Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure

Abstract

This report provides the first detailed neuropathological study of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced parkinsonism in humans. All 3 subjects self‐administered the drug under the impression it was “synthetic heroin” and subsequently developed severe and unremitting parkinsonism, which was L‐dopa responsive, at least in the earlier stages of illness. Survival times ranged from 3 to 16 years. Neuropathological examination revealed moderate to severe depletion of pigmented nerve cells in the substantia nigra in each case. Lewy bodies were not present. In Patients 1 and 2, there was gliosis and clustering of microglia around nerve cells. Patient 3 had a similar picture and also showed large amounts of extraneuronal melanin. These findings are indicative of active, ongoing nerve cell loss, suggesting that a time‐limited insult to the nigrostriatal system can set in motion a self‐perpetuating process of neurodegeneration. Although the mechanism by which this occurs is far from clear, the precedent set by the cases could have broad implications for human neurodegenerative disease.

Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and ERK1/2-dependent NADPH oxidase

“…In the substantial nigra, a brain region enriched in dopaminergic neurons, microglial activation is associated with neurochemical changes such as the decrease in dopamine synthesis (Barcia et al, 2004;Scheller et al, 2005;Wu et al, 2003). In fact, changes in neurochemical parameters are observed before development of obvious lesions, suggesting that a short exposure to an insult may initiate a continuous process leading to neurodegeneration (Langston et al, 1999).…”

“…Activated microglial cells were observed in primates given MPTP and humans accidentally exposed to MPTP (Barcia et al, 2004;Langston et al, 1999). However, despite the increase in microglia in the PD brain as compared to normal controls, mechanism(s) linking activation of microglia to neuronal damage has not been elucidated.…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…MPP + thus accumulates in dopaminergic neurons where it inhibits the mitochondrial complex I of the electron transport chain, resulting in ATP depletion and subsequent inability to release sufficient amounts of dopamine and ultimately leading to apoptosis [231]. However, Lewy bodies were not observed in the brain of PD patients exposed to MPTP, revealing a significant difference between MPTP-induced neurotoxicity and PD itself despite the considerable clinical similarities [134].…”

“…Langston et al found that in postmortem examination of brains from humans exposed to MPTP activated microglia were present up to 16 years after exposure, indicating a protracted inflammatory response [134]. These observations are strongly indicative of a process by which an ongoing stimulus could lead to disease progression long after the initial toxic insult.…”

Test–retest repeatability of self-reported environmental exposures in Parkinson's disease cases and healthy controls

“…Since, the discovery of a Parkinsonian syndrome induced by the chemical MPTP 1 , the search for environmental risk factors for Parkinson's disease (PD) has returned mixed results. Epidemiological studies have, to varying extents, implicated exposures such as pesticides, solvents, neurotoxic metals, well-water consumption, and rural residency 2,3 .…”