Chronic treatment with adenosine A1 receptor antagonist promotes neurogenesis and improves outcome after cerebral ischemia

Adenosine A1 receptors (A1ARs) are promising targets for stroke treatment, potentially due to their relatively unexplored effects on proliferation and differentiation of newborn neurons. In this study, we investigated the impact of chronic treatment with the A1ARs antagonist DPCPX on neurogenesis following MCAO in rodents, using PET with [¹⁸F]FLT in rats and immunohistochemistry in mice. In addition, we assessed the therapeutic properties of DPCPX on stroke recovery with a comprehensive battery of neurological and behavioral tests. The outcome shows that blocking A1ARs signaling with DPCPX improved immunohistochemical results in 8 to 28 days after MCAO in mice. PET imaging with [¹⁸F]FLT revealed an increase in cellular proliferation following DPCPX treatment in the subventricular zone at day 8 post-ischemia in rats, a result further supported by IHC in SVZ of ischemic animals. Furthermore, DPCPX enhanced the production and integration of newborn neurons while reducing astrocytic differentiation in the ischemic areas. Finally, behavioral tests showed that chronic treatment with DPCPX ameliorated motor and memory deficits after brain ischemia. All taken in consideration, our results provide novel and compelling evidence of the therapeutic potential of the A1AR antagonist DPCPX for ischemic stroke recovery.