Effects of GABA(A) receptor blockade on regional cerebral blood flow and blood-brain barrier disruption in focal cerebral ischemia

Abstract

In cerebral ischemia, transmission by the inhibitory neurotransmitter, γ-aminobutyric acid (GABA) is altered. This study was performed to determine whether blockade of GABA(A) receptor would affect regional cerebral blood flow (rCBF) and blood-brain barrier (BBB) permeability in a focal ischemic area of the brain. Rats were anesthetized with isoflurane and mechanically ventilated. Fifteen minutes after a permanent middle cerebral artery (MCA) occlusion, one half of the rats were infused with bicuculline 1mg/kg/min iv for 2 min followed by 0.1mg/kg/min iv to the end of the experiment. The other half were infused with normal saline. At one hour after MCA occlusion, rCBF was determined using ¹⁴C-iodoantipyrine and BBB permeability was determined by measuring the transfer coefficient (Ki) of ¹⁴C-α-aminoisobutyric acid. With MCA occlusion, rCBF was decreased in the ischemic cortex (IC) (-70%) in the control rats. In the bicuculline treated rats, the rCBF of the IC was lower (-48%) than the contralateral cortex but higher than the rCBF of the IC of the control rats (+55%). MCA occlusion increased Ki in the IC of the control rats (+72%) and bicuculline administration increased Ki further (+53%) in the IC. Blockade of GABA(A) receptors did not significantly affect rCBF or BBB permeability in the non-ischemic brain regions under isoflurane anesthesia. Our data demonstrated that blockade of GABA(A) receptors increased rCBF and enhanced the BBB disruption in focal cerebral ischemia. Our data suggest that GABA(A) receptors are involved, at least in part, in modulating rCBF and BBB disruption in focal cerebral ischemia.