Monocarboylate Transporter, Intermittent Hypoxia and Stroke

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Sleep-disordered breathing (SDB), a condition affecting up to 15% of aging people is associated with an increased prevalence and severity of ischemic stroke. Furthermore, the functional recovery after stroke in patients with SDB is markedly worse. The mechanisms underlying the increased vulnerability of neural tissue to ischemia in the context of SDB are unknown. However, it has been well established that neurons preferentially use monocarboxylates such as lactate and pyruvate as their source of energy, in particular during conditions of limited energy supply such as during a stroke, that astrocytes are the predominant purveyors of such monocarboxylates, and that specific monocarboxylate transporters (MCT) are required to facilitate this process. This application aims to examine the fundamental hypothesis that the intermittent hypoxia during sleep (CIH) that characterizes SDB downregulates the expression of monocarboxylate transporter 2 (MCT2) in neurons, and that such changes increase the vulnerability of neuronal cells to acute hypoxia/ischemia (AHI). Based on exciting and highly confirmatory preliminary findings, we propose to test the validity of this hypothesis, and have developed 3 experimental paradigms, namely: (1) To examine changes in MCT2 and MCT1 expression during CIH and chronic sustained hypoxia (CSH) in the hippocampus and cortex of adult rats and the causal relationship between reduced expression and/or function of MCT2 in stroke models using pharmacological approaches. ; (2) To confirm the role of MCT2 in neuronal survival during AHI using transgenic approaches. ; and (3) To examine the role of MCT2 in the tolerance of neurons to ischemia. These experiments will conclusively demonstrate that CIH increases the susceptibility of neural tissue to AHI, and that such phenomenon is mediated by inappropriate decreases elicited by CIH but not CSH in the expression of MCT2. Furthermore, increased understanding of the role played by MCT in neuronal energy homeostasis and survival may permit future development of pharmacological strategies aiming to reduce infarct size in patients suffering from cerebrovascular accidents.