[ashleyk]

Every so often there is another post on a promising drug for stopping Parkinson's but as the thread on CEP-1347 shows, there appears to be, yet again, disappointment. However, there has been a lot of work done with rodents at the NIH and other labs showing that there are drugs which can greatly reduce the progression of PD. Some of these drugs can be used today like dextromethorphan and naltrexone (naloxone). Naltrexone is harder to get but many people take it now, including myself. Below is a report on many of the substances that have been studied. If they work in rodents there is every reason to believe they could work in people. These drugs have mostly already been approved by the FDA and should be made available off-label before very expensive clinical trials are done which would take years for a drug that has lost it's patent. What is even better is that they are inexpensive, used at very low doses and have little side effects.
Ashley

http://www.aapsj.org/view.asp?art=aapsj080369
Naloxone
Naloxone is a nonselective opioid receptor antagonist that can interact with all 3 classic opioid receptors (ie, μ-, κ-, and δ-opioid receptors).151 Association of naloxone with opioid receptors is stereospecific in that only (-)-naloxone is capable of high affinity binding dissociation constant, Kd in the nanomolar range (Kd). Its stereoisomer, (+)-naloxone, on the other hand has very little affinity for opioid receptors (Kd in low micromolar range). However, both naloxone enantiomers have been shown to possess novel anti-inflammatory activity. In particular, both (-)-naloxone and (+)-naloxone can effectively inhibit ROS generation in activated microglia.152-154 Not only is their inhibitory effect on ROS generation not mediated through the opioid receptor system but they do not possess anti-oxidant activity. In a cell free system used to test anti-oxidant activity, neither naloxone stereoisomer exhibited a significant effect on the reduction of cytochrome c by the superoxide generated in the xanthine-xanthine oxidase system (Figure 3). In the mesencephalic neuron-glia cultures, naloxone isomers significantly protected DA neurons from LPS-induced inflammatory damages.152 Systemic infusion of naloxone enantiomers dose-dependently inhibited LPS-induced microglial activation and protected against LPS-induced loss of DA neurons in the SN.31,155 The microglial activity-modulating and neuroprotective property of naloxone isomers did not appear to be limited to LPS-induced DA neurodegeneration. Naloxone isomers effectively protected primary cortical neurons against degeneration induced by either LPS or β-amyloid peptide.154,156 In addition, naloxone, administered together with an NSAID, indomethacin, effectively reduced LPS-induced microglial activation, depletion of striatal DA, and locomotor abnormalities in rats.157
Dextromethorphan
Dextromethorphan (DM) is a nonopioid cough suppressant widely present in a variety of over-the-counter preparations. Although it was considered an N-methyl D-aspartate (NMDA) receptor antagonist, the precise mechanism responsible for its antitussive activity remains unclear. In mesencephalic neuron-glia cultures, DM significantly inhibited LPS-induced microglial activation and production of TNFα, nitric oxide (NO), and superoxide and protected DA neurons against LPS-induced degeneration.158 In mice, DM significantly reduced the MPTP-induced loss of SN DA neurons.91 In addition, DM was able to prevent the enhanced loss of SN DA neurons and depletion of striatal DA in a mouse PD model induced by the combination of MPTP and diethyldithiocarbamate, a putative inhibitor of superoxide dismutase.159 The degeneration of striatal fibers induced by methamphetamine was inhibited by a combination of DM and MK-801, an NMDA receptor antagonist, possibly through the inhibition of microglial activation.160
Conclusion
Microglial activation, either as a reactive response to neuronal injuries induced by various neurotoxins, or induced directly by immunologic stimuli appears to play an important role in the degeneration of nigrostriatal DA pathway in PD. Activated microglia, as well as astroglia to a lesser extent, can produce excessive quantities of various pro-inflammatory and neurotoxic factors that include cytokines, free radicals, and lipid metabolites. The participation of microglia in the progressive DA neurodegenerative process in PD seems to occur at a much earlier point than previously thought. This view is strongly supported by findings from epidemiological studies, analysis of postmortem PD brains, determination of the contribution of individual microglia (glia)-derived factors in various PD models, and evaluation of the neuroprotective activity of microglial activity-modulating agents in these models.

Modulation of Microglial Pro-inflammatory and Neurotoxic Activity for the Treatment of Parkinson’s Disease
Bin Liu1
1Department of Pharmacodynamics, College of Pharmacy, the McKnight Brain Institute, University of Florida, Gainesville, FL



Received: June 14, 2006; Accepted: June 27, 2006; Published: September 29, 2006