Baclofen mediates neuroprotection on hippocampal CA1 pyramidal cells through the regulation of autophagy under chronic cerebral hypoperfusion

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.

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

“…Baclofen, a GABABR agonist, improved the down-regulation of GABABR2 expression associated with cognitive impairment and special working memory impairment , while also reversed neuronal damage with autophagy regulation under chronic cerebral hypoperfusion (Liu et al, 2015). Similar to our synaptic results, AP2-associated protein kinase 1 (AAK1) expression was significantly reduced in the hippocampal CA1 region under chronic cerebral hypoperfusion, which could be restored by baclofen to the control level (Li et al, 2014) (Fig.…”

Baclofen Protects Primary Rat Retinal Ganglion Cells from Chemical Hypoxia-Induced Apoptosis Through the Akt and PERK Pathways

“…It has been reported that the upregulation of GABA B receptor activity could inhibit NMDA-receptor-mediated nitric oxide (NO) production by neuronal NO synthase (nNOS) in brain ischemic injury (Zhou et al, 2008). Recent studies have revealed that, under chronic cerebral hypoperfusion, the effects of GABA B receptors activated by baclofen could reverse neuronal damage by increasing the activation of Akt, GSK-3β and ERK and upregulating the bcl-2/bax ratio, which suppress cytodestructive autophagy (Liu et al, 2015). Another study has shown that baclofen markedly improves memory impairment and alleviates neuronal damage in chronic ischemic rats by increasing the expression and regulating the function of the TPR-containing Rab8b-interacting protein (TRIP8b; Li et al, 2014b).…”

Inhibition of MicroRNA-96 Ameliorates Cognitive Impairment and Inactivation Autophagy Following Chronic Cerebral Hypoperfusion in the Rat

“…Many studies have reported that autophagy is essential for cells in response to fluctuating environments during acute ischemia or CCH. For example, the level of LC3 is increased at 2 or 5 weeks after CCH [8,9]. In addition, the levels of LC3 and beclin-1 and the number of autophagosomes are increased at 8 weeks after 2VO surgery.…”

“…For example, the accumulation of autophagic vacuoles and elevated microtubule-associated protein 1 light chain 3 (LC3) levels were found in the cortex of 2VO rats at 2 weeks after surgery [8]. Liu et al reported that the level of LC3 was significantly increased in both the cortex and hippocampal CA1 area of 2VO rats at 5 weeks after surgery, and GABA receptors reversed the neuronal damage by activating autophagy [9]. These studies suggested that autophagy may play a critical role in CCH-induced brain damage.…”