Search

Up-regulation of proBDNF in ischemic brain and the detrimental role of proBDNF on cellular survival has already been established. We propose that the up-regulated proBDNF may trigger the harmful events and evoke a secondary ischemic damage after ischemia. This study aimed to establish the neuroprotective effects of anti-proBDNF antibody in a rat photothrombotic ischemic model. Photothrombotic ischemic model was performed on Sprague Dawley rats and anti-proBDNF antibodies were administered intraperitoneally to the ischemic rats at a dose of 5 mg/kg after 6 hours (6 h) and on 3 days (3d) after ischemia. Behavioural tests were performed for sensorimotor functional analyses. Animals were euthanized at 7d for histochemical and biochemical studies. We observed higher proBDNF expression around the ischemic infarct. Higher level of apoptosis and inflammation was evident at 7d after ischemia on brain sections. Interestingly, the anti-proBDNF treatment instigated significant reduction of the infarction size as detected by Haematoxylin and Eosin (H&E) staining. Similar reduction of apoptotic signaling proteins in western blot and immunostaining after anti-proBDNF treatment was found. Up-regulation of synaptic protein expression was also observed after this treatment. Significant sensorimotor functional improvements were also noticed at 7d after anti-proBDNF treatment. We conclude that anti-proBDNF treatment is anti-apoptotic and anti-inflammatory, and plays advantageous role in promoting cellular growth and improving sensorimotor function after ischemic insult. Taken together, our study suggests that this anti-proBDNF treatment can be considered as a therapeutic approach for ischemic recovery., (Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.)

Brain derived neurotrophic factor (BDNF) is a member of the neurotrophin family, best characterized for its survival and differentiative effects in the central nervous system. Pro-BDNF, known as the precursor of BDNF, is believed to have opposite functions to mature BDNF (mBDNF). The opposing effects of Pro-BDNF and mBDNF have led researchers to propose a 'yin' (Pro-BDNF) and 'yang' (mBDNF) model of which, the specific mechanism of its opposing functions is unclear and requires further investigation. In order to elucidate pro-BDNF's explicit role, we established a pro-BDNF knockout (KO) mouse model. This BDNF pro-domain KO mouse model showed significant weight loss, impaired righting reflex, abnormal motor behaviours and short lifespan (less than 22 days), mimicking a Huntington's disease (HD)-like phenotype. ELISA results showed BDNF pro-domain KO not only blocked pro-BDNF, but also significantly affected the level of mBDNF. Abnormal morphologic changes were found in the dentate gyrus (DG) of the hippocampus in pro-BDNF KO mice, and western blot confirmed significant cell apoptosis in pro-BDNF KO mice brains. Furthermore, the expression of glutamic acid decarboxylase 65/67 (GAD65/67) was significantly reduced in pro-BDNF KO mice, indicating impaired inhibitory neurotransmission. Heterozygous (Het) mice showed impaired learning and memory capability and depressive-like behaviours, compared with wild type (WT) mice. Overall, these results support that pro-domain of BDNF is an indispensable part of the BDNF gene; without the proper formation of pro-BDNF, mBDNF cannot be produced successfully and function correctly on its own. Our study also supports the BDNF hypothesis in the pathogenesis of HD., (Copyright © 2020. Published by Elsevier Ltd.)