Advanced theranostic nanocarrier-mediated delivery of NGF in a combination therapy trigger enhanced recovery after stroke

Abstract

Background: The majority of people who survive the acute phase of stroke remain permanently disabled. So far, no treatment to improve function exist, nerve growth factor (NGF) has emerged as excellent candidate to boost recovery processes. However, the approach to effective deliver NGF has not been possible since it does not pass the blood brain barrier. Aim: To evaluate if use of an advanced theranostic nano- carrier-mediated delivery of NGF to after stroke enhance recovery of the brain by inducing endogenous repair mechanisms such as neurogenesis and angiogenesis. Method: Transient middle cerebral artery occlusion was induced in male rats for two hours followed by reperfusion. The specific MEK1/2 inhibitor U0126 was administered i.p at 6 and 24 hours and the NGF was given i.v at day 3 post-reperfusion. Neurological functions were assessed up to 4 weeks after stroke and 9.4 T magnetic resonance imaging was used to monitor perfusion and morphological changes. Recovery processes such as neurogenesis and angiogenesis were evaluated at 4 weeks post stroke by Western Blot. Results: The combination therapy with NGF and U0126 significantly improved neurological function, perfusion and recovery processes compared to vehicle and U0126 treat- ment alone. An enhanced NGF protein levels and activa- tion of the TRKa/b signaling pathway in addition to enhanced neurogenesis were observed. Conclusion: NGF delivered by advanced theranostic nanocarrier promotes recovery processes after stroke and most importantly our delivery approach has demonstrated to be successful. This will be the first step that will lead to novel treatment strategies for neurological disorders.