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NEUROPHARMACOLOGY

Regulation of Blood-Brain Barrier Na,K,2Cl-Cotransporter through Phosphorylation during in Vitro Stroke Conditions and Nicotine Exposure

Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas

Nicotine, a major constituent of tobacco smoke, has important effects on brain recovery after focal ischemia (Wang et al., 1997). The purpose of this work is to systematically test the effects of nicotine during stroke conditions on blood-brain barrier (BBB) potassium transport, protein expression of the Na,K,2Cl-cotransporter (NKCC), and cell signaling pathways that control NKCC activity at the BBB. Confluent bovine brain microvessel endothelial cells (BBMECs) were exposed to both a hypoxic/aglycemic (H/A) environment to model BBB function during stroke conditions and nicotine and cotinine (N/C) to model plasma levels seen in smokers. BBMECs exhibit both Na,K-ATPase and NKCC activity (60 and 34 nmol/min/g, respectively) that contribute to 98% of the K⁺ uptake in cultured endothelial cells. An adaptive up-regulation of NKCC activity was identified to occur on the basolateral surface of the BBB after in vitro stroke conditions. Twenty-four hours of N/C exposure, at doses equivalent to plasma levels of smokers, combined with 6 h of H/A, reduced NKCC protein expression and total NKCC activity (shown by bumetanide-sensitive ⁸⁶RB uptake) compared with 6 h of H/A alone (P < 0.01). Basolateral K⁺ transport was found to be modulated by nicotinic acetylcholine receptors expressed at the BBB. NKCC activity on the basolateral surface of the BBB is controlled by an ongoing phosphorylation/dephosphorylation processes. We have identified a potential mechanism in altered BBB response to stroke conditions with prior N/C exposure directly implicating damage to brain-to-blood K⁺ transport mediated at the BBB and perhaps neuronal recovery after stroke.

Address correspondence to: Dr. Thomas J. Abbruscato, Texas Tech University Heath Sciences Center, School of Pharmacy, 1300 Coulter, Amarillo, TX 79106. E-mail: tja{at}ama.ttuhsc.edu

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