| Objective:GABA receptors play an important role in ischemic brain injury. Studies have indicated that autophagy is closely related to neurodegenerative diseases. However, during chronic cerebral hypoperfusion, the changes of autophagy in the hippocampal CA1 area, the correlation between GABA receptors and autophagy, and their influences on hippocampal neuronal apoptosis have not been well established.Methods:2VO and OGD-Rep injury of brain slices model were established. The Morris water maze (MWM) was used to evaluate the spatial learning and memory performances of rats. H&E and TUNEL staining was utilized to examine the degenerative changes of hippocampal CA1 area. Western blotting analysis was applied to detect the protein expression.Results:chronic cerebral hypoperfusion resulted in rat hippocampal atrophy, neuronal apoptosis, enhancement and redistribution of autophagy, downregulation of Bcl-2/Bax ratio, elevation of cleaved caspase-3 levels, reduction of surface expression of GABAA receptor al subunit and an increase in surface and mitochondrial expression of connexin 43 (CX43) and CX36. Chronic administration of GABAB receptors agonist baclofen significantly alleviated neuronal damage. Meanwhile, baclofen could up-regulate the ratio of Bcl-2/Bax and increase the activation of Akt, GSK-3p and ERK which suppressed cytodestructive autophagy. The study also provided evidence that baclofen could attenuate the decrease in surface expression of GABAA receptor al subunit, and down-regulate surface and mitochondrial expression of CX43 and CX36, which might enhance protective autophagy. In addition, Baclofen could attenuate 2VO-induced damage of autophagosomes retrograde transport and lysosome function. However, the mechanism remains to be fully elucidated.Conclusion:The current findings suggested that, under chronic cerebral hypoperfusion, the effects of GABAB receptors activation on autophagy regulation could reverse neuronal damage. |
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