Improving stroke outcome through increasing the activity of the BDNF/TrkB system
Alhusban, Ahmed Yusuf Ahmed
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Despite significant improvement in our understanding of stroke pathophysiology and management, it is still a leading cause of death and disability worldwide. Interventions directed toward blood pressure reduction have proven beneficial in reducing stroke incidence and recurrence. Extrapolating these possible beneficial effects to the acute phase has been avoided, which limits exploitation of possible blood pressure independent effects of some antihypertensive agents. BDNF has been demonstrated to improve stroke outcome, by its dual ability to induce angiogenesis and neurogenesis. The aim of this work is to assess the interaction between blood pressure reduction with candesartan and BDNF/TrkB mediated improvement in functional outcome after stroke. To achieve this aim, the interaction between candesartan and BDNF was assessed in normotensive and hypertensive animals and in human cerebrovascular endothelial cells (hCMECs). Furthermore, the involvement of BDNF in candesartan induced long-term functional outcome improvement was assessed using shRNA mediated BDNF knockdown in normotensive animals. Additionally, the ability of candesartan to affect BDNF/TrkB activity after stroke was evaluated in hypertensive animals. To dissect the involvement of blood pressure reduction in candesartan mediated effects, a sub-hypotensive dose of candesartan and intervention to override candesartan induced hypotensive effect was also used. Candesartan was found to positively interact with BDNF/TrkB both in vitro and in vivo. This interaction was detected in normotensive and hypertensive animals, without regard to whether they have been exposed to cerebral ischemia or not. Additionally, this positive interaction was demonstrated to be independent of its hypotensive effect. Interestingly, the angiogenic effect of candesartan was found to be mediated by BDNF/TrkB activity which was shown to be modulated by AT2 signaling. In conclusion, the positive interaction between candesartan and BDNF/TrkB is not dependent on its hypotensive effect.