Page - (000281) - in Biomedical Chemistry: Current Trends and Developments

NMDA receptors located outside the synapse (extrasynaptic NMDA receptors) may initiate different and more damaging molecular cascades than calcium entering neurons via synaptically-located NMDA receptors (Hardingham & Bading, 2010). 3.2.5 The Role of Calcium in Excitotoxic Neuronal Biochemistry Controlled increases in glutamatergic activity can result in increased postsynaptic calcium, which plays a critical role in neuronal processes supporting learning and memory. Over-activation of glutamate receptors, however, can lead to excitotoxic concentrations of calcium. This can lead to neuronal death and degeneration through a variety of molecular mechanisms. Intracellular calcium activates a number of enzymes that can have deleterious effects including phosphatases, proteases, lipases, caspases, and endonucleases and eventually the cell can undergo apoptosis through activation of caspases. Additionally, the NMDA receptor interacts directly with nitric oxide synthase, an enzyme sensitive to calcium influx that induces the production of toxic nitric oxide along with reactive oxygen species (Szydlowska & Tymianski, 2010). One of the earliest findings of pathological excitotoxicity was the release of glutamate into extracellular space minutes after spinal cord injury by neurons that were at the site of injury. This non-controlled glutamate release can stimulate glutamate receptors, further stimulating the local cohort of neurons. In stroke patients, blood flow is reduced to inadequate levels and the concentration of extracellular glutamate rises, causing uncontrolled excitation of glutamate receptors. This excitatory insult is thought to be exacerbated by a lack of oxygen and glucose to power the machinery to remove the glutamate from the effected area. The effect of the increased concentrations of glutamate in the extracellular space is that neurons are strongly depolarized to the point where the removal of the magnesium ion that normally blocks NMDA receptors occurs. This, of course, then results in uncontrolled calcium entry through the NMDA receptors into a previously unaffected neuron, thus propagating the cellular insult. In addition, it has been shown that