Seite - (000288) - in Biomedical Chemistry: Current Trends and Developments

The progression of Parkinson’s disease involves the loss of the dopaminergic neurons in the substantia nigra. These neurons help control muscle movement and as they degenerate, patients lose control of voluntary and spontaneous muscle movement presenting symptoms that include resting tremors, slowed movement, difficulty with movement, and balance problems. In addition, a number of cognitive symptoms typically develop as the disease progresses, including memory loss, depression, and eventually dementia. The mechanism behind the initial neuronal degeneration is only known in a small percentage of cases, termed familial Parkinson’s, which has been linked to an inherited genetic mutation. However, like AD, most other cases are sporadic Parkinson’s and there is no known cause. However, recent research has implicated glutamate excitotoxicity as a factor as the reduction in dopaminergic transmission leads to a loss of regulation of striatal neurons, resulting in an in increase in glutamatergic activity (Koutsilieri & Riederer, 2007; Meissner, 2011; Mony, 2009). A logical method to prevent glutamate-mediated excitotoxicity is to prevent glutamate release and/or binding to the iGluRs. Recent experimental treatments have included drugs that do just this (Meissner, 2011). The results have interestingly demonstrated that, in animal models of Parkinson’s, a shift in the subunit composition of the NMDA receptor is found, which is thought to be a potential excitotoxic mechanism. L-DOPA treatment was shown to alter NMDA receptor subunit composition as well, leading to L-DOPA induced dyskinesia. Unfortunately, though general NMDA receptor antagonists have been found to be successful in treating both Parkinsonian and dyskinesia symptoms in animal models of the disease, the side effects of these agents in humans preclude their use in the clinic. In an effort to circumvent these side effects, drug developers have focused on compounds targeted to the NR2B subunit of the NMDA receptor. One such compound, CP-101,606 (Traxoprodil) worked well for the treatment of both Parkinsonian and dyskinetic symptoms in animal models, but in human trials only appeared to treat dyskinetic symptoms (Koutsilieri & Riederer, 2007; Mony, 2009). 3.2.6.7 Traumatic Brain or Spinal Cord Injury