Estrogen synthesis in the central nucleus of the amygdala following middle cerebral artery occlusion: Role in modulating neurotransmission

Stroke-induced lesions of the insular cortex in the brain have been linked to autonomic dysfunction (sympatho-excitation) leading to arrhythmogenesis and sudden cardiac death. In experimental models, systemic estrogen administration in male rats has been shown to reduce stroke-induced cell death in the insular cortex as well as prevent sympatho-excitation. The central nucleus of the amygdala has been postulated to mediate sympathoexcitatory output from the insular cortex. We therefore set out to determine if endogenous estrogen levels within the central nucleus of the amygdala are altered following stroke and if microinjection of estrogen into the central nucleus of the amygdala modulates autonomic tone. Plasma estrogen concentrations were not altered by middle cerebral artery occlusion (22.86 +/- 0.14 pg/ml vs. 21.24 +/- 0.33 pg/ml; P>0.05). In contrast, estrogen concentrations in the central nucleus of the amygdala increased significantly following middle cerebral artery occlusion (from 20.83 +/- 0.54 pg/ml to 76.67 +/- 1.59 pg/ml; P<0.05). Local infusion of an aromatase inhibitor, letrozole, into the central nucleus of the amygdala at the time of middle cerebral artery occlusion prevented the increase in estrogen concentration suggesting that this increase was dependent on aromatization from testosterone. Furthermore, bilateral microinjection of estrogen (0.5 mu M in 200 nl) directly into the central nucleus of the amygdala significantly decreased arterial pressure and sympathetic tone and increased baroreflex sensitivity, and these effects were enhanced following co-injection with either an N-methyl-D-aspartate or non-N-methyl-D-aspartate receptor antagonist. Taken together, the results suggest that middle cerebral artery occlusion resulted in synthesis of estrogen within the central nucleus of the amygdala and that this enhanced estrogen level may act to attenuate overstimulation of central nucleus of the amygdala neurons to prevent middle cerebral artery occlusion-induced autonomic dysfunction. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.