Selective MAO-A and B inhibitors, radical scavengers and nitric oxide synthase inhibitors in Parkinson's desease

Abstract

In the absence of identification of either an endogenously or an exogenously derived dopaminergic neurotoxin, the most valid hypothesis currently envisaged for etiopathology of Parkinson's disease (PD) is selective oxidative stress (OS) in substantia nigra (SN). Although OS is not proven, a significant body of evidence from studies on animal and Parkinsonian brain neurochemistry supports it. This hypothesis is based on excessive formation of reactive oxygen species (O 2 and OH.) and demise of systems involved with scavenging or preventing the formation of such radicals from H 2O 2, generated as a consequence of dopamine oxidation (autoxidation and deamination). Since MAO (monoamine oxidase A and B are the major H 2O 2 generating enzymes in the SN much attention has been paid to their selective inhibitors as symptomatic and neuroprotective agents in PD. Attention should also be given to radical scavengers (e.g. iron chelators, lipid peroxidative inhibitors and Vitamin E derivatives) as therapeutic neuroprotective agents in PD. This is considered valid since a significant elevation of iron is known to occur selectively in SN zone compacta and within the remaining melanized dopamine neurons of Parkinsonian brains. Although all the mechanism of iron induced oxygen free radical formation is not fully known there is no doubt that it participates with H 2O 2 (Fenton chemistry) to generate cytotoxic hydroxyl radical (OH.) and induce tissue OS and neurodegeneration in 6-hydroxydopamine model of PD. The dramatic proliferation of reactive amoeboid macrophages and microglia seen in SN of PD brains together with OS is highly compatible with an inflammatory process, similar to what has been observed in Alzheimer's disease and multiple sclerosis brains. This has led us to examine the ability of reactive macrophages to produce oxygen free radicals in response to nitric oxide (NO) production. The latter radical has been implicated in the excitotoxicity of glutaminergic neurons innervating the striatum and SN. Indeed we have now observed that in reactive macrophages NO acts as a signal transducer of O 2 production which can synergize with dopamineoxidation.