GABAB receptor antagonist promotes hippocampal neurogenesis and facilitates cognitive function recovery following acute cerebral ischemia in mice

Purpose and background: Previous studies have suggested that promoting endogenous neurogenesis has great significance for the recovery of cognitive dysfunction caused by cerebral ischemia (CI). Pharmacological inhibition of GABA_B receptor can enhance neurogenesis in adult healthy and depressed mice. In the study, we intended to investigate the effects of GABA_B receptor antagonists on cognitive function and hippocampal neurogenesis in mice following CI.

Methods: Adult mice were subjected to bilateral common carotid artery occlusion (BCCAO) for 20 min to induce CI and treated with CGP52432 (antagonist of GABA_B receptor, CGP, 10 mg/kg intraperitoneal injection) starting 24 h after CI. The Morris water maze test was performed to test spatial learning and memory at day 28. Immunofluorescence was applied to detect neurogenesis in the DG region at day 14 and 28. In in vitro experiments, cell proliferation was detected by CCK8 and immunofluorescence, and the expression of cAMP/CREB signaling pathway-related proteins was detected by ELISA assay and Western blot.

Results: CGP significantly improved spatial learning and memory disorders caused by CI, and it enhanced the proliferation of neural stem cells (NSCs), the number of immature neurons, and the differentiation from newborn cells to neurons. In vitro experiments further confirmed that CGP dose-dependently enhanced the cell viability of NSCs, and immunofluorescence staining showed that CGP promoted the proliferation of NSCs. In addition, treatment with CGP increased the expression of cAMP, PKA, and pCREB in cultured NSCs.

Conclusion: Inhibition of GABA_B receptor can effectively promote hippocampal neurogenesis and improve spatial learning and memory in adult mice following CI.