Page - (000287) - in Biomedical Chemistry: Current Trends and Developments

initiates excitotoxic molecular mechanisms (Lipton, 2006). After a stroke, excess calcium is also able to enter neurons by a non- glutamate receptor pathway. The Transient Receptor Potential (TRP) channels allow calcium to enter neurons in response to ischemic-linked changes in extracellular levels of divalent cations, pH, and levels of reactive oxygen species. Further, the stored calcium that is normally localized to the endoplasmic reticulum or mitochondria may also be released into the cytoplasm following ischemia, further exacerbating the condition by increasing the concentration of calcium in the neuronal cytoplasm (Szydlowska & Tymianski, 2010). A number of drugs have been developed specifically to treat excitotoxicity in the aftermath of stroke and, for the most part, they are aimed at preventing calcium entry into neurons or by targeting downstream molecules involved in the excitotoxic cascade, but clinical trials have been largely unsuccessful. These compounds include glutamate receptor antagonists, glutamate release blockers, nitric oxide synthase inhibitors, and free radical scavengers that are designed to prevent oxidative damage. Most of these agents that have been tested unfortunately have been ineffective or have had intolerable side effects precluding their use in the clinic (Lau & Tymianski, 2010). An additional molecular factor that may increase the excitotoxic effects of stroke is an upregulation of calcium-permeable AMPA receptors. As described in the introduction to glutamate receptors previously, most AMPA receptors contain a GluA2 subunit that prevents calcium from passing through the ion channel. However, following some types of ischemic events, it has been found that the expression of GluA2 mRNA is reduced; suggesting that there could be an increased expression of calcium-permeable AMPA receptors (i.e. those that lack the GluA2 subunit) would result. An increase in these receptors offers yet another possible means for calcium to enter into neurons already suffering from hyperactivation, leading to abnormally long periods of depolarization and excessive calcium influx (Lau & Tymianski, 2010). 3.2.6.6 Parkinson’s Disease