Neuroprotection by Lowering Cholesterol
In stroke, cerebral hypoxia/ischemia, and traumatic brain injury, the development of neurotoxocity is provoked by enhanced extracellular glutamate, which is released from nerve cells mainly by glutamate transporter reversal—a distinctive feature of these pathological states. Transporter-mediated glutamate release from the synaptosomes: (1) stimulated by depolarization of the plasma membrane; (2) by means of heteroexchange with competitive transportable inhibitor of glutamate transporters DL-threo-β-hydroxyaspartate; (3) in low-[Na+] medium; and (4) during dissipation of the proton gradient of synaptic vesicles by the protonophore FCCP; was decreased under conditions of cholesterol deficiency by approximately 24, 28, 40, 17%, respectively.
A decrease in the level of membrane cholesterol attenuated transporter-mediated glutamate release from nerve terminals. Therefore, lowering cholesterol may be used in neuroprotection in stroke, ischemia, and traumatic brain injury that are associated with an increase in glutamate uptake reversal. This data can explain the neuroprotective effects of statins in these pathological states and provide one of the mechanisms of their neuroprotective action. However, besides these disorders lowering cholesterol may cause harmful consequences decreasing glutamate uptake by nerve terminals.
KeywordsTraumatic Brain Injury Synaptic Vesicle Nerve Terminal Glutamate Release Glutamate Transporter
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