Mitohondrijalna disfunkcija u mozgu pacova perinatalno tretiranih fenciklidinom - efekat antipsihotika

Abstract

Shizofrenija je neuropsihijatrijski poremećaj sloţene etiologije, sa globalnom prevalencom oko 1%. U terapiji shizofrenije ĉesto je neophodna dugotrajna primena tipiĉnih i/ili atipiĉnih antipsihotika, koji se razlikuju po efikasnosti i imaju razliĉite neţeljene efekte. Postoji veliki broj hipoteza o poreklu bolesti, ali najveći broj istraţivanja govori u prilog neurorazvojne hipoteze prema kojoj poremećaj tokom razvoja mozga dovodi do narušavanja procesa sinaptogeneze i neurotransmisije, pre svega dopaminergiĉkog i glutamatergiĉkog sistema. Fenciklidin (PCP) je nekompetitivni antagonist glutamatskih N-metil-D-aspartat receptora i njegova perinatalna administracija u pacova uzrokuje patofiziološke promene koje odgovaraju patološkim karakteristikama uoĉenim u shizofreniji. Mitohondrije imaju vaţnu ulogu u neurorazvoju i brojne studije povezuju abnormalnosti u strukturi i funkciji mitohondrija sa razvojem shizofrenije. Disfunkcija mitohondrija moţe rezultirati poremećajem u produkciji energije i aktivacijom procesa ćelijske smrti apoptozom i/ili autofagijom. Poremećaji odvijanja procesa apoptoze i autofagije su dokumentovani kod pacijenata obolelih od shizofrenije. Novije studije ukazuju na tesnu povezanost ova dva procesa. MeĊutim, još uvek ostaje nerazjašnjeno da li su uoĉene promene posledica tretmana antipsihoticima ili karakteristika same bolesti. Cilj: UtvrĊivanje neposrednih i dugotrajnih efekata perinatalne primene fenciklidina, kao i efekata haloperidola (tipiĉnog antipsihotika) i klozapina (atipiĉnog antipsihotika) na aktivnost enzima respiratornog lanca, ekspresiju proteinskih markera apoptotoze i autofagije, zastupljenost pojedinih vrsta ćelija nervnog sistema i ultrastrukturne promene u korteksu i hipokampusu pacova. Materijal i metode: Deset grupa Wistar pacova je subkutano tretirano 2, 6, 9. i 12. postnatalnog dana (PN) fenciklidinom (10 mg/kg) ili fiziološkim rastvorom (0.9% NaCl). Jedna NaCl i jedna PCP grupa su ţrtvovane PN13, dok su druge dve NaCl i PCP grupe ţrtvovane PN70. Preostale grupe su ţrtvovane PN100. Od PN35 do PN100, jedna NaCl (NaCI-H) i jedna PCP (PCP-H) grupa su primale haloperidol (1 mg/kg/dan) dok su druga NaCl (NaCl-K) i PCP (PCP-K) grupa primale klozapin (20 mg/kg/dan) rastvoren u vodi za piće. Preostale NaCl (kontrola) i PCP grupa su primale vodu za piće bez rastvorenih supstanci...

Schizophrenia (SCH) is a neuropsychiatric disorder with complex etiology and global prevalence of 1%. Disease usually requires long-term medication with typical and atypical antipsychotics, that have different effectiveness and side effects. There are a number of hypotheses about the origin of SCH, but most research support neurodevelopmental hypothesis according to which alterations during the brain development lead to disturbances of synaptogenesis and neurotransmission, primarily dopaminergic and glutamatergic systems. Phencyclidine (PCP) acts as a non-competitive antagonist of glutamatergic N-methyl-D-aspartate receptors, and its perinatal administration to rats causes pathophysiological changes that mimic some pathological features of schizophrenia. Mitochondria play a crucial role in the neurodevelopment and numerous data indicate that abnormalities in mitochondrial structure and function could be associated with the development of schizophrenia. Mitochondrial dysfunction may affect energy production and could lead to apoptotic cell death and/or autophagy. Altered apoptosis and autophagy processes have been identified in schizophrenia patients. Also, recent investigations indicate that these two processes are tightly correlated. However, remains unclear whether the observed changes are consequence of medication or disease itself. Aim of this study: Assess immediate and long-term effects of perinatal PCP administration, as well as, the effects of typical (haloperidol) and atypical (clozapine) antipsycotics on mitochondrial function determining the activity of respiratory chain enzymes, expression of apoptosis and autophagy markers, density of nervous system cells and ultrastructural changes in the cortex and hippocampus of the rat brain. Material and methods: Ten groups of Wistar rats were subcutaneously treated on 2nd, 6th, 9th and 12th postnatal days (PN), with either PCP (10 mg/kg) or saline (0.9% NaCl). One NaCl and one PCP group were sacrificed on PN13; other two NaCl and PCP groups were sacrificed on PN70...