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here is no cure for Parkinson’s disease (PD), a disorder that primarily affects the aging population. Despite considerable research effort, the mechanisms of neurodegeneration remain vague and there is a lack of effective neuroprotective therapy. Mitochondrial defects appear to underlie neuropathology in a large percentage of PD patients. Much of the research in our laboratory has been targeted to unraveling neurodegenerative processes and to identifying potential sites for therapeutic intervention to stop disease progression. To this end, our studies have focused on various aspects of dopamine, glutamate and adenosine signaling within the basal ganglia under conditions of metabolic stress as created by inhibition of mitochondrial function.
Aging is a predisposing factor for many diseases including Parkinson’s disease (PD) which afflicts 1% of the population older than 65 years of age. While the neuropathology of PD is fairly well-characterized, the causes of neurodegeneration remain obscure. The devastating loss of motor function in PD is due to the progressive and profound degeneration of dopamine-containing neurons in the substantia nigra and the consequent loss of their axon projections in the striatum. Treatment for PD is only symptomatic. To date, there is no effective treatment available for preventing or slowing the progression of the disease.
Much of the research in PD over the last two decades has been driven by early studies with the neurotoxicant, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant in street drug preparations of a heroin-like substance that led to a rapid onset PD in several young individuals. The outcome of the MPTP studies revealed two important findings: 1) that PD could be caused by environmental exposure, findings that have subsequently led to epidemiological studies that provide a link between pesticide exposure and idiopathic PD; and 2) that the MPTP metabolite, 1-methyl-4-phenylpyridinium (MPP+), is an effective mitochondrial inhibitor, observations that subsequently led to the discovery that a large percentage of PD patients have defective mitochondria.
Our present research focuses on several aspects of mitochondrial dysfunction as well as its effects on dopamine (DA) homeostasis and neuronal activity within the basal ganglia. In collaboration with colleagues at RWJMS and other institutions, we have found that infusions of mitochondrial inhibitors into the striatum produce DA nerve terminal loss in this region as well as retrograde DA cell death in the substantia nigra. In order to define potential mechanisms and identify possible sites for therapeutic intervention, we have examined the roles of dopamine, glutamate, and adenosine in mediating damage produced by mitochondrial inhibition and metabolic stress.
In studies supported by the NIH, we found that a striatal infusion of a mitochondrial inhibitor (MPP+ or malonate) increases DA release in freely moving animals. Moreover, we found that DA is a crucial component of the neurodegenerative process as its depletion prior to imposition of the metabolic stress protects against toxicity produced by the mitochondrial inhibitor. We also determined that DA release under these conditions is via reversal of the plasma membrane DA transporter (i.e., releases dopamine from within the cell to the extracellular space), which normally functions to take synaptically released DA back up into the cell. Interestingly, blockade of this transporter by various DA transport inhibitors provides protection against malonate-induced damage to the striatal DA neurons.
We propose that reverse DA transport occurs with the metabolic stress for several reasons including loss of energy, disruption of vesicle stores of DA, reduced membrane potential and modified sodium fluxes. Although we do not yet know how the released DA contributes to neurodegeneration or how the DA transport inhibitors protect, we postulate that it could be due to a reduction in energy needs of the neuron (since uptake of DA into the neuron is energy dependent) and/or because of a reduction in damaging extracellular DA-derived oxidative products. Reports of the clinical efficacy of DA transport inhibitors (e.g., methylphenidate, tesofensine) in PD patients are mixed. But only limited clinical studies have been performed with these drugs and none of the studies have been long term, which would be required to assess any neuroprotective effect.
In other research, sponsored by the NIH and the American Parkinson’s Disease Association, we are examining interactions between DA, glutamate and adenosine within the basal ganglia. This work has revealed some novel and interesting findings. First, a localized mitochondrial impairment created by a direct infusion of the mitochondrial inhibitor within the striatum produces a modest increase in glutamate release in the substantia nigra, likely mediated by the indirect striatal-nigral pathway with an increase in the activity of the glutamatergic neurons projecting from the subthalamic nucleus to the substantia nigra. Second, striatal DA nerve terminal loss produced by the striatal metabolic stress can be attenuated by blockade of glutamate N-methyl-D-aspartate (NMDA) receptors or A2A antagonists within the substantia nigra (but not the striatum). While glutamate is critically important for mediating neuronal firing, over-stimulation of the glutamate N-methyl-D-aspartate (NMDA) receptors can lead to neuronal cell death via an excitotoxic mechanism.
Our findings suggest that the malonate-induced increase in nigral glutamate is sufficient to produce excitotoxicity to the nigral DA neurons. Moreover, it is surprising that the A2A receptor antagonist exerted protection when infused into the nigra and not the striatum as the latter brain region is densely populated with A2A receptors. The protection afforded by the nigral administration of the A2A antagonist likely reflects its ability to reduce glutamate release within the substantia nigra. Consistent with this hypothesis, ablation of the indirect pathway provides protection against the striatal mitochondrial infusions. Future studies are planned to explore the role of the indirect pathway and the effect of nigral A2A receptor blockade on nigral glutamate release.
Overall, these findings implicate roles for glutamate and adenosine signaling within the substantia nigra in mediating neurodegeneration of stressed DA neurons and also identify the substantia nigra as a potential site for intervention. Clinical studies are currently underway to examine the efficacy of A2A antagonists in symptomatic relief in PD patients. Our work and that of others suggest that they may also be neuroprotective. Although blockade of NMDA receptors is an unlikely therapeutic approach, other investigators are finding that modification of glutamate metabotropic receptor function may be protective by reducing glutamate release, similar to actions seen with A2A antagonists. Whether they will be effective in PD requires clinical trials.
In summary, we and other investigators have identified several sites for intervening with DA cell degeneration. While some of the current investigational pharmacological agents are being tested for efficacy in symptomatic relief, they may also have the added benefit of slowing the progression of neurodegeneration.
Patricia K. Sonsalla is professor and acting director of the Mollie and Jerome Levine Neuroscience Division in the RWJMS Department of Neurology with secondary appointments in the pharmacology and psychiatry departments. She received her PhD in pharmacology and toxicology at the University of Utah and her post-doctoral mentoring by the late Dr. Richard Heikkila at RWJMS. Dr. Sonsalla has been the recipient of many grants from federal and non-federal sources, has served on many NIH study sections and has reviewed grants for the Department of Defense and other granting agencies. She has been active in the American Society for Pharmacology and Experimental Therapeutics, serving in many capacities, including secretary-treasurer. She is a member of the editorial boards of The Journal of Pharmacology and Experimental Therapeutics and The Journal of Neurochemistry.
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