Neuroprotective progesterone potential

Poremećena moždana cirkulacija, koja je karakteristična za starenje i mnoga cerebrovaskularna i/ili neurodegenerativna oboljenja, povezuje se sa prooksidativnim i proapoptotskim promenama mnogobrojnih biomolekula, uključujući lipide, proteine i DNK, i narušavanjem strukture i funkcije ćelija prečeone moždane kore (PFC) i hipokampusa (HIPP). Do sada je testiran efekat brojnih jedinjenja da bi se ublažile posledice narušenog protoka krvi kroz moždano tkivo, ali adekvatna terapija još uvek nije dostupna. Ipak, kao jedan od mogućih terapeutika, izdvaja se steroidni hormon, progesteron (pregn-4-en-3,20-dion, P4), za kojeg je pokazano da ispoljava zaštitne efekte u mnogim životinjskim eksperimentalnim modelima kojima se oponašaju pojedini aspekti poremećaja strukture i funkcije moždanih ćelija primećeni kod starijih ljudi i obolelih od cerebrovaskularnih i/ili neurodegenerativnih bolesti. Stoga, fokus ovog rada je pružanje mogućnosti boljeg razumevanja molekulskih mehanizama delovanja P4 u mozgu u fiziološkom stanju, kao i terapijskog potencijala koji iskazuje u animalnim modelima cerebrovaskularnih i neurodegenerativnih bolesti, sa posebnim osvrtom na trajnu moždanu hipoperfuziju (MH) gde pokazuje regionalno-specifično dejstvo. Iako se P4, za sada, u humanoj populaciji pokazao kao neadekvatan terapeutik u lečenju patološkog stanja povezanog sa poremećenom moždanom cirkulacijom, dodatne kliničke studije bi obezbedile saznanja o efektu ovog potentnog neurosteroida kod obolelih od drugih cerebrovaskularnih i/ili neurodegenerativnih bolesti, dok bi u slučaju ohrabrujućih rezultata, P4 terapija mogla znatno olakšati kvalitet života obolelih.Disturbed cerebral circulation, characteristic for aging and many cerebrovascular and/or neurodegenerative diseases, is associated with prooxidative and proapoptotic changes of various biomolecules, including lipids, proteins and DNA, and with compromised cell structure and function in prefrontal cortex (PFC) and hippocampus (HIPP). Numerous compounds, until today, have been tested to alleviate the outcomes of impaired blood flow through brain tissue, but adequate therapy is not yet available. However, one of the possible therapeutics is singled out, the steroid hormone, progesterone (pregn-4-en-3,20-dione, P4), which has been shown to exert protective effects in many animal experimental models that mimic certain aspects of brain structural and functional changes observed in the elderly and those suffering from cerebrovascular and/or neurodegenerative diseases. Therefore, this paper is focused on providing a better understanding of physiological P4-mediated brain molecular mechanisms, as well as its therapeutic potential in animal models of cerebrovascular and neurodegenerative diseases with the emphasis on permanent cerebral hypoperfusion (CH) where the regional-specific response is observed. Although P4 is shown as inadequate for treating a pathological condition associated with disturbed cerebral circulation, additional clinical studies would provide insights into the potential therapeutic capacity of this potent neurosteroid in other cerebrovascular and/or neurodegenerative diseases and conditions. In the case of encouraging results, P4 therapy could significantly improve the quality of patients’ life