Uticaj malih doza spironolaktona na inflamatorni odgovor prouzrokovan reperfuzijom moždanog tkiva u eksperimentalnom mišjem modelu ishemičnog moždanog udara

Abstract

Ishemični moždani udar predstavlja drugi uzrok smrtnosti i prvi uzrok trajnog invaliditeta u razvijenim zemljama. Visoka cena lečenja i rehabilitacije ovih pacijenata svrstava moždani udar u jedan od najvećih socioekonomskih problema današnjeg društva. Glavni nedostaci primene trombolitičke terapije, kao jedine odobrene terapije moždanog udara, su kratak prozor delovanja, reperfuziono oštećenje i hemoragija. U osnovi svih komplikacija trombolitičke terapije nalazi se jak inflamatorni odgovor tkiva nastao naglom rekanalizacijom krvnog suda. Upotreba malih doza spironolaktona nakon reperfuzije kod eksperimentalnog mišjeg modela ishemičnog moždanog udara pokazala je značajno smanjenje ekspresije inflamatornih medijatora (citokina, hemokina, slobodnih radikala i adhezionih molekula) endotelnih ćelija i celog tkiva mozga kao rezultat stabilizacije NF-κB-IκBα kompleksa i onemogućavanje relokalizacije transkripcionog faktora NF-κB u jedro što ima za posledicu smanjenje inflamacije, infarkta i edema mozga, blažih neuroloških oštećenja, brži oporavak i smanjenje smrtnosti. Rezultati ove studije otkrivaju do sada nepoznatu ulogu spironolaktona u modulisanju inflamatornog odgovora endotelnih ćelija mozga, kao i molekularni mehanizam ovog dejstva na ishemično reperfuziono oštećenje nakon eksperimentalnog mišjeg modela moždanog udara otvarajući mogućnost korišćenja ovog dobro poznatog leka u terapiji moždanog udara i drugih inflamatornih stanja endotela koja favorizuju nastanak moždanog udara.

Stroke is one of the most frequent causes of death and disability worldwide, and has significant clinical and socioeconomic impact. Recombinant tissue plasminogen activator (rtPA) is currently the only drug approved for treatment of acute stroke. However, thrombolytic therapy with rtPA can be associated with a number of complications. Many of the rtPA related complications result from its thrombolytic action including bleeding (intracerebral and systemic haemorrhage), reperfusion injury with oedema, and angioedema. Beside all this complications is profound tissue inflammatory response following recanalization of occluded vessel. In our study, the administration of a low dose Spironolactone showed strong anti-inflammatory effects at the brain endothelial cells and whole brain tissue, blocking cytokine, chemokine, reactive oxygen species and adhesion molecule expression, after experimental model of stroke in in vivo and in vitro experiments. Animals treated with low dose Spironolactone during the onset of reperfusion exhibit less brain edema, smaller infarct volume and mortality rate, better neurological scores and better stroke recovery. This effect of Spironolactone was achieved by diminishing the activity of NF B transcription  factor in brain endothelial cells, a master regulator of pro-inflammatory cytokine/chemokine/adhesion molecule expression during the ischemia-reperfusion injury. Anti-inflammatory effect of low dose- Spironolactone treatment on ischemia-reperfusion injury after stroke based on its effects in this study represents for the first time a potential of Mineralocorticoid receptor antagonist Spironolactone in prevention and stroke therapy.