Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis
25 Feb 1983-Science (American Association for the Advancement of Science)-Vol. 219, Iss: 4587, pp 979-980
TL;DR: It is proposed that this chemical selectively damages cells in the substantia nigra in patients who developed marked parkinsonism after using an illicit drug intravenously.
Abstract: Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.
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TL;DR: PD models based on the manipulation of PD genes should prove valuable in elucidating important aspects of the disease, such as selective vulnerability of substantia nigra dopaminergic neurons to the degenerative process.
4,872 citations
Cites background from "Chronic Parkinsonism in humans due ..."
...Clearly, this issue is of great consequence in deciding about possible therapeutic strategies for PD.syndrome nearly identical to PD (Langston et al., 1983) is a prototypic example of how an exogenous toxin can Misfolding and Aggregation of Proteins The abnormal deposition of protein in brain…...
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...…of paraquat to mice leads to SNpc of a street preparation of 1-methyl-4-phenyl-4-propion-dopaminergic neuron degeneration accompanied by oxypiperidine (MPPP), an analog of the narcotic meperi- -synuclein containing inclusions, as well as increases dine (Demerol) (Langston et al., 1983)....
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TL;DR: The findings suggest that nonspecific histopathology exists in the limbic system, diencephalon, and prefrontal cortex, that the pathology occurs early in development, and that the causative process is inactive long before the diagnosis is made.
Abstract: • Recent research on schizophrenia has demonstrated that in this disorder the brain is not, strictly speaking, normal. The findings suggest that nonspecific histopathology exists in the limbic system, diencephalon, and prefrontal cortex, that the pathology occurs early in development, and that the causative process is inactive long before the diagnosis is made. If these findings are valid and not epiphenomena, then the pathogenesis of schizophrenia does not appear to fit either traditional metabolic, posttraumatic, or neurodegenerative models of adult mental illness. The data are more consistent with a neurodevelopmental model in which a fixed "lesion" from early in life interacts with normal brain maturational events that occur much later. Based on neuro-ontological principles and insights from animal research about normal brain development, it is proposed that the appearance of diagnostic symptoms is linked to the normal maturation of brain areas affected by the early developmental pathology, particularly the dorsolateral prefrontal cortex. The course of the illness and the importance of stress may be related to normal maturational aspects of dopaminergic neural systems, particularly those innervating prefrontal cortex. Some implications for future research and treatment are considered.
3,562 citations
TL;DR: Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.
Abstract: Mounting evidence indicates that microglial activation contributes to neuronal damage in neurodegenerative diseases. Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an overactivated state and release reactive oxygen species (ROS) that cause neurotoxicity. Pattern recognition receptors expressed on the microglial surface seem to be one of the primary, common pathways by which diverse toxin signals are transduced into ROS production. Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.
3,511 citations
TL;DR: This article reviews what is known about the prevalence, incidence, risk factors, and prognosis of PD from epidemiological studies and suggests that major gene mutations cause only a small proportion of all cases.
Abstract: The causes of Parkinson's disease (PD), the second most common neurodegenerative disorder, are still largely unknown. Current thinking is that major gene mutations cause only a small proportion of all cases and that in most cases, non-genetic factors play a part, probably in interaction with susceptibility genes. Numerous epidemiological studies have been done to identify such non-genetic risk factors, but most were small and methodologically limited. Larger, well-designed prospective cohort studies have only recently reached a stage at which they have enough incident patients and person-years of follow-up to investigate possible risk factors and their interactions. In this article, we review what is known about the prevalence, incidence, risk factors, and prognosis of PD from epidemiological studies.
3,474 citations
TL;DR: It is reported that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity.
Abstract: The cause of Parkinson's disease (PD) is unknown, but epidemiological studies suggest an association with pesticides and other environmental toxins, and biochemical studies implicate a systemic defect in mitochondrial complex I. We report that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity. Nigral neurons in rotenone-treated rats accumulate fibrillar cytoplasmic inclusions that contain ubiquitin and alpha-synuclein. These results indicate that chronic exposure to a common pesticide can reproduce the anatomical, neurochemical, behavioral and neuropathological features of PD.
3,472 citations
Cites background from "Chronic Parkinsonism in humans due ..."
...After the pro-toxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was reported to produce in humans an acute parkinsonian syndrome that is virtually indistinguishable from idiopathic P...
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References
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TL;DR: Biogenic amines and metabolites in the cerebrospinal fluid and microscopic evaluation of the brain at necropsy were consistent with damage to aminergic neurons in the substantia nigra.
Abstract: Abuse of 4-propyloxy-4-phenyl-N-methylpiperidine, a meperidine congener, produced parkinsonism in a 23-year-old man. Unlike other drug-induced motor disturbances, the syndrome persisted for 18 months and responded to drugs that stimulate dopamine receptors. Biogenic amines and metabolites in the cerebrospinal fluid and microscopic evaluation of the brain at necropsy were consistent with damage to aminergic neurons in the substantia nigra.
1,365 citations
TL;DR: Apraxia of lid opening is a nonparalytic motor abnormality characterized by the patient's difficulty in initiating the act of lid elevation and differs from paralytic ptosis by being present only momentarily at the start of lidOpening.
Abstract: Apraxia of lid opening is a nonparalytic motor abnormality characterized by the patient's difficulty in initiating the act of lid elevation. It differs from paralytic ptosis by being present only momentarily at the start of lid opening, and it differs from ordinary forms of blepharospasm by occurring without unusual contraction of the orbicularis oculi. Although apraxia of lid closure has long been documented in the literature (Lewandowsky, 1907),1apraxia of lid opening has scarcely been mentioned. Schilder (1927)2described it, however, in two patients who had difficulty with both opening and closing their eyes. One of these patients had Huntington's chorea and both patients developed a trick of opening their eyes by a thrust of their heads backward. Riese (1930)3described apraxia of lid opening in a patient with a bullet injury to his frontotemporal region. We have not found other reports of this abnormality but suspect
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