfanekiso 1) [15,170]. Bakhuthaza ukuvuvukala okuyingozi. I-cytokines ezichasayo ziquka i-IL-4, i-IL-5 kunye ne-IL-10. Ngokubanzi zifihlwa yi-astroglia,�I-Th2 lymphocytes, i-T regs kunye ne-M2 phenotype monocytes / macrophages [15,52,74]. Bangakwazi ukunciphisa ukuvuvukala okuyingozi [15,74] ngokuguqula i-M1-pheno-type ye-proinflammatory ibe yi-M2-phenotype enenzuzo ye-antiinflammatory [15], kwaye inokwenzeka ngokukhuthaza i-neuroprotective microglial phenotype [15,17,74,163,166]. Indima ye-proinflammatory / antiinflammatory cytokines kwi-psychiatric disorders ixhaswa yimizila emininzi yobungqina (Umfanekiso 1, iThebhile 2) [15,17,29,52,74].

Kwi-MDD, uhlalutyo lwe-meta lwamva nje (izifundo ze-29, i-822 MDD, i-726 yokulawula okunempilo) ye-serum proinflammatory cytokines iqinisekisile ukuba i-soluble IL-2 receptor, i-IL-6 kunye ne-TNF-? amanqanaba anyuswa kwi-MDD (amanqaku eempawu) [91], ngelixa, i-IL-1 ?, IL-2, IL-4, IL-8 kunye ne-IL-10, ayifani ngokwezibalo ukusuka kulawulo [91]. Kuphononongo oluphambili lwe-cytokine oluthelekisa ii-MDD subgroups (47 suicidal- MDD, 17 non-suicidal MDD, 16 health controls), zombini i-sera IL-6 kunye ne-TNF-? zaziphezulu kakhulu, ngelixa amanqanaba e-IL-2 ayephantsi kakhulu kwizifundo ze-MDD ezizibulele ngokumalunga namanye amaqela [96]. Oku kufunyanisiweyo kubonisa ukuba IL-6 kunye TNF-? zikwangamakishi karhulumente e-MDD [96]. Ukuncipha kwamanqanaba e-serum IL-2 ahambelana nokuziphatha okubukhali kokuzibulala kunokubonakalisa ukunyuka kokubopha kwi-receptor yayo elawulwayo kwingqondo; ngokuhambelana nohlalutyo lwemeta olukhankanywe ngasentla olubonisa ukunyuka kwe-IL-2 receptor kwi-MDD [91]. Uphononongo oluphanda ukubaluleka kweklinikhi ye-cytokines kwi-MDD lubonise ukuba amanqanaba e-serum cytokine aphakanyisiwe ngexesha lokudakumba okukhulu [171,172] kunye nokuqhelekileyo okulandela ukuphumelela, kodwa akuphumeleli, unyango kunye ne-antidepressants [17] kunye ne-electro-convulsive therapy [29]; ezi ziphumo zibonisa indima enokwenzeka ye-pathogenic yeecytokines.

Kwi-BPD, ukuguqulwa kwe-serum cytokine kwashwankathelwa kuphononongo lwakutsha nje; I-TNF-?, i-IL-6 kunye ne-IL-8 iphakanyisiwe ngexesha le-manic kunye ne-depressive phases, kanti i-IL-2, i-IL-4 kunye ne-IL-6 iphakanyisiwe ngexesha le-mania [92]. Ezinye izifundo zibonise ukuba sera IL-1? kunye ne-IL-1 amanqanaba e-receptor awahlukanga ngokwezibalo kulawulo olunempilo [92], nangona izifundo zezicubu zibhalwe amanqanaba okwanda kwe-IL-1? kunye ne-IL-1 i-receptor kwi-BPD yangaphambili cortex [69].

Kwi-schizophrenia, iziphumo ezivela kwizifundo eziphanda ukungahambi kakuhle kwe-cytokine ziphikisana (Itheyibhile 2). Nangona ezinye izifundo zifumene zombini i-serum proinflammatory (IL-2, IFN-?) kunye nokunyuka kwe-serum kunye ne-CSF antiinflammatory cytokines (IL-10) [52], abanye bafumene i-serum ephakamileyo ye-pro- kunye ne-antiinflammatory cytokines, kunye ne-proinflammatory type dominance [22,173,174] ]. Enye i-cytokine meta-analysis (izifundo ze-62, i-2,298 schizophrenia, i-858 yokulawula okunempilo) ibonise amanqanaba okwanda kwe-IL-1R antagonist, i-sIL-2R kunye ne-IL-6 [174]. Nangona kunjalo, olu phononongo aluzange luqwalasele ukusetyenziswa kwe-antipsychotics, ekucingelwa ukuba iphucula imveliso ye-cytokine ye-proinflammatory [52]. Uhlalutyo lwamva nje lwe-cytokine meta (izifundo ezingama-40, i-2,572 schizophrenics,Ulawulo lwe-4,401) olubhekiselele kwi-antipsychotics, lufumene ukuba i-TNF-?, IFN-?, IL-12 kunye ne-sIL-2R zihlala ziphakanyisiwe kwi-schizophrenia engapheliyo ezimeleyo kwimisebenzi yesifo (impawu zeempawu), ngelixa i-IL-1?, IL-6 kunye ukuguqula ukukhula kwe-beta kuhambelana kakuhle nomsebenzi wesifo (abaphawuli bakarhulumente)[173]. Iinkcubeko zeeseli ze-peripheral blood mononuclear cells (PBMC) ezifunyenwe kwizigulane ze-schizophrenic zivelise amanqanaba aphezulu e-IL-8 kunye ne-IL-1? ngokuzenzekelayo nasemva kokukhuthazwa yi-LPS, ecebisa indima ye-monocytes/macrophages esebenzayo kwi-schizophrenia pathology [175].

Kwi-OCD, iziphumo ezivela kwi-survey random ye-sera kunye ne-CSF cytokines, kunye nezifundo ze-PBMC ezivuselelwe i-LPS, azihambelani [93-95,176-179]. Kukho ulungelelwaniso phakathi kwe-OCD kunye ne-polymorphism esebenzayo kummandla wokukhuthaza we-TNF-? gene [34], nangona izifundo eziphantsi kwamandla aphantsi azizange ziqinisekise lo mbutho [180]. Ngoko ke, iziphumo ezixubeneyo ezivela kwizifundo ezibhaliweyo zanda okanye zehla i-TNF-? amanqanaba e-cytokine [93,176-178] angabonakalisa ukubandakanywa kwabo okuguquguqukayo kwe-subset yezifundo ze-OCD kunye nale polymorphism ethile kumaqela abo.

I-Cytokine Response Polarization kwi-Major Depression & Schizophrenia

I-phenotypes ye-cytokine yokuphendula i-phenotypes ihlelwa njenge-proinflammatory Th1 (IL-2, IFN-?) Ngelixa i-cytokines ye-Th2 ilawula ukugonywa kweeseli ezijoliswe kwii-antigens ze-intra-cellular, ii-cytokines ze-Th4 zilawula ukhuseleko lwe-humoral olujoliswe kwii-antigens zangaphandle [5]. I-cytokines ye-Th10 iveliswa yi-Th1 lymphocytes kunye ne-M2 monocytes kanti i-cytokines ye-Th29,52 iveliswa yi-Th1 lymphocytes kunye ne-M1 monocytes [1]. Engqondweni, i-microglia ikhupha ii-cytokines ze-Th2, ngelixa i-astroglia ifihla ii-cytokines ze-Th2 [2]. Umyinge we-reciprocal ratio ye-Th29,52:Th1 cytokines, ukusukela ngoku �Th2-Th29,52 seesaw,� ichatshazelwa ngumyinge we-microglia evuliweyo (i-Th1 engaphezulu) ukuya kwi-astroglia (i-Th2 engaphezulu) kunye nonxibelelwano phakathi kweeseli ze-T ezivuliweyo kunye namanqanaba aphezulu e-CNS eglutamate esiwacingayo. ukuthanda impendulo ye-Th1 (Umfanekiso 2) [1].

I-Th1-Th2 ukungalingani kwe-seesaw inokuchaphazela i-tryptophan metabolism ngokuguqula i-enzymes yayo [21,52] ngaloo ndlela iguqule i-tryptophan catabolism ukuya kwi-kynurenine (KYN) kunye ne-KYN catabolism ngokubhekiselele kuyo nayiphi na i-metabolites yayo ephantsi; i-microglia quinolinic acid eyi-Th1 impendulo-mediated okanye i-astroglial kynurenic acid (KYNA) (Umfanekiso 1) oyi-Th2 impendulo-mediated [21,29,170].

I-Tryptophan metabolism enzymes echaphazelekayo yi-Th1-Th2 seesaw ibandakanya (Umfanekiso 1): i-indoleamine 2,3-dioxygenase (IDO) echazwe yi-microglia kunye ne-astroglia, i-enzymes yokunciphisa izinga elidibanisa ukuguqulwa kwe-tryptophan kwi-KYN kunye ne-serotonin kwi-5- i-hydroxyindoleacetic acid[21,29]. I-Kynurenine 3-monooxygenase (KMO), echazwe kuphela yi-microglia, yi-enzyme yokunciphisa izinga eliguqula i-KYN kwi-3-hydroxykynurenine (3-OH-KYN), eyongezelelekileyo i-metabolized kwi-quinolinic acid [21,29]. I-Tryptophan-2,3-dioxygenase (TDO), ebonakaliswa kuphela yi-astroglia, yi-enzayim enciphisa izinga eliguqulayo.tryptophan ukuya KYN [21,29]. I-Kynurenine aminotransferase (KAT), echazwe ngokukodwa kwiinkqubo zeenkwenkwezi, yi-enzyme yokunciphisa izinga elidibanisa ukuguqulwa kwe-KYN kwi-KYNA [21,29].

I-Th1 cytokines ivula i-microglial IDO kunye ne-KMO, isusa i-microglial KYN catabolism isiya kwi-quinolinic.i-asidi (i-NMDAR agonist) i-synthesis, ngelixa i-Th2 i-cytokines i-activate microglial IDO kunye ne-KMO, i-astroglial KYN catabolism ukuya kwi-TDO- kunye ne-KAT-mediated KYNA (i-NMDAR antagonist) synthesis (Figure 1) [21,29].

I-Th1 kunye ne-Th2 eziphambili ze-immunophenotypes ziye zacetywayo kwi-MDD kunye ne-schizophrenia, ngokulandelanayo, ngokusekelwe kwi-peripheral, kunokuba i-CNS, iipatheni ze-cytokines [52,173]. Sikholelwa ukuba iipateni zeperipheral cytokines ziziphawuli ezingathembekanga ze-surrogate yezo zikwi-CNS. Enyanisweni, amanqanaba e-cytokine e-peripheral angaphenjelelwa ngamanqanaba amaninzi e-extra-CNS, angalawulwa ngokuqhubekayo kwizifundo ezininzi ze-cytokines ze-peripheral, ezibandakanya: 1) ubudala, i-index mass body, amayeza e-psychotropic, ukutshaya, uxinzelelo kunye nokuguquguquka kwe-circadian; 2) impembelelo ka�umsebenzi wesifo / urhulumente ekuveliseni i-cytokines synthesis ekhethiweyo [95,173]; kunye ne-3) imiphumo ye-psychotropic agents kwimveliso ye-cytokines [52]. Ubomi besiqingatha esifutshane kunye nokuguqulwa okukhawulezileyo kwe-serum cytokines [181] (umzekelo, imizuzu eyi-18 ye-TNF-? amanqanaba alinganiswa ukusuka kwisampulu yesera engacwangciswanga.

Kwi-MDD, kukho ukuvumelana ukuba impendulo ye-Th1 ye-immunophenotype ye-proinflammatory ibeka phambili (Itheyibhile 2) [17,29]. Amanqanaba aphezulu e-quinolinic acid kwi-post-mortem ye-MDD brains [53], iphakamisa ubukho bempendulo ye-Th1 elawulwayo (Umfanekiso 1) [21,29]. I-quinolinic acid ephakanyisiweyo yeCNS inokukhuthaza ukungena kwekhalsiyam mediated apoptosis ye-astroglia yabantu [184], enokuthi ngokuqikelelwa iyenze ibe buthuntu.I-astroglia-ephuma kwi-Th2 impendulo [29], inika i-Th1 xa ithelekiswa ne-Th2 ibhalansi ye-seesaw ngokuthanda impendulo ye-microglial Th1. I-CNS hyposerotonergia [29] yongeza inkxaso eyongezelelweyo kwimpendulo ye-Th1 engaphezulu, eboniswa ukunciphisa i-CNS serotonin synthesis [185] kunye nokwandisa ukuthotywa kwayo (Umfanekiso 1) [21,29].

I-CNS hyperglutamatergia inokuba negalelo kwimpendulo ye-Th1 engaphezulu kwengqondo (Umfanekiso 2). Uphononongo lwe-in vitro lubonisa ukuba i-peripheral yokuphumla kwe-T lymphocytes ngokusemthethweni ichaza i-metabotropic glutamate receptor 5 (mGluR5) [164], ebophelela kwi-glutamate inhibits ukukhululwa kwe-lymphocytic IL-6, ngaloo ndlela inciphisa i-auto-reactive T-effector cell proliferation [164]. I-T lymphocytes esebenzayo, kodwa ingaphumli i-lymphocytes ye-T, inokuwela i-BBB [37].

Idatha yovavanyo iphakamisa ukuba ukusebenzisana phakathi kwe-T cell receptors ye-T lymphocytes esebenzayo kunye neeseli zabo ezibonisa i-antigen ziyakwazi ukunciphisa i-mGluR5 kwaye zenze i-mGluR1 intetho [164]. Kwiimodeli zezilwanyana, ukubopha i-glutamate engaphezulu kwi-lymphocytic mGluR1 receptors ikhuthaza ukuveliswa kwee-cytokines ze-Th1, kuquka i-IFN-? [164].

Sicinga ukuba kwezinye izigulane ze-MDD, ngokuhambelana nedatha yovavanyo [164], ukubophelela kwe-CNS glutamate engaphezulu kwi-lymphocytic i-mGluR1 i-receptors ye-lymphocytic inokufaka isandla kwimpendulo ye-Th1 engaphezulu, kuquka i-IFN-? (Umfanekiso 2). Siqikelela ukuba IFN-? ngexabiso elincinci, elifana nemiphumo ye-in vitro kwi-microglia [166], inokubangela ukubonakaliswa kwe-microglial ye-MHC-II kunye ne-EAAT2 [163,166], ivumela i-microglia ukuba isebenze njenge-cognate antigen ebonisa iiseli kunye nokubonelela nge-glutamate reuptake function [163,164,166], ngaloo ndlela iguqula i-microglia eyingozi ibe yi-neuroprotective phenotype [163,166] ethatha inxaxheba ekupheliseni i-glutamate engaphezulu kwe-extracellular [163,164,166]. Ke ngoko, siphinda sicinge ukuba impendulo engaphezulu kwe-Th1 kumacandelwana ezigulane ze-MDD likrele elintlangothi-mbini, ukukhuthaza ukudumba okuyingozi kunye nokusebenza njengendlela yokulawula enenzuzo enokunciphisa ubuninzi be-neuroexcitotoxicity enxulumene ne-glutamate (Umfanekiso 2).

Kwi-schizophrenia, ngelixa ezinye izifundo ze-cytokine ze-peripheral zibonisa ubukho be-Th2 immunophenotype / impendulo ye-antiinflammatory [52], abanye bayayiphikisa le [173,174]. Nangona kunjalo, siyavumelana nababhali abacinga ukuba impendulo ye-Th2 yi-phenotype ebalaseleyo kwi-schizophrenia [52]. Ubuchopho obuphakanyisiweyo, i-CSF, kunye namanqanaba e-serum ye-KYNA [21,52] icebisa ukuthotywa kwe-micro-glial IDO kunye ne-KMO, engumsebenzi wempendulo ye-Th2 etshintsha i-astroglial KYN catabolism kwi-KYNA synthesis (Umfanekiso 1) [21,52]. Ukunciphisa umsebenzi we-KMO kunye nokubonakaliswa kwe-KMO mRNA kwi-post-mortem schizophrenic brains [73] ihambelana nempendulo ye-Th2 engaphezulu (Umfanekiso 1). Ukwanda kokuxhaphaka kwe-Th2-mediated humoral immune abnormalities kumacandelwana abaguli be-schizophrenia - njengoko kungqinwa kukwanda kwenani leeseli ze-B [21,76], ukwanda.ukuveliswa kwee-autoantibodies ezibandakanya izilwa-ntsholongwane ezilwa nentsholongwane [76] kunye nokwanda kwe-immunoglobulin E [52] �yongeza inkxaso eyongezelelekileyo kwi-Th2 impendulo yokulawula i-hypothesis.

Neuroinflammation & CNS Glutamate Dysregulation

I-Glutamate idibanisa ukuqonda kunye nokuziphatha [186]. Amanqanaba e-Syn-aptic glutamate alawulwa yi-high-affinity sodium-dependent glial kunye ne-neuronal EAATs, oko kukuthi, inkqubo ye-XAG ejongene ne-glutamate reuptake / aspartate release [137,164] kunye ne-sodium-independent astroglial glutamate/cystine antiporter system (Xc-) uxanduva lokukhululwa kwe-glutamate / i-cystine reuptake [164]. I-Astroglial EAAT1 kunye ne-EAAT2 zibonelela ngaphezulu kwe-90% ye-glutamate yokubuyisela kwakhona [79].

I-Neuroinflammation inokuguqula i-glutamate metabolism kunye nomsebenzi wabathuthi bayo [15,29,187,188], ukuvelisa ukukhubazeka kwengqondo, ukuziphatha, kunye nokuphazamiseka kwengqondo [15,21,29,79,186,188,189]. Ukungaqhelekanga komsebenzi we-EAATs / inkcazo kunye ne-glutamate metabolism kwi-MDD, i-BPD, i-schizophrenia, kunye ne-OCD zishwankathelwa kwiThebhile 2.

Kwi-MDD, kukho ubungqina be-cortical hyperglutamatergia (Itheyibhile 2). Amanqanaba e-Cortical glutamate ahambelana ngokufanelekileyo kunye nobukhulu beempawu zokudakumba, kunye nekhosi yeeveki ezintlanu ze-antidepressants zanciphisa i-serum glutamate concentrations [85,86]. I-dose enye ye-ketamine, umchasi onamandla we-NMDAR, unokuguqula i-MDD ye-refractory ngeveki [17,21,29,85]. Ukugqithisa kwe-CNS amanqanaba e-glutamate kunokubangela ukuvuvukala kwe-neurotoxicity-mediated-inflammation [163,164,188], kuquka impendulo ye-Th1 ye-proinflammatory (Umfanekiso 2) [164].

Ubungqina obuncinci be-in vitro bubonisa ukuba ukuvuvukala / i-proinflammatory cytokines inokunyusa amanqanaba e-CNS glutamate [188] kumjikelezo wesondlo ngeendlela ezininzi ezinokubakho: i-1) i-proinflammatory cytokines inokuthintela [15,17,168] ​​kunye nokubuyisela umva [45,137] i-astroglial EAAT-mediated glutamate umsebenzi wokubuyisela kwakhona; I-2) i-cytokines ye-proinflammatory inokuphucula i-microglial quinolinic acid synthesis [53], eye yaboniswa ngovavanyo ukukhuthaza ukukhululwa kwe-synaptosomal glutamate [15,17,29,190]; 3) ukwanda kwe-COX-2 / PGE-2 kunye ne-TNF-? amanqanaba anokwenza i-calcium influx [137], esekelwe kwidatha ye-vitro, inokunyusa i-astroglial glutamate kunye ne-D-serine release [191]; kunye ne-4) i-microglia esebenzayo ingabonakalisa iinkqubo ezigqithisileyo ze-Xc-antiporter ezidibanisa ukukhululwa kwe-glutamate [164,192].

Kwi-schizophrenia, i-prefrontal cortical hypoglutamatergia [87,90,193,194] (Itheyibhile 2) kunye nokunciphisa ukusebenza kwe-NMDAR kufunyenwe [5]. I-H1 yakutshanje ye-magnetic resonance spectroscopy (MRS) uhlalutyo lwemeta (izifundo ezingama-28, i-647 schizophrenia, ulawulo lwe-608) luqinisekisile ukuncipha kwe-glutamate kunye nokunyuka kwamanqanaba e-glutamine kwi-cortex yangaphambili ye-medial [90]. Indima yegalelo lokuvuvukala kwi-hypoglutamatergia ayingqinwanga. Ukuphakama kwe-KYNA synthesis kwi-schizophrenia brains [21,52], ngokuqhelekileyo umsebenzi wempendulo ye-Th2 (Umfanekiso 1), unokuthintela i-NR1 subunit ye-NMDAR kunye ne-alpha 7 nicotinic.i-acetylcholine receptor (?7nAchR) [195], ekhokelela ekunciphiseni umsebenzi we-NMDAR kunye nokunciphisa ukukhululwa kwe-glutamate ye-7nAchR [195].

Kwi-BPD kunye ne-OCD, idatha ibonisa i-CNS cortical hyper-glutamatergia kuzo zombini izifo (iThebhile 2) [78,84,88,131]. Igalelo lokuvuvukala (BPD kunye ne-OCD) kunye ne-autoantibodies (OCD) [7,77,84,88,130] ukunyuka kwamanqanaba e-CNS glutamate kufuna uphando olongezelelweyo.

Indima ye-S100B

I-S100B yi-10 kDa calcium-binding protein eveliswa yi-astroglia, i-oligodendroglia, kunye ne-choroid plexus ependymal cells [196]. Idibanisa iziphumo zayo kwi-neurons ejikelezileyo kunye ne-glia ngokusebenzisa i-receptor ye-glycation end-product [196]. Amanqanaba e-Nanomolar extracellular S100B abonelela ngemiphumo enenzuzo ye-neurotrophic, ukunciphisa uxinzelelo olunxulumene nokulimala kwe-neuronal, inhibit microglial TNF-? ukukhulula, kunye nokwandisa i-astroglial glutamate reuptake [196]. Ugxininiso lwe-Micromolar S100B, oluveliswa kakhulu yi-astroglia esebenzayo kunye ne-lymphocytes [196,197], zineempembelelo ezinobungozi ezidluliswa yi-receptor kwimveliso yokuphela kwe-glycation equka i-neuronal apoptosis, imveliso ye-COX-2 / PGE-2, i-IL-1? kunye neentlobo ze-nitric oxide inducible, kunye nokulawulwa kwe-monocytic / microglial TNF-? imfihlo [21,196,198].

I-Serum kwaye, ngakumbi, i-CSF kunye ne-brain tissue amanqanaba e-S100B zizibonakaliso ze-glial (ikakhulukazi i-astroglial) isebenze [199]. Kwi-MDD kunye ne-psychosis, amanqanaba e-serum S100B ahambelana ngokufanelekileyo kunye nobunzima bokuzibulala, ngaphandle kokuxilongwa kwengqondo [200]. Uhlalutyo lwe-post-mortem lwe-S100B lubonise amanqanaba anciphileyo kwi-dorso-lateral prefrontal cortex ye-MDD kunye ne-BPD, kunye namanqanaba okwandisa kwi-parietal cortex ye-BPD [196].

Uhlalutyo lwe-Meta (i-193 i-mood disorder, i-132 yokulawula okunempilo) iqinisekisile i-serum ephakamileyo kunye namanqanaba e-CSF S100B kwiingxaki zengqondo, ngakumbi ngexesha lokudakumba okugqithisileyo kunye ne-mania [201].

Kwi-schizophrenia, ingqondo, i-CSF kunye ne-serum S100B amanqanaba aphakanyisiweyo [199,202]. Uhlalutyo lwe-Meta (izifundo ze-12, i-380 schizophrenia, i-358 yokulawula impilo) iqinisekisile amanqanaba aphezulu e-serum S100B kwi-schizophrenia [203]. Kwiingqondo ze-post-mortem zezifundo ze-schizophrenia, i-astroglia ye-S100B-immunoreactive ifumaneka kwiindawo ezichaphazelekayo kwi-schizophrenia, kuquka i-anterior cingulate cortex, i-dorsolateral prefrontal cortex, i-orbitofrontal cortex kunye ne-hippocampi [154]. Amanqanaba aphakamileyo e-S100B ahambelana ne-paranoid [154] kunye ne-negativistic psychosis [204], ukuqonda okungahambi kakuhle, ukuphendula kakubi kwonyango kunye nobude bokugula [202]. I-polymorphisms ye-Genetic kwi-S100B [32] kunye ne-receptor ye-glycation end-product genes kwi-schizophrenia cohorts (Itheyibhile 2) [32,33,205] icebisa ukuba oku kungaqhelekanga kunokuthi kube yiprayimari / i-pathogenic kunokuba i-secondary / biomarkers. Ewe, ukuhla kumanqanaba e-serum S100B kulandela unyango olune-antidepressants [201] kunye ne-antipsychotics [196] icebisa.okunye ukufaneleka kweklinikhi ye-S100B kwi-pathophysiology yokuphazamiseka kwengqondo.

I-Neuroinflammation & Ukonyuka koxinzelelo lwe-Oxidative

Uxinzelelo lwe-oxidative yimeko apho ukugqithisa kwee-oxidants konakalisa okanye ukuguqula i-macromolecules yezinto eziphilayo ezifana ne-lipids, iiprotheni kunye ne-DNA [206-209]. Oku kugqithiswa kubangelwa ukunyuka kwemveliso ye-oxidant, ukunciphisa ukupheliswa kwe-oxidant, ukukhuselwa kwe-antioxidant enesiphene, okanye indibaniselwano ethile [206-209]. Ingqondo isengozini ngakumbi kuxinzelelo lwe-oxidative ngenxa: 1) amanani aphezulu e-peroxidizable polyunsaturated fatty acids; 2) umxholo ophezulu kakhulu we-trace minerals eyenza i-lipid peroxidation kunye ne-oxygen radicals (umzekelo, isinyithi, ubhedu); 3) ukusetyenziswa kweoksijini ephezulu; kunye ne-3) iindlela ezinqamlekileyo zokulwa ne-oxidation [206,207].

Uxinzelelo olugqithisileyo lwe-oxidative lungenzeka kwi-MDD [206], i-BPD [206,207], i-schizophrenia [207,209], kunye ne-OCD [206,208]. Iimpawu ze-peripheral zokuphazamiseka kwe-oxidative ziquka ukunyuka kweemveliso ze-lipid peroxidation (umzekelo, i-malondialdehyde kunye ne-4-hydroxy-2-nonenal), ukunyuka kwe-nitric oxide (NO) imetabolites, ukunciphisa i-antioxidants (umzekelo, i-glutathione) kunye nokuguqula amanqanaba e-enzyme ye-antioxidant [206,207].

Kwi-MDD, ukwanda kwemveliso ye-superoxide radical anion correlates kunye nokunyuka kwe-oxidation-mediated neutrophil apoptosis [206]. Amanqanaba e-serum e-antioxidant enzymes (umzekelo, i-superoxide dismutase-1) iphakanyisiwe ngexesha lee-episodes ezixinzelelekileyo kwaye ziqhelekileyo emva kokukhetha unyango lwe-serotonin reuptake inhibitors (SSRIs) [206]. Oku kuphakamisa ukuba kwi-MDD, amanqanaba e-serum e-antioxidant ye-enzyme ngumakishi karhulumente, onokubonisa indlela yokubuyisela echasene nokunyuka okukrakra koxinzelelo lwe-oxidative. [206]. Kwi-schizophrenia ngokwahlukileyo, amanqanaba e-CSF e-soluble superoxide dismutase-1 ancipha kakhulu kwizigulane zokuqala ze-schizophrenic ezinxulumene nezigulana ezingapheliyo ze-schizophrenic kunye nolawulo olunempilo. Oku kuphakamisa ukuba ukunciphisa amanqanaba e-enzyme ye-antioxidant yengqondo kunokufaka isandla kumonakalo we-oxidative kwi-schizophrenia enzima [210], nangona izifundo ezinkulu ziyafuneka ukuze kuqinisekiswe oku kufunyaniswayo.

Izifundo ezininzi ezongezelelweyo zovavanyo kunye nezomntu zihlolwe ngokubanzi kwiindlela eziphantsi kwe-pathophysiology yokwanda koxinzelelo lwe-oxidative kwingxaki yengqondo [206-262]. Kwiimodeli zezilwanyana zokudakumba, amanqanaba engqondo ye-glutathione ayancitshiswa ngelixa i-lipid peroxidation kunye namanqanaba e-NO anyuswa [206,262].

Izifundo ze-Postmortem zibonisa amanqanaba obuchopho ancitshisiweyo e-glutathione epheleleyo kwi-MDD, BPD [206] kunye nezifundo ze-schizophrenic [206,207]. I-Fibroblasts ekhuliswe kwizigulane ze-MDD ibonisa ukunyuka kwengcinezelo ye-oxidative ezimeleyo kumanqanaba e-glutathione [262], ephikisana nendima ephambili yokunciphisa i-glutathione njengendlela enkulu yoxinzelelo lwe-oxidative kuxinzelelo.

Ukusebenza kwe-Microglial kunokunyusa uxinzelelo lwe-oxidative ngokuveliswa kwe-cytokines ene-proinflammatory kunye ne-NO [206-209]. I-proinflammatory cytokines kunye namanqanaba aphezulu e-NO anokukhuthaza ukubunjwa kwe-oksijeni esebenzayo (i-ROS), ethi ikhawuleze i-lipid peroxidation, i-membrane eyonakalisa i-phospholipids kunye ne-membrane-bound-bound monoamine neurotransmitter receptors kunye nokuphelisa i-antioxidants engapheliyo. Ukunyuka kweemveliso ze-ROS kunokuphucula i-microglial activation kunye nokwandisa imveliso ye-proinflammatory ngokuvuselela i-NF-?B [208], leyo yona iqhubekisela phambili ukulimala kwe-oxidative [208], ukudala amandla okuba ne-pathological positive feedback loop kwezinye izifo zengqondo [206-209]. Nangona i-neuroinflammation inokunyusa amanqanaba e-brain glutamate [85,86], indima ye-glutamatergic hyperactivity njengesizathu soxinzelelo lwe-oxidative ihlala ingaxhaswanga [207].

Ukungasebenzi kakuhle kweMitochondrial kunokufaka isandla ekwandeni koxinzelelo lwe-oxidative kwi-MDD, BPD kunye ne-schizophrenia [206]. Izifundo ze-Postmortem kwezi ngxaki zityhila ukungaqhelekanga kwi-DNA ye-mitochondrial, ehambelana nokuxhaphaka okuphezulu kokuphazamiseka kwengqondo kwi-primary mitochondrial disorders [206]. Izifundo zezilwanyana ze-in vitro zibonisa ukuba i-proinflammatory cytokines, njenge-TNF-?, inokunciphisa ubuninzi be-mitochondrial kwaye iphazamise imetabolism ye-oxidative ye-mitochondrial [211,212], ekhokelela ekunyuseni kwemveliso ye-ROS [206,213]. Ezi ziphumo zovavanyo zingathetha unxibelelwano lobuchwephesha phakathi kwe-neuroinflammation, ukungasebenzi kakuhle kwe-mitochondrial kunye noxinzelelo lwe-oxidative [206,213], olufanele uphando olongezelelekileyo kwezi ndlela ziphambanayo ze-pathogenic kwingxaki yengqondo yomntu.

Ukuba semngciphekweni kwezicubu ze-neural kumonakalo we-oxidative kuyahluka phakathi kwezifo zengqondo ezahlukeneyo ezisekelwe kwi-neuroanatomical, neurochemical kunye neendlela ze-molecular ezibandakanyekayo kwingxaki ethile [207]. Iziphumo zonyango zinokuthi zibaluleke kakhulu, njengoko ubungqina bokuqala bubonisa ukuba i-antipsychotics, i-SSRIs kunye ne-mood stabilizers zinezakhiwo ze-antioxidant [206,207,262]. Indima yonyango ye-antioxidant ye-adjuvant (umzekelo, iivithamin C kunye no-E) kwingxaki yengqondo ihlala ingqinisiswa ngamalingo onyango angenamkhethe. I-N-acetylcysteine ​​ibonisa ezona ziphumo zithembisayo ukuza kuthi ga ngoku, kunye nezilingo ezininzi ezilawulwa yi-placebo ezibonisa ukusebenza kwayo kwi-MDD, BPD kunye ne-schizophrenia [207].

Igazi �Ukungasebenzi kakuhle kwesithintelo sobuchopho

I-BBB ikhusela imeko yokhuseleko lwengqondo ngokuthintela ukungena kwabalamli be-peripheral inflammatory mediators, kubandakanywa ii-cytokines kunye ne-antibodies ezinokuphazamisa ukuhanjiswa kwe-neurotransmission [214,215]. I-hypothesis ye-BBB yokuphuka kunye nendima yayo kwezinye izigulana zengqondo [60,214,216,217] ihambelana nokunyuka kwe-comorbidity yengqondo kwizifo ezinxulumene nokungasebenzi kwayo, kuquka i-SLE [97], i-stroke [11],�isithuthwane [218] kunye ne-autoimmune encephalitides (Itheyibhile 1). I-CSF ephakamileyo: i-serum albumin ratio kwizigulane ezine-MDD kunye ne-schizophrenia iphakamisa ukunyuka kwe-BBB yokungena [214].

Kwisifundo esinye (izifundo ze-63 zengqondo, ulawulo lwe-4,100), ukungaqhelekanga kwe-CSF ebonisa umonakalo we-BBB kufunyenwe kwi-41% yezifundo zengqondo (i-14 MDD kunye ne-BPD, i-14 schizophrenia), kubandakanywa ne-intrathecal synthesis ye-IgG, i-IgM, kunye / okanye i-IgA, i-pleocytosis ye-CSF ethambileyo (i-5 ukuya kwiiseli ze-8 nge-mm3) kunye nobukho bee-oligoclonal ezine ze-IgG [216]. Olunye uphononongo lwe-post-mortem ultrastructural kwi-schizophrenia lubonise ukungahambi kakuhle kwe-BBB kwi-prefrontal kunye ne-visual cortices, ebandakanya ukuhla kwe-vacuolar yeeseli ze-endothelial, iinkqubo ze-astroglial-end-foot- process, kunye nokuqina kunye nokungahambi kakuhle kwe-basal lamina [60]. Nangona kunjalo, kolu cwaningo, ababhali abazange baphawule malunga negalelo elinokubakho lokutshintsha kwe-postmortem kwiziphumo zabo. Olunye uphando oluphanda i-transcriptomics yeeseli ze-BBB endothelial kwingqondo ye-schizophrenic ichonge umahluko omkhulu phakathi kwemfuza echaphazela ukusebenza kwe-immunological, engazange ibonwe kulawulo [217].

Ukungasebenzi kakuhle kwe-oxidation-mediated endothelial kunokuba negalelo kwi-pathophysiology yokungasebenzi kakuhle kwe-BBB kwiziphazamiso zengqondo. Ubungqina obungathanga ngqo obuvela kwizifundo zeklinikhi kunye novavanyo lokudakumba [219] kwaye, ukuya kwinqanaba elingaphantsi, kwi-schizophrenia [220] ibonisa ukuba ukunyuka kwe-oxidation kunokufaka isandla kwi-endothelial dysfunction. Ukungasebenzi kwe-Endothelial kungamela indlela ekwabelwana ngayo kwintlangano eyaziwayo phakathi kokudakumba kunye nesifo senhliziyo [219,221], enokuthi ihambelane nokunciphisa amanqanaba e-vasodilator NO [221-223]. Izifundo zovavanyo zibonisa ukuba amanqanaba e-endothelial ancitshisiweyo e-NO adityaniswe ngoomatshini kunye nokungabandakanywa kwe-endothelial nitric oxide synthase (eNOS) ukusuka kwi-co-factor yayo ebalulekileyo ye-tetrahydrobiopterin (BH4), ukuguqula i-substrate yayo kwi-L-arginine ukuya kwi-oksijini [224-226]. I-eNOS engadityaniswanga ikhuthaza ukuhlanganiswa kwe-ROS (umzekelo, i-superoxide) kunye neentlobo ze-nitrogen ezisebenzayo (i-RNS) (umzekelo, i-peroxynitrite; imveliso yokusebenzisana kwe-superoxide nge-NO) [227] kunokuba HAYI, ekhokelela kwi-oxidation-mediated endothelial dysfunction [ 224-226].

Idatha yezilwanyana ibonise ukuba i-SSRIs inokubuyisela amanqanaba e-NO endothelial engekhoyo [219], ebonisa ukuba iindlela zokuchasana ne-oxidative zinokuba negalelo kwimiphumo yazo yokudakumba. Ebantwini, i-L-methylfolate inokubangela iziphumo ezichasayo ze-SSRIs [228], ngokunyusa amanqanaba e-BH4, eyi-cofactor ebalulekileyo ye-eNOS yokudibanisa kwakhona-mediated anti-oxidation [229], kunye nesantya. -ukunciphisa i-enzymes ye-monoamine (oko kukuthi, i-serotonin, i-norepinephrine, i-dopamine) synthesis [228].

Kuthatyathwe kunye, zombini umsebenzi wamva nje ugxininisa indima ye-eNOS-induced oxidative stress in the pathogenesis of vascular disease [230,231] kunyeIzifundo ze-epidemiological eziseka ukudakumba njengento exhomekeke kumngcipheko we-vascular pathologies, njenge-stroke kunye nesifo senhliziyo [219,221], yongeza inkxaso eyongezelelweyo kukubaluleka kwekliniki ye-eNOS-mediated endothelial oxidative endothelial umonakalo ekudakaleni. Ngaphandle kobungqina obuninzi bokungahambi kakuhle kwe-cytokine kwizifo zengqondo yabantu kunye nedatha yovavanyo ebonisa ukuba i-cytokines ye-proinflammatory inokunciphisa i-eNOS intetho [212] kwaye yandise ukunyanzeliswa kwe-BBB [215], ubungqina bomntu obudibanisa ngokuthe ngqo i-cytokines ye-proinflammatory kwi-eNOS ukungasebenzi kunye / okanye ukukhubazeka kwe-BBB. ukuswela.

Ukwenza umfanekiso kunye nokuNyanga ukudumba kwiSigulo seNgqondo

Ukwenza umfanekiso weNeuroinflammation kwiSitu

Ngokonyango, ukucinga nge-neuroinflammation kunokuqinisekisa ukuba kubalulekile ekuchongeni iqela labagula ngengqondo abane-neuroinflammation abanokuthi baphendule ngokufanelekileyo kunyango lwe-immunomodulatory. Ukongeza, ukucinga okunjalo kunokuvumela oogqirha ukuba bajonge umsebenzi wesifo esinxulumene ne-neuroinflammation kunye nokuphendula kwayo kunyango lomzimba kwizigulana zengqondo. Ukucinga ukudumba ebuchotsheni bomntu ngokwesiko kuxhomekeke kwi-MRI okanye kwi-CT yokubonwa kwe-extravagated intravenous agents, ebonisa ukophuka kwendawo ye-BBB. I-MRI ephuculweyo ye-Gadolinium ngamaxesha athile ibonisa ukuphuka okunjalo kwimimandla ye-limbic ehambelana nokucutshungulwa kwengqondo kwizigulane ezineengxaki zengqondo ezibangelwa yi-paraneoplastic okanye enye i-encephalitides [107,109,113]. Kulwazi lwethu, nangona kunjalo, ukuphuculwa okungaqhelekanga akukaze kuboniswe kuyo nayiphi na ingxaki yengqondo yeklasi [21,214,232], ngaphandle kokusebenza [214,216] kunye nokungaqhelekanga kwe-BBB [60].

Nokuba ngaba i-neuroinflammation efihlakeleyo inokubonwa na kwi-vivo kwiziphazamiso zengqondo zamandulo azikaziwa. Enye indlela ethembisayo yi-positron emission tomography (PET) isebenzisa i-radiotracers, njenge-C11- PK11195, ebophelela kwiprotheni ye-translocator, eyaziwa ngokuba yi-peripheral benzodiazepine receptor, echazwe yi-microglia esebenzayo [233,234].

Ukusebenzisa le ndlela, izigulane ezine-schizophrenia zibonakaliswe ukuba zine-activation enkulu ye-microglial kuyo yonke i-cortex [235] kunye ne-hippocampus ngexesha le-psychosis enzima [236]. Olunye uphando (i-14 schizophrenia, ulawulo lwe-14) alufumananga mmahluko obalulekileyo phakathi kwe- [11C] i-DAA1106 ebophelelayo kwi-schizophrenia ngokubhekiselele kulawulo, kodwa ulungelelwaniso oluthe ngqo phakathi kwe- [11C] i-DAA1106 yokubopha kunye nobukhulu beempawu ezintle kunye nobude bokugula kwi-schizophrenia [236].

Abaphandi abavela kwiziko lethu basebenzise i-C11-PK11195 PET ukubonisa ukuvuvukala kwe-bi-hippocampal kwisigulane esine-neuropsychiatric dysfunction, kuquka i-psychotic MDD, i-epilepsy, kunye ne-anterograde amnesia, ehambelana ne-anti-GAD antibodies [237]. Nangona kunjalo, i-PK11195 PET ineiimpawu ezisezantsi zomqondiso-kwingxolo kwaye zifuna i-cyclotron ekwisiza.

Ngokufanelekileyo, uphando lunikezelwa ekuphuhliseni i-translocator protein ligands ephuculweyo ye-PET kunye ne-SPECT. Izifundo zobuchopho zasemva kokubhubha zamandla aphezulu zisebenzisa ubungakanani beprotheyini ejolise ekucaciseni iindlela ze-metabolic kunye nokudumba, i-CNS cytokines kunye ne-receptors zabo ezibophayo, kwingxaki yengqondo iyafuneka ukuqhubela phambili ukuqonda kwethu i-autoimmune pathophysiology.

Indima yeZiyobisi ezichasayo kwiingxaki zengqondo

Izifundo ezininzi zabantu kunye nezilwanyana zibonisa ukuba iziyobisi ezithile ezichasayo zinokudlala indima ebalulekileyo eyongezelelweyo kunyango lwezifo zengqondo (Itheyibhile 3). Iziyobisi eziqhelekileyo ziyi-cyclooxygenase inhibitors (Itheyibhile 3) [238-245], i-minocycline (iThebhile 3) [240-245], i-omega-3 fatty acids [246,247], kunye neurosteroids [248].

Izifundo ezininzi zabantu zibonise ukuba i-COX-2 inhibitors inokuphucula iimpawu zengqondo ye-MDD, BPD, schizophrenia kunye ne-OCD (Itheyibhile 3) [248]. Ngokwahlukileyo, unyango oluncedisayo kunye ne-COX-inhibitors engakhethiyo (oko kukuthi, i-non-steroidal antiinflammatory drugs (NSAIDs)) inokunciphisa ukusebenza kwe-SSRIs [249,250]; Izilingo ezibini ezikhulu zichaze ukuba ukuvezwa kwi-NSAID (kodwa kungekhona kwi-COX-2 inhibitors okanye i-salicylates ekhethiweyo) yadibaniswa nokunyuka okukhulu kokudakumba phakathi kweseti yabathathi-nxaxheba bophando [249,250].

Kulingo lokuqala, olubandakanya izigulane ezicinezelekileyo ze-1,258 eziphathwe nge-citalopram kwiiveki ze-12, izinga lokuxolelwa laliphantsi kakhulu phakathi kwabo bathathe ii-NSAID ubuncinane kanye xa benxulumene nabo bangazange (45% ngokuchasene ne-55%, OKANYE 0.64, P = 0.0002) [249]. Olunye ulingo, olubandakanya izifundo ze-MDD ze-1,545, lubonise izinga lokudakumba konyango laliphezulu kakhulu phakathi kwabo bathatha ii-NSAIDs (OR 1.55, 95% CI 1.21 kwi-2.00) [231]. Ukwanda kokudakumba kumaqela e-NSAID kunokungadityaniswa nonyango lwe-NSAID kodwa endaweni yoko kunxulumene neemeko zonyango ezingapheliyo [10,12-18] ezifuna ii-NSAID zexesha elide kwaye zaziwa ngokuzimeleyo ezinxulumene nazo. ukwanda komngcipheko wokudakumba okunganyangekiyo kunyango [249,251]. Izifundo zexesha elizayo eziphanda impembelelo ye-NSAID ekudandathekeni kunye nokuphendula kwii-antidepressants kubantu ziyafuneka.

Kwezinye izifundo zovavanyo zisebenzisa i-acute-stress paradigms ukukhuthaza imeko efana nokudakumba kwiimpuku, i-citalopram yanda i-TNF-?, i-IFN-?, kunye ne-p11 (i-molecular factor edityaniswe nokuziphatha okudakumba kwizilwanyana) kwi-cortex yangaphambili, ngelixa i-NSAID ibuprofen zehla ezi molekyuli; Ii-NSAID ziphinde zithintele iziphumo ezichasayo ze-SSRIs kodwa hayi ezinye i-antidepressants [249]. Ezi ziphumo zibonisa ukuba i-proinflammatory cytokines inokuthi isebenzise ngokumangalisayo iziphumo zokudambisa uxinzelelo ngaphandle kobungqina obuninzi obuvela.izifundo zabantu ngokuchaseneyo (njengoko kuhlaziywe ngasentla), ezinokuthi zithintelwe yi-NSAIDs [249]. Ubuncinci iingqwalasela ezimbini zinokuthi ziphendule le ngqungquthela ebonakalayo: i-1) phantsi kweemeko ezithile zokulinga, i-cytokines ye-proinflammatory idibene nendima ye-neuroprotective, [251; (kuba�umzekelo, IFN-? kumanqanaba aphantsi anokubangela i-neuroprotective microglia (Umfanekiso 2) [163,166,251]); kunye ne-2) ingaba ezi mpendulo zibonwe kumxholo we-paradigm yoxinzelelo olunzima kwimodeli yezilwanyana zisebenza kwi-MDD engapheliyo kubantu zihlala zingacacanga [251].

Iziphumo zonyango ze-COX-2 inhibitors kwizifo zengqondo zingabandakanya ukuguqulwa kwe-biosynthesis ye-COX-2-derived prostaglandins, kubandakanywa ne-proinflammatory PGE2 kunye ne-antiinflammatory 15-deoxy-?12,14-PGJ2 (15d- PGJ2) [252,253]. I-COX-2 inhibitors inokunciphisa i-PGE2-ukuvutha okuphakathi, okunokuthi kube negalelo kwi-pathophysiology yezifo zengqondo [252,253]. Basenokuphinda baguqule amanqanaba e-15d-PGJ2, kunye nomsebenzi we-nuclear receptor ye-peroxisome proliferator-activated nuclear receptor gamma (PPAR-?) [252,253].

Izifundo ezininzi zibonisa ukuba i-15d-PGJ2 kunye ne-nuclear receptor PPAR-? inokusebenza njengeziphawuli zebhayoloji zeschizophrenia [253]. Kwizigulane ze-schizophrenic, amanqanaba e-serum e-PGE2 anyuswa, ngelixa amanqanaba e-serum ye-15d- PGJ2 ayancipha, njengoko kubonakaliso lwe-nuclear receptor PPAR-? kwi-PBMC [252]. Ngelixa i-COX-2 inhibitors inokunciphisa iziphumo ezinokuthi zibe luncedo zokulwa nokudumba kwe-COX-2�exhomekeke �15d-PGJ2/PPAR-? Indlela, banokunciphisa ngokunenzuzo iziphumo zayo ezinobungozi, kubandakanywa ne-1) ingozi eyongeziweyo ye-myocardial infarction kunye nosulelo oluthile (umzekelo, i-cytomegalovirus kunye ne-Toxoplasma gondii) kwizigulane ze-schizophrenic [254] kunye ne-2) iziphumo zayo ze-pro-apoptotic ezibonwayo Umhlaza womntu kunye nesilwanyana [255]. Ezinye iindlela ezinokubakho ze-COX-2 inhibitors iziphumo zonyango zinokubandakanya ukukwazi kwabo ukunciphisa amanqanaba e-cytokine e-proinflammatory [163], ukunciphisa i-quinolinic acid excitotoxicity (njengakwi-MDD) kunye nokunciphisa amanqanaba e-KYNA (njenge-schizophrenia) [128].

I-Minocycline inokusebenza kwiingxaki zengqondo (iThebhile 3) [248]. Idatha ye-in vitro iphakamisa ukuba i-minocycline inqanda i-MAP, i-cytokine secretion, �COX-2 / PGE-2 intetho, kunye ne-inducible nitric oxide synthase [256]. I-Minocycline inokuchasana ne-dysregulated glutamatergic kunye ne-neurotransmission ye-dopaminergic [256].

I-Omega-3 fatty acid esebenzayo kwingxaki yengqondo ayicacanga [248]. Kwi-2011 meta-analysis of 15 randomized-controlled trials (916 MDD), i-omega-3 supplements equkethe i-eicosapentaenoic acid ?60% (i-dose range 200 ukuya kwi-2,200 mg / d ngaphezu kwe-docosahexaenoic acid dose) iyancipha kakhulu iimpawu zokudakumba njenge unyango oluncedisayo kwi-SRIs (P <0.001) [246]. Uhlalutyo olwalandelayo lwe-meta, nangona kunjalo, lugqibe ekubeni akukho nzuzo ibalulekileyo ye-omega-3 fatty acids ekudakaleni kwaye oko kufunwa ukuba kusebenza kakuhle kusisiphumo sokupapashwa kwe-bias [247]. Uhlalutyo lwe-2012 ye-meta-analysis ye-5 izilingo ezilawulwa ngokungahleliwe ezibandakanya abathathi-nxaxheba be-291 be-BPD bafumanisa ukuba ukudakumba, kodwa kungekhona i-manic, iimpawu ziphuculwe kakhulu phakathi kwezo zi-randomized kwi-omega-3 fatty acids ngokumalunga nalabo bathatha indawo ye-placebo (Hedges g 0.34, P = 0.025) [257]. Kulingo olulawulwa ngokungahleliwe lwezifundo ze-schizophrenic ezilandelwayo ukuya kwiinyanga ze-12, zombini iimpawu ezintle kunye nezibi zeempawu zehla kakhulu phakathi kwabathathi-nxaxheba be-66 ngokungaqhelekanga kwi-omega-3 ye-long-chain (1.2 g / imini kwiiveki ze-12; P = 0.02 kunye ne-0.01, ngokulandelelanayo) [258]; i�Ababhali baphetha ukuba i-omega-3 yokwandisa ngexesha lokuqala kwe-schizophrenia inokuthintela ukuphindaphinda kunye nokuqhubela phambili kwesifo [258].

Uhlalutyo lwe-meta lwe-2012 lwezilingo ezisixhenxe ezilawulwa ngokungahleliwe ezivavanya i-omega-3 yokwandisa kwizigulane ze-168 ze-schizophrenic azifumananga nzuzo yonyango [259]. Ababhali bolu hlalutyo lwe-meta bachaza ngokuthe ngqo ukuba akukho sigqibo sinokuthathwa malunga nokuthintela ukuphindaphinda okanye ukuqhubela phambili kwesifo [259]. Idatha yovavanyo ibonisa ukuba i-eicosapentaenoic acid kunye ne-docosahexaenoic acid idibanisa imiphumo yabo yokulwa nokuvuvukala ngokukhuthaza ukuhlanganiswa kwe-resolvins kunye nezikhuseli, ezinokuthintela ukungena kwe-leukocyte kunye nokunciphisa ukuveliswa kwe-cytokine [248].

I-Neurosteroids, kuquka i-pregnenolone kunye ne-down-stream metabolite allopregnanolone, ingaba nendima enenzuzo kwezinye izifo zengqondo [248,260]. Kwi-MDD, izifundo ezininzi zifumene amanqanaba e-plasma / CSF allopregnanolone ehlayo ehambelana nobukhulu beempawu, eziye zaqheleka emva konyango oluyimpumelelo kunye nama-antidepressants athile (umzekelo, i-SSRIs), kunye nonyango lwe-electroconvulsive [261]. Kwi-schizophrenia, amanqanaba e-brain pregnenolone anokuguqulwa [248] kwaye amanqanaba e-serum allopregnanolone anokunyusa emva kwezidakamizwa ezithile ze-antipsychotic (umzekelo, i-clozapine kunye ne-olanzapine) [260]. Kwizilingo ezithathu ezilawulwa ngokungenamkhethe (i-100 schizophrenia (ihlanganiswe); ubude bonyango, malunga neeveki ezisithoba) iimpawu ezintle, ezingalunganga, kunye neengqondo, kunye nemiphumo ye-extrapyramidal ye-antipsy-chotics yaphuculwa kakhulu kulingo olunye okanye ngaphezulu phakathi kwezo zicwangcisiweyo ukuya. i-pregnenolone enxulumene nabo bafumana indawo ye-placebo [248]. Kwilingo elinye, ukuphuculwa kwaxhaswa kunye nonyango lwe-pregnenolone yexesha elide [248]. I-Pregnenolone inokulawula ukuqonda kunye nokuziphatha ngokufaka umsebenzi we-NMDA kunye ne-GABAA receptors [248]. Ngaphezu koko, i-allopregnanolone inokusebenzisa i-neuroprotective kunye ne-anti-inflammatory effects [248]. Izifundo ezininzi ze-RCT ziyafuneka ukuze kuqinisekiswe indima enenzuzo ye-neuroactive steroids ekuqaleni kokuphazamiseka kwengqondo ebantwini.

Silindele iziphumo zezilingo ezininzi eziqhubekayo zeklinikhi eziphanda imiphumo yonyango yezinye ii-anti-inflammatory agents, kuquka i-salicylate, i-inhibitor ye-NF-?B (NCT01182727); i-acetylsalicylic acid (NCT01320982); i-pravastatin (NCT1082588); kunye ne-dextromethorphan, umchasi ongakhuphisananga we-NMDAR onokukhawulela ukuvuvukala okubangelwa ukwenzakala kwe-dopaminergic neuronal (NCT01189006).

IziCwangciso zoNyango lwexesha elizayo

Nangona unyango lwangoku lwangoku lwe-immune (umzekelo, i-IVIG, i-plasmapheresis, i-corticosteroids kunye ne-immunosuppressive agents) zihlala zisebenza kakuhle ekunyangeni i-autoimmune encephalitides apho ukudumba kubukhali, kunamandla kwaye kuphuma imvelaphi eguquguqukayo, ukusebenza kwabo kwingxaki yengqondo yakudala apho ukudumba kungapheliyo,buthathaka kakhulu, kwaye ubukhulu becala imvelaphi yokuzalwa, ilinganiselwe [2]. Uphuhliso lwenoveli yonyango kufuneka lujolise ekubuyiseleni ilahleko ye-glial [46,138], ezantsi-elawula i-MAP eyingozi, ngelixa kulungiswa i-endogenous neuroprotective T regs kunye ne-MAP enenzuzo, kunokucinezela ngokungakhethiyo ukudumba njengoko kwenzeka kwiiarhente zangoku zokugonyela. Ukongeza, uphuhliso lwe-antioxidant enamandla ye-co-adjuvant enokubuyisela umva ukwenzakala kwe-oxidative kwingxaki yengqondo iyafuneka.

izigqibo

Ukuzilawula ngokuzenzekelayo kunokubangela inkitha yeengxaki ze-neuropsychiatric ezinokuthi ziqale zibonise iimpawu ezizimeleyo zengqondo. Ukuvuvukala okungaphakathi / ukuzimela ngokuzenzekelayo kunokubaluleka kwi-pathogenesis yeempawu zengqondo kwi-subset yezigulane ezineengxaki ze-classical psychiatric. Ukudumba okungaphakathi kunokunxulunyaniswa ngokobuchwephesha kwizinto ezingaqhelekanga ze-monoaminergic kunye ne-glutamatergic kunye nokwanda kokwenzakala kwe-oxidative okuxelwe kwizigulo zengqondo.

Souhel Najjar1,5*, Daniel M Pearlman2,5, Kenneth Alper4, Amanda Najjar3 kunye noOrrin Devinsky1,4,5

izifinyezo

3-OH-KYN: 3-hydroxy-kynurenine; ?7nAchR: I-Alpha 7 i-nicotinic acetylcholine receptors; I-AMPAR: I-Amino-3-hydroxy-5-methyl-l-4-isoxazolepropionic acid receptors; I-APC: Iseli ebonisa i-Antigen; BBB: Isithintelo segazi;
BH4: iTetrahydrobiopterin; I-BPD: I-bipolar disorder; CI: Ixesha lokuzithemba;
I-CNS: Inkqubo ye-nervous central; COX-2: Cyclooxegenase-2; CSF: Cerebrospinal fluid; I-DSM-IV: I-Diagnostic and Statistical Manual of Mental Disorders 4th Edition; I-EAATs: Abathuthi be-amino acid abanomdla; eNOS: Endothelial nitric oxide synthase; I-GABAB: I-Gamma aminobutyric acid-beta; I-GAD: ​​I-Glutamic acid decarboxylase; I-GFAP: Iprotheni ye-glial fibrillary acidic; I-GLX: I-1H MRS i-glutamate ebonakalayo, i-glutamine, i-gamma aminobutyric acid composite;
IDO: Indoleamine 2,3-dioxygenase; Ig: Immunoglobulin; IL: Interleukin; I-IL-1RA: I-Interleukin 1 i-receptor antagonist; IFN-?: I-Interferon gamma;
KAT: Kynurenine aminotransferase; KMO: Kynurenine 3-monooxygenase; I-KYN: I-Kynurenine; I-KYNA: i-kynurenic acid; LE: i-Limbic encephalitis;
LPS: Lipopolysaccharide; I-MAP: Ukusebenza kwe-Microglial kunye nokwanda;
MDD: Ingxaki enkulu yokudakumba; mGluR: I-Metabotropic glutamate receptor; MHC: II Major histocompatibility iklasi entsonkothileyo yesibini; I-MRI: I-imaging resonance magnetic; Nkskz: iMagnetic resonance spectroscopy; NF-?B: Umba weNyukliya kappa B; I-NMDAR: i-N-methyl-D-aspartate receptor; I-NR1: Indawo yeGlycine;
I-OCD: I-Obsessive-compulsive disorder; OKANYE: Umlinganiselo wemiba; I-PANDAS: Izifo ze-autoimmune ze-neuropsychiatric zabantwana ezinxulumene ne-streptococcal infections; I-PBMC: Iiseli zegazi ze-mononuclear ze-peripheral; I-PET: I-Positron emission tomography; PFC: I-cortex yangaphambili; I-PGE-2: I-Prostaglandin E2; PPAR-
?: I-gamma ye-nuclear receptor efakwe i-peroxisome; I-QA: i-Quinolinic acid; RNS: Iintlobo zenitrogen ezisebenzayo; I-ROS: Iintlobo ze-oksijini ezisebenzayo;
I-sIL: I-interleukin enyibilikayo; SLE: Systemic lupus erythematosus; SRI: Serotonin reuptake inhibitor; TNF-?: I-Tumor necrosis factor alpha; I-T-regs: CD4 + CD25 + FOXP3 + T iiseli ezilawulayo; TDO: Tryptophan-2,3-dioxygenase; Th: T-helper; I-VGKC: Ishaneli ye-potassium ene-Voltage-gated; I-XAG-: I-Glutamate aspartate transporter; Xc-: I-astroglial glutamate/cystine ezimeleyo enesodium
inkqubo ye-antiporter

Ukugqithisa inzala

Ababhali bavakalisa ukuba abanalo inxaxheba.

Ababhali��Amagalelo
I-SN kunye ne-DMP yenze uphononongo olubanzi loncwadi, itoliko yedatha, yalungisa umbhalo wesandla, amanani kunye neetafile. I-KA ilungiselele icandelo eliphathelele kwiindlela ze-oxidative kwaye ibe negalelo kuhlaziyo lombhalo-ngqangi. I-AN kunye ne-OD zihlaziywe ngokunzulu kwaye zaphucula uyilo kunye nomgangatho wombhalo-ngqangi. Bonke ababhali bafunde kwaye bavuma umbhalo-ngqangi wokugqibela.

Imibulelo

Sivuma ngombulelo uGqr. UJosep Dalmau, MD, PhD, Tracy Butler, MD, kunye noDavid Zazag, MD, PhD, ngokubonelela ngobuchule babo kwi-encephalitides ye-autoimmune, i-neuroinflammation imaging, kunye ne-neuropathology, ngokulandelanayo.

Umbhali�Iinkcukacha

I-1 yeSebe le-Neurology, iYunivesithi yaseNew York yeSikolo sezoNyango, i-550 First Avenue, eNew York, NY 10016, eU.SA. I-2Geisel School of Medicine e-Dartmouth, i-Dartmouth Institute for Health Policy and Practice Clinical, 30 Lafayette Street, HB 7252, Lebanon, NH 03766, USA. I-3 yeSebe le-Pathology, iCandelo le-Neuropathology, i-New York University School of Medicine, i-550 First Avenue, eNew York, NY 10016, eU.SA. I-4 yeSebe le-Psychiatry, iYunivesithi yaseNew York yeSikolo sezoNyango, eNew York, NY, eU.SA. I-5 yeYunivesithi yaseNew York i-Comrehensive Epilepsy Centre, i-550 First Avenue, eNew York, NY 10016, eU.SA.