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Research Undertakings

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Hypoglycemia | Cerebral Ischemia | IL-1β and System xc- at the Cross-Roads of Injury and Protection

Hypoglycemia

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Hypoglycemia, more commonly referred to as “low blood sugar”, is a serious medical condition that arises in diabetic mellitus patients attempting to tightly regulate blood glucose levels through the use of insulin or other blood glucose lowering drugs. It is considered to be the limiting factor in the development of strategies that aim to maintain normoglycemia in diabetic patients. In the case of severe hypoglycemia, brain glucose levels can approach zero, resulting in cognitive impairment, seizures, unconsciousness, coma and eventually neuronal cell death. While there is evidence that in both in vitro and in vivo models hypoglycemic neuronal cell death is mediated by glutamate excitotoxicity, the cellular and molecular mechanisms involved remain incompletely defined. Toward this end, our laboratory recently reported that glutamate efflux from astrocytes via the anionic cystine/glutamate antiporter, system xc-, contributed to glucose-deprivation induced neuronal cell death in vitro. Research in the lab is focused on determining the precise mechanism by which system xc- activity links to glutamate-mediated aglycemic neuronal injury.


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Cerebral Ischemia

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The poor prognosis following stroke (i.e., cerebral ischemia)  is exacerbated by the void in treatment options to protect against secondary injury. Previously, we studied the regulation of cyclooxygenase-2 (COX-2) and the therapeutic potential of its inhibition. Our data argue that short-term benefits could be gained in individuals afflicted with acute neurological disorders associated with NMDA receptor over-activation. However, fears associated with the demonstrated increased risk of adverse cardiovascular events associated with prolonged dosing makes it unlikely that selective COX-2 inhibition will be considered a therapeutic option for even acute neurological disease. As brain levels of arachidonic acid (AA) can reach 10-fold higher concentrations during cerebral ischemia than that estimated under normal physiological conditions, modulating AA metabolism should still be considered a viable therapeutic target. Hence, current studies are focused on elucidating the contribution of L- 12/15 Lipoxygenase to the evolution and/or resolution of injury in the damaged brain.


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IL-1β and System xc- at the Cross-Roads of Injury and Protection

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Injury to the brain caused by cerebral ischemia is a major public health concern. Studies have determined that the brain damage associated with cerebral ischemia is mediated by over-stimulation of excitatory amino acid receptors, oxidative stress, as well as inflammatory factors. Previously, our laboratory demonstrated that astrocyte-mediated alterations in system xc- (cystine/glutamate antiporter) activity contributes to the development and progression of inflammatory (IL-1b-enhanced) hypoxic neuronal injury ─a model of the ischemic penumbra. Interestingly, this same transporter has a well-characterized role in the synthesis and maintenance of the antioxidant molecule glutathione (GSH) raising the intriguing possibility that under certain circumstances, IL-1β may upregulate processes that protect against oxidative stress. Hence, we speculate that IL-1β upregulation of astrocyte system xc- may have evolved as a protective mechanism to counteract oxidative stress in injured tissue. However, this increase becomes maladaptive in the setting of compromised glutamate uptake, which occurs in the setting of our hypoxia model in vitro and stroke in vivo. Studies to specifically address these issues, including how system xc- is regulated at the molecular (i.e., transcriptional, post-transcriptional and translational) level, are ongoing. 


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