Impaired glutamate homeostasis and programmed cell death in a chronic MPTP mouse model of Parkinson's disease.
The pathogenesis of Parkinson's disease is not fully understood, but there is evidence that excitotoxic mechanisms contribute to the pathology. However, data supporting a role for excitotoxicity in the pathophysiology of the disease are controversial and sparse. The goal of this study was to determine whether changes in glutamate signaling and uptake contribute to the demise of dopaminergic neurons in the substantia nigra. Mice were treated chronically with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and probenecid or vehicle (probenecid or saline alone). Extracellular levels of glutamate in the substantia nigra were substantially increased, and there was an increase in the affinity, but no change in the velocity, of glutamate transport after MPTP/probenecid treatment compared to vehicle controls. In addition, the substantia nigra showed two types of programmed death, apoptosis (type I) and autophagic (type II) cell death. These data suggest that increased glutamate signaling could be an important mechanism for the death of dopaminergic neurons and trigger the induction of programmed cell death in the chronic MPTP/probenecid model.
Meredith
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GE
Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University, 3333 Green Bay Road, North Chicago, IL 60064, USA. gloria.meredith@rosalindfranklin.edu
Totterdell
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Beales
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Meshul
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D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000378:metabolism* / Q000503:physiopathology; D011339:Probenecid / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation / Q000502:physiology; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism
D000277:Adjuvants, Pharmaceutic; D050496:Vesicular Glutamate Transport Proteins; D018698:Glutamic Acid; D011339:Probenecid; D004298:Dopamine