Effects of 17β-Estradiol on Blood-brain Barrier Disruption in Focal Ischemia during GABA_A Receptor Inhibition

Abstract

We performed this study to determine whether γ-aminobutyric acid (GABA_A) receptor inhibition could reverse the effect of 17β-estradiol on blood-brain barrier (BBB) disruption in focal cerebral ischemia. Young ovariectomized rats were implanted with a 500 µg 17β-estradiol 21-day release pellet or with a vehicle pellet 21 days before the experiments. Forty-five minutes after middle cerebral artery (MCA) occlusion, half of each group was infused with bicuculline (a GABA_A receptor antagonist) 1 mg/kg/min for 2 min followed by 0.1 mg/kg/min up to the end of experiments. The other half was infused with the same volume of normal saline. The transfer coefficient (Ki) of ¹⁴C-α-aminoisobutyric acid and the volume of ³H-dextran distribution (70,000 Daltons) were determined to measure the degree of BBB disruption one hour after MCA occlusion. In the control vehicle -treated animals, the Ki in the ischemic cortex (7.2 ± 2.6 µl/g/min) was higher than in the contralateral cortex (2.5 ± 1.4 µl/g/min ). After bicuculline infusion, the Ki in the ischemic cortex increased (10.6 ± 5.4 µl/g/min ) although the increase was not statistically significant. In the 17β-estradiol treated animals, the Ki in the ischemic cortex (3.8 ± 1.6 µl/g/min) was lower than control vehicle-treated rats. With bicuculline infusion, the Ki in the ischemic cortex (14.5 ± 6.8 µl/g/min) was markedly increased. In the non-ischemic cortex, there was no significant difference in Ki among the experimental groups. The volume of dextran distribution was not significantly different between the experimental groups in the ischemic or non-ischemic cortex. Our data suggests that part of the reason for the decreased BBB disruption in the focal ischemic area after 17β-estradiol treatment could be due to the interaction between GABA_A receptors and 17β-estradiol.

Key words

Brain - Capillary permeability - Estrogen - Stroke - Bicuculline

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