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

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 μL 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.