ATP Stimulation Promotes Functional Recovery after Intracerebral Haemorrhage by Increasing the mBDNF/proBDNF Ratio

摘要

Brain-derived neurotrophic factor (BDNF), including mature BDNF (mBDNF) and precursor BDNF (proBDNF), plays a pivotal role in neuronal survival, synaptic plasticity and neurogenesis. However, the functional effect of the mBDNF/proBDNF ratio in haemorrhagic stroke remains unclear. ATP is a known mediator of BDNF production in neurons and glia. Therefore, we hypothesized that ATP could facilitate BDNF production, increase the mBDNF/proBDNF ratio and thereby alleviate cerebral haemorrhage-induced injury. In this experiment, a model of intracerebral haemorrhage (ICH) was produced by injecting 50 mu L autologous blood into the right corpus striatum in healthy male rats. ATP was injected to promote BDNF production and increase the mBDNF/proBDNF ratio. After ATP pretreatment, P2X4R-shRNA and SB203580 were used to inhibit P2X4R and p38-MAPK, respectively. We provide direct evidence that ATP administration was successful in promoting mBDNF expression and increasing the mBDNF/proBDNF ratio after ICH injury. Additionally, ATP stimulation could significantly improve cerebral neurological function and alleviate neuronal damage. Furthermore, ATP injection was able to upregulate the expression of P2X4R and p-p38-MAPK. Moreover, both P2X4R-shRNA and SB203580 could effectively abolish the effect of ATP injection on the levels of P2X4R and p-p38-MAPK and the mBDNF/proBDNF ratio. Together, these findings show that ATP stimulation contributes to functional recovery after cerebral haemorrhage and that neuroprotection induced by ATP administration in ICH rats is accompanied by a strong increase in the mBDNF/ proBDNF ratio. Here, we also show a significant role of P2X4R-p38-MAPK signalling in the ATP-induced increase in the mBDNF/proBDNF ratio in ICH. (C) 2021 IBRO. Published by Elsevier Ltd. All rights reserved.