Abstract
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. Here, we found that chronic cerebral hypoperfusion resulted in rat hippocampal atrophy, neuronal apoptosis, enhancement and redistribution of autophagy, down-regulation of Bcl-2/Bax ratio, elevation of cleaved caspase-3 levels, reduction of surface expression of GABAA receptor α1 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-3β and ERK which suppressed cytodestructive autophagy. The study also provided evidence that baclofen could attenuate the decrease in surface expression of GABAA receptor α1 subunit, and down-regulate surface and mitochondrial expression of CX43 and CX36, which might enhance protective autophagy. The current findings suggested that, under chronic cerebral hypoperfusion, the effects of GABAB receptors activation on autophagy regulation could reverse neuronal damage.
Highlights
Stress may promote cell death[5,6]
We found that, in the brain slice model of oxygen-glucose deprivation (OGD)-Rep injury, the LC3 immunoreactivity was robustly elevated compared with sham group, whereas in the OGD-Rep+ baclofen (100 μ M) group, the LC3 immunoreactivity was declined towards basal levels
To investigate whether autophagy is involved in the neuroprotection of GABAB receptors activation under chronic cerebral hypoperfusion, we firstly examined the activation of autophagy in cortex and hippocampal cornu ammonis 1 (CA1) area
Summary
Stress may promote cell death[5,6]. More importantly, studies have reported that autophagy can play both beneficial and detrimental roles in many pathological conditions, such as cancer[7] and cardiac ischemia[8]. GABAA and GABAB receptors have been shown to play a neuroprotective role in experimental models of middle cerebral artery occlusion (MCAO)[30], transient brain ischemia[31,32,33,34,35,36] and oxygen-glucose deprivation (OGD)[31,32,37,38,39,40]. Little is known about the co-regulation of GABAB receptors and GABAA receptors and the influences of them on autophagy in the hippocampal CA1 area under chronic cerebral hypoperfusion. We used a rat model of chronic cerebral hypoperfusion induced by permanent occlusion of bilateral common carotid arteries (2VO) to evaluate the changes of autophagy and the influences of them on neuronal apoptosis in the hippocampal CA1 area. We investigated the possible mechanisms of correlation between GABAB receptors, GABAA receptors and autophagy in the hippocampal CA1 area of 2VO rats
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