Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Jackson‐Lewis, Vernice; Jakowec, Michael W.; Burke, Robert E.; Przedborski, Serge

doi:10.1016/1055-8330(95)90015-2

Cited by 558 publications

(328 citation statements)

References 51 publications

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“…2B and 2C). This was in good agreement with previous findings that MPP ϩ treatment did not generate internucleosomal DNA fragments (15,33). A similar result was observed over a wide concentration range of MPP ϩ but more protracted (5-100 µM; not shown).…”

Section: Morphological Characterization Of Mpp ϩ -Induced Cell Deathsupporting

confidence: 93%

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Characterization of MPP+-Induced Cell Death in a Dopaminergic Neuronal Cell Line: Role of Macromolecule Synthesis, Cytosolic Calcium, Caspase, and Bcl-2-Related Proteins

Choi

Canzoniero

Sensi

et al. 1999

Experimental Neurology

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Section: Morphological Characterization Of Mpp ϩ -Induced Cell Deathsupporting

confidence: 93%

“…Specifically, inhibition of the mitochondrial respiratory chain by rotenone, which, like MPP ϩ , targets Complex I, induces necrotic cell death (37). This is in agreement with studies demonstrating that no signs of DNA fragmentation are found in tyrosine hydroxylasepositive dopaminergic neurons from MPTP-treated C57/bl mice (15).…”

Section: Introductionsupporting

confidence: 93%

Characterization of MPP+-Induced Cell Death in a Dopaminergic Neuronal Cell Line: Role of Macromolecule Synthesis, Cytosolic Calcium, Caspase, and Bcl-2-Related Proteins

Choi

Canzoniero

Sensi

et al. 1999

Experimental Neurology

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“…In the striatum MHC II levels were not elevated until 14 days after MPTP treatment which is consistent with previous work (Kurkowska‐Jastrzebska et al, 1999b). This increase occurs after the peak of dopaminergic neuron death (Jackson‐Lewis et al, 1995) and is more likely to be a result from the degeneration of the dopaminergic terminals rather than being an active component of the degeneration.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a role of adaptive immune response in the disease pathogenesis of the MPTP mouse model of Parkinson's disease

Martin

Santoro

Mustafa

et al. 2015

Glia

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Parkinson's disease (PD) is the second most common neurodegenerative disease and results from the loss of dopaminergic neurons of the nigrostriatal pathway. The pathogenesis of PD is poorly understood, but inflammatory processes have been implicated. Indeed increases in the number of major histocompatibility complex II (MHC II) reactive cells have long been recognised in the brains of PD patients at post‐mortem. However whether cells expressing MHC II play an active role in PD pathogenesis has not been delineated. This was addressed utilising a transgenic mouse null for MHC II and the parkinsonian toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). In wild‐type mice MHC II levels in the ventral midbrain were upregulated 1–2 days after MPTP treatment and MHC II was localized in both astrocytes and microglia. MHC II null mice showed significant reductions in MPTP‐induced dopaminergic neuron loss and a significantly reduced invasion of astrocytes and microglia in MHC II null mice receiving MPTP compared with controls. In addition, MHC II null mice failed to show increases in interferon‐γ or tumour necrosis factor‐α in the brain after MPTP treatment, as was found in wild‐type mice. However, interleukin‐1β was significantly increased in both wild‐type and MHC II null mice. These data indicate that in addition to microglial cell/myeloid cell activation MHC Class II‐mediated T cell activation is required for the full expression of pathology in this model of PD. GLIA 2016;64:386–395

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“…Mice were treated with four doses of either saline or 16 mg͞kg N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (free base; Research Biochemicals, Natick, MA; intraperitoneal injections 2 hr apart on 1 day), doses previously identified as producing moderate levels of dopaminergic cell killing in wild-type mice, and sacrificed 7 days after the last injection as previously described (33). To quantitate substantia nigra dopaminergic neurons, consecutive 20-m cryostat sections were cut through the entire midbrains of paraformaldehyde-perfused mouse brains, immunostained using specific antibodies directed against TH (1:1,000 dilution; Eugene Tech, Ridgefield Park, NJ), and cell counts for TH-positive nigral neurons were performed by an investigator unaware of the genotype or treatment status of the animal, as previously described (31).…”

Section: Methodsmentioning

confidence: 99%

“…Levels of GABA, derivatized with O-phtaldialdehyde͞ter-butylthiol, were determined by HPLC using a C18 column (HR-80, ESA), elution at 1 ml͞min with 5% ethyl acetate͞40% methanol͞55% sodium phosphate (pH 6.9), and electrodetection using a Coulochem 5100A detector (GC ϭ 600 mV, E1 ϭ 250 mV, E2 ϭ 650 mV; ESA) (32). Levels of MPP ϩ were estimated using a UV absorbance assay as described (31,33).…”

Section: Methodsmentioning

confidence: 99%

VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity

Takahashi

Miner

Sora

et al. 1997

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

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377

312

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The brain vesicular monoamine transporter (VMAT2) pumps monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1-methyl-4-phenyl-phenypyridinium (MPP ؉ ) from neuronal cytoplasm into synaptic vesicles, from which amphetamines cause their release. Amphetamines and MPP ؉ each also act at nonvesicular sites, providing current uncertainties about the contributions of vesicular actions to their in vivo effects. To assess vesicular contributions to amphetamine-induced locomotion, amphetamine-induced reward, and sequestration and resistance to dopaminergic neurotoxins, we have constructed transgenic VMAT2 knockout mice. Heterozygous VMAT2 knockouts are viable into adult life and display VMAT2 levels one-half that of wild-type values, accompanied by smaller changes in monoaminergic markers, heart rate, and blood pressure. Weight gain, fertility, habituation, passive avoidance, and locomotor activities are similar to wild-type littermates. In these heterozygotes, amphetamine produces enhanced locomotion but diminished behavioral reward, as measured by conditioned place preference. Administration of the MPP ؉ precursor N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to heterozygotes produces more than twice the dopamine cell losses found in wild-type mice. These mice provide novel information about the contributions of synaptic vesicular actions of monoaminergic drugs and neurotoxins and suggest that intact synaptic vesicle function may contribute more to amphetamine-conditioned reward than to amphetamine-induced locomotion.

show abstract

Time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Cited by 558 publications

References 51 publications

Characterization of MPP+-Induced Cell Death in a Dopaminergic Neuronal Cell Line: Role of Macromolecule Synthesis, Cytosolic Calcium, Caspase, and Bcl-2-Related Proteins

Characterization of MPP+-Induced Cell Death in a Dopaminergic Neuronal Cell Line: Role of Macromolecule Synthesis, Cytosolic Calcium, Caspase, and Bcl-2-Related Proteins

Evidence for a role of adaptive immune response in the disease pathogenesis of the MPTP mouse model of Parkinson's disease

VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity

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