Continuous Deadly Brain Degeneration Follows MPTP Injection
December 1, 1999 3 minutes read
Continuous Deadly Brain Degeneration Follows MPTP Injection
abstract & commentary
Source: Langston JW, et al. Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure. Ann Neurol 1999;46:598-605.
For the last 25 years, there has been a great debate among movement disorders physicians about the role of environmental vs. genetic factors in the etiology of Parkinson’s disease (PD). The recent discovery of four different genes that cause parkinsonism has swayed many in the field to favor genetic etiologies. A large-scale study of PD in twins (Tanner CM. JAMA 1999;281:341-346), however, suggested that most PD occurring in people older than the age of 50 is probably the result of environmental causes.
One of the most persuasive arguments for the role of environmental toxins was the 1983 discovery by Bill Langston of the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in a series of young drug addicts in northern California. A synthetic byproduct of a misguided attempt to produce the meperidine analog, MPPP-MPTP, produced profound, acute, and irreversible parkinsonism in a significant fraction of exposed individuals. Patients with MPTP-induced parkinsonism responded dramatically to levodopa, but this response was often short-lived and usually complicated by dyskinesias, motor fluctuations, and psychiatric toxicity. Subsequently, it was discovered that MPTP expressed its toxicity only after conversion by monoamine oxidase B to MPP+. The latter is selectively taken up by the dopamine transporter, accumulates in the mitochondria, and inhibits complex I.
In addition to lending support to the role of environmental toxins, MPTP provided an extremely useful model to use for producing experimental parkinsonism. In this report, Langston and colleagues review the detailed neuropathology of three individuals with well-documented MPTP-induced parkinsonism. All had steadily worsened from parkinsonian changes from the time of their drug ingestion until death, 16, 12, and three years later.
Common to all three cases, and expected from the clinical severity of these patients, was the finding of severe depigmentation of the substantia nigra, with near total loss of dopaminergic cells within the substantia nigra. No Lewy bodies were seen, distinguishing this condition from classic PD.
The unexpected findings in these three cases were a massive accumulation of extraneuronal melanin, accompanied by marked astrocytic and microglial activation. These features are seen only in active, ongoing neurodegeneration. Langston et al conclude that a single, acute insult induced a delayed continuous degeneration in the substantia nigra.
Commentary
These findings have major implications for the evolution of PD and for neurodegenerative illnesses as a group. MPTP was never shown to be available after the 1982 epidemic, so it is unlikely that continued exposure to the drug was responsible for the neuropathologic features in these patients. Rather, we are left with the powerful conclusion that a single, severe chemical insult to brain structures can instigate and continuously produce active neurodegeneration that continues until death. The findings suggest an unexpected and exciting new window for pursuing prevention of neuronal injury in patients with PD and other neurodegenerative illnesses. —rt
In the study by Langston and colleagues, which of the following was not seen in any of the cases of MPTP-induced parkinsonism?
a. Severe depigmentation of the substantia nigra
b. Near total loss of dopaminergic cells within the substantia nigra
c. Massive accumulation of extraneuronal melanin
d. Astrocytic and microglial activation
e. Lewy bodies
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