Page - (000286) - in Biomedical Chemistry: Current Trends and Developments

symptoms are often accompanied by cognitive decline. The cause of the disease is a mutation in the gene that encodes the huntington protein, which results in the production of a longer than normal sequence of glutamine residues at the N-terminus of the protein (Okamoto, 2009). Although the exact mechanism by which the mutation causes the progressive death of these neurons remains unknown, some evidence suggests that the mechanism may be a dysregulation in expression of NMDA receptors at synapses and, more importantly, expression of these receptors at extrasynaptic locations. When intracellular calcium concentrations are increased due to extrasynaptic NMDA receptor activity, the calcium appears to trigger different downstream cascades than calcium ions that enter the neuron through synaptic NMDA receptors. As discussed previously, controlled increases in calcium that result from synaptic activity can activate beneficial, synapse building pathways; equivalent increases through extrasynaptic NMDA receptor activity were shown to cause disruptions to mitochondrial membrane potential and cell death (Hardingham & Bading, 2010; Milnerwood, 2010). It has been suggested that weak glutamate antagonists such as memantine, or NR2B subunit specific antagonists, may provide a clinically relevant outcome if they can be designed to block extrasynaptic NMDA receptors without preventing normal synaptic NMDA receptor activity (Mony, 2009). 3.2.6.5 Stroke During a stroke, the blood flow to part of the brain is disrupted either due to a blockage in a blood vessel feeding the brain (ischemic stroke) or due to a rupture in one of these vessels (hemorrhagic stroke). Neurons in the area of the brain that are supplied by the affected vessel are often deprived of the required supply of oxygen and glucose and are thus unable to continue operating the energy-demanding ion transporters that establish the negative membrane potential. With a loss of these pumps, the membrane begins to depolarize and when it has sufficiently depolarized to the point that magnesium plugs have been ejected from the NMDA receptors, calcium ions enter the neuron at the slightest exposure to glutamate. As already discussed, this calcium entry then