Sustained Baclofen-Induced Activation of GABA B Receptors After Cerebral Ischemia Restores Receptor Expression and Function and Limits Progressing Loss of Neurons

Abstract

One important function of GABA _B receptors is the control of neuronal activity to prevent overexcitation and thereby excitotoxic death, which is a hallmark of cerebral ischemia. Consequently, sustained activation of GABA _B receptors with the selective agonist baclofen provides neuroprotection in in vitro and in vivo models of cerebral ischemia. However, excitotoxic conditions severely downregulate the receptors, which would compromise the neuroprotective effectiveness of baclofen. On the other hand, recent work suggests that sustained activation of GABA _B receptors stabilizes receptor expression. Therefore, we addressed the question whether sustained activation of GABA _B receptors reduces downregulation of the receptor under excitotoxic conditions and thereby preserves GABA _B receptor-mediated inhibition. In cultured neurons subjected to oxygen and glucose deprivation (OGD), to mimic cerebral ischemia, GABA _B receptors were severely downregulated. Treatment of the cultures with baclofen after OGD restored GABA _B receptor expression and reduced loss of neurons. Restoration of GABA _B receptors was due to enhanced fast recycling of the receptors, which reduced OGD-induced sorting of the receptors to lysosomal degradation. Utilizing the middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia, we verified the severe downregulation of GABA _B receptors in the affected cortex and a partial restoration of the receptors after systemic injection of baclofen. Restored receptor expression recovered GABA _B receptor-mediated currents, normalized the enhanced neuronal excitability observed after MCAO and limited progressive loss of neurons. These results suggest that baclofen-induced restoration of GABA _B receptors provides the basis for the neuroprotective activity of baclofen after an ischemic insult. Since GABA _B receptors regulate multiple beneficial pathways, they are promising targets for a neuroprotective strategy in acute cerebral ischemia.

Keywords: GABAB receptor; MCAO; OGD; baclofen; cerebral ischemia; neuroprotection.