Chronic MPTP treatment reproduces in baboons the differential vulnerability of mesencephalic dopaminergic neurons observed in parkinson's disease

Varastet, Marina; Riché, D.; Mazière, M.; Hantraye, Philippe

doi:10.1016/0306-4522(94)90006-x

Cited by 112 publications

(59 citation statements)

References 51 publications

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“…The SN is most susceptible to PD pathology, whereas the adjacent VTA DA neurons are less vulnerable and hypothalamic DA neurons are spared (3)(4)(5)(6)49). The same selective vulnerability of DA neuron subpopulations has been observed in rodent and primate models of PD (7,(50)(51)(52). The sparing of VTA neurons could be mediated by selective expression of neuroprotective factors, including neurotrophic factors (BMP-2, PACAP, and ANP), detoxifying enzymes (EC-SOD, lipoprotein lipase, and UDPglucuronosyltransferase), the antiapoptotic factor PARM-1, and decreased levels of the proapoptotic PKC-␦.…”

Section: Discussionmentioning

confidence: 72%

“…Selective degeneration of DA neurons in the SN but not in the VTA or the hypothalamus leads to Parkinson's disease (PD) (3)(4)(5)(6)(7), whereas abnormal function of the VTA DA neurons has been linked to schizophrenia, attention deficit, addiction, and hyperactivity disorders (8)(9)(10)(11). In addition, dysfunction of hypothalamic DA neurons can cause hyperprolactinemia, an endocrine disorder of the reproductive system (12), whereas changes in the activity of the NA system have been linked to depression as well as sleep disorders (13,14).…”

mentioning

confidence: 99%

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Molecular basis for catecholaminergic neuron diversity

Grimm

Mueller

Hefti

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

134

141

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Catecholaminergic neurons control diverse cognitive, motor, and endocrine functions and are associated with multiple psychiatric and neurodegenerative disorders. We present global gene-expression profiles that define the four major classes of dopaminergic (DA) and noradrenergic neurons in the brain. Hypothalamic DA neurons and noradrenergic neurons in the locus coeruleus display distinct group-specific signatures of transporters, channels, transcription, plasticity, axon-guidance, and survival factors. In contrast, the transcriptomes of midbrain DA neurons of the substantia nigra and the ventral tegmental area are closely related with <1% of differentially expressed genes. Transcripts implicated in neural plasticity and survival are enriched in ventral tegmental area neurons, consistent with their role in schizophrenia and addiction and their decreased vulnerability in Parkinson's disease. The molecular profiles presented provide a basis for understanding the common and population-specific properties of catecholaminergic neurons and will facilitate the development of selective drugs.C atecholaminergic (CA) neurons producing the neurotransmitters dopamine (DA) and noradrenalin (NA) are organized in anatomically discrete groups and constitute Ϸ1 of 10 7 cells in the vertebrate CNS (1, 2). The most prominent groups of DA neurons reside in the substantia nigra (SN; A9 cell group; Ϸ10,000 neurons in the rat) and the ventral tegmental area (VTA; A10; Ϸ25,000 neurons) of the midbrain. The SN neurons provide the nigrostriatal ascending inputs to the telencephalon and comprise a key component of the extrapyramidal motor system controlling postural reflexes and initiation of movement. DA neurons in the adjacent VTA give rise to mesocortical and mesolimbic pathways that are implicated in control of emotional balance, reward-associated behavior, attention, and memory. Additional groups of DA neurons reside in the medial zona incerta of the hypothalamus (A13; Ϸ900 neurons) and participate in the regulation of endocrine functions. The largest collection of NA neurons resides in the pontine locus coeruleus (LC; Ϸ1,500 neurons). These neurons form a modulatory projection system to most CNS areas and contribute to the regulation of emotional status, sensory perception, arousal, sleepwake patterns, and most autonomic functions.Consistent with their varied functions, the CA neurons are associated with multiple neurodegenerative, psychiatric, and endocrine disorders. Selective degeneration of DA neurons in the SN but not in the VTA or the hypothalamus leads to Parkinson's disease (PD) (3-7), whereas abnormal function of the VTA DA neurons has been linked to schizophrenia, attention deficit, addiction, and hyperactivity disorders (8-11). In addition, dysfunction of hypothalamic DA neurons can cause hyperprolactinemia, an endocrine disorder of the reproductive system (12), whereas changes in the activity of the NA system have been linked to depression as well as sleep disorders (13,14).The drugs currently available for therapy reflec...

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Section: Discussionmentioning

confidence: 72%

mentioning

confidence: 99%

Molecular basis for catecholaminergic neuron diversity

Grimm

Mueller

Hefti

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

134

141

View full text Add to dashboard Cite

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“…Our results suggest that nigral and enteric dopamine neurons exhibit grossly similar levels of sensitivity to parenteral MPTP, but the relative vulnerability between gut and brain dopamine neurons is difficult to assess. Given the graded levels of susceptibility to MPTP of central dopamine neurons (e.g., substantia nigra > ventral tegmental area > hypothalamus), investigation of lower or more chronic doses of MPTP may provide provocative information about where enteric dopamine neurons fit into that continuum (Braak, et al, 2003, German, et al, 1992, Varastet, et al, 1994.…”

Section: Discussionmentioning

confidence: 99%

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Anderson

Noorian

Taylor

et al. 2007

Experimental Neurology

207

196

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Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility include early satiety and nausea from delayed gastric emptying, bloating from poor small bowel coordination, and constipation and defecatory dysfunction from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the prototypical parkinsonian neurotoxin, MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), is a selective dopamine neuron toxin in the enteric nervous system (ENS). When examined 10 days after treatment, there was a 40% reduction of dopamine neurons in the ENS of C57Bl/6 mice administered MPTP (60 mg/kg). There were no differences in the density of cholinergic or nitric oxide neurons. Electrophysiological recording of neural-mediated muscle contraction in isolated colon from MPTP-treated animals confirmed a relaxation defect associated with dopaminergic degeneration. Behaviorally, MPTP induced a transient increase in colon motility, but no changes in gastric emptying or small intestine transit. These results provide the first comprehensive assessment of gastrointestinal pathophysiology in an animal model of PD. They provide insight into the impact of dopaminergic dysfunction on gastrointestinal motility and a benchmark for assessment of other PD model systems.

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“…Neuropathological features are also very similar [41,70,78]. The response to levodopa (L-DOPA) treatment and the development of motor complications during long-term therapy are also similar to those seen in PD patients.…”

Section: Mptp Modelmentioning

confidence: 66%

Mitochondrial Toxins in Basal Ganglia Disorders: From Animal Models to Therapeutic Strategies

Bonsi

Cuomo

Martella

et al. 2006

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Current knowledge of the pathogenesis of basal ganglia disorders, such as Huntington's disease (HD) and Parkinson's disease (PD) appoints a central role to a dysfunction in mitochondrial metabolism. The development of animal models, based upon the use of mitochondrial toxins has been successfully introduced to reproduce human disease, leading to important acquisitions. Most notably, experimental evidence supports the existence, within basal ganglia, of a peculiar regional vulnerability to distinct mitochondrial toxins. MPTP and rotenone, both selective inhibitors of mitochondrial complex I have been extensively used to mimic PD. Accordingly, in human PD, a specific dysfunction of complex I activity was found in vulnerable dopaminergic neurons of the substantia nigra. Conversely, in HD a selective impairment of mitochondrial succinate dehydrogenase, key enzyme in complex II activity was found in medium spiny neurons of the caudate-putamen. The relevance of such finding is further demonstrated by the evidence that toxins able to primarily target mitochondrial complex II, such as malonic acid and 3-nitropropionic acid (3-NP), strikingly reproduce the main phenotypic and pathological features of HD.Despite the advances obtained from these experimental models, a deeper understanding of the molecular and cellular mechanisms underlying such neuronal vulnerability is lacking.The present review provides a brief survey of currently utilized animal models of mitochondrial intoxication, in attempt to address the cellular mechanisms triggered by energy metabolism failure and to identify potential therapeutic targets.

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Chronic MPTP treatment reproduces in baboons the differential vulnerability of mesencephalic dopaminergic neurons observed in parkinson's disease

Cited by 112 publications

References 51 publications

Molecular basis for catecholaminergic neuron diversity

Molecular basis for catecholaminergic neuron diversity

Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease

Mitochondrial Toxins in Basal Ganglia Disorders: From Animal Models to Therapeutic Strategies

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