Page - (000282) - in Biomedical Chemistry: Current Trends and Developments

the NMDA receptors found on oligodendrocytes, the cells that provide myelin sheaths the axons in the CNS, are activated as well, thereby exacerbating excitotoxicity. Once in the cell, the increased calcium activates kinases, but also has an effect on mitochondria. In response to high calcium, the mitochondrial permeability transition pore is opened and it is presently thought that pore opening may allow the release of reactive oxygen species, further contributing to apoptosis and slowing or halting the local production of adenosine triphosphate (ATP). Lack of ATP quickly eliminates the electrochemical gradient across the membrane of some ions, which in turn shuts down glutamate transporters, the proteins that remove glutamate from extracellular space, to terminate glutamatergic signaling. The result of this excitotoxic cascade is the accumulation of glutamate in the extracellular milieu which can spread to neighboring neurons. 3.2.6 Diseases that are Potentially Exacerbated by Calcium- mediated Excitotoxicity 3.2.6.1 Amyotrophic Lateral Sclerosis (ALS) Calcium dysregulation is a central factor in the incurable neurodegenerative disorder ALS (Grosskreutz, 2010). This disorder results in muscle atrophy followed by paralysis and eventual death of patients 3-5 years after the presentation of symptoms. The underlying cause of ALS is the selective degeneration of motor neurons in the spinal cord and brain stem as well as the motor cortex. Degeneration of these cells results in difficulty of movement, speech, and swallowing and progresses to problems with respiratory function. A dismaying psychological factor is that patients with ALS typically suffer no cognitive deficit and are thus fully cognizant of their own demise as the disease progresses inexorably toward death. Present numbers on the prevalence of ALS indicate that the adult lifetime risk for ALS is near 1 in 400, a number which is similar to that for multiple sclerosis (Benatar & Wuu, 2012). The best known genetic factor for familial ALS, occurring in about