Severe acute neurotoxicity reflects absolute intra-carotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine dose in non-human primates

Norris, Scott A.; White, Hcb; Tanenbaum, Aaron; Williams, Edna; Cruchaga, Carlos; Schmidt, Robert E.; Perlmutter, Joel S.

doi:10.1016/j.jneumeth.2021.109406

Cited by 2 publications

(2 citation statements)

References 31 publications

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“…These parent biomarker studies relied on the minimum number of animals necessary to achieve statistical power for respective a-priori hypotheses. From this existing cohort, animals with severe acute MPTP toxicity ( 10 ) or exposure to dopaminergic medications or carboxyfullerene were excluded for the current analysis ( 11 , 12 ). Furthermore, as the current study aimed to determine the relationship between peak acute transient dystonia and degree of parkinsonism, animals euthanized prior to anticipated peak parkinsonism were excluded.…”

Section: Methodsmentioning

confidence: 99%

“…To obtain a dose response curve, a randomized dose between 0 and 0.25 mg/kg of MPTP (Sigma, St. Louis, MO) diluted in normal saline was infused IC in a concentration of 0.1 mg/mL at a rate no faster than 1 mL per minute. The mean absolute dose of MPTP administered was 1.28 mg ± 0.71 across monkeys injected ( 10 ). A repeat angiogram was performed following infusion of MPTP to document maintenance of proper positioning and distal blood flow.…”

Section: Methodsmentioning

confidence: 99%

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Transient dystonia correlates with parkinsonism after 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine in non- human primates

Norris¹,

Tian²,

Williams³

et al. 2023

Dystonia

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Unilateral internal carotid artery 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) infusion in non-human primates produces transient contralateral hemi-dystonia followed by stable contralateral hemi-parkinsonism; the relationship between dystonia and parkinsonism remains unclear. We hypothesized that transient dystonia severity following MPTP correlates with parkinsonism severity. In male Macaca nemestrina (n = 3) and M. fascicularis (n = 17) we administered unilateral intra-carotid MPTP, then correlated validated blinded ratings of transient peak dystonia and delayed parkinsonism. We also correlated dystonia severity with post-mortem measures of residual striatal dopamine and nigral neuron counts obtained a mean 53 ± 15 days following MPTP, after resolution of dystonia but during stable parkinsonism. Median latency to dystonia onset was 1 day, and peak severity 2.5 days after MPTP; total dystonia duration was 13.5 days. Parkinsonism peaked a median of 19.5 days after MPTP, remaining nearly constant thereafter. Peak dystonia severity highly correlated with parkinsonism severity (r[18] = 0.82, p < 0.001). Residual cell counts in lesioned nigra correlated linearly with peak dystonia scores (r[18] = −0.68, p=<0.001). Dystonia was not observed in monkeys without striatal dopamine depletion (n = 2); dystonia severity correlated with striatal dopamine depletion when residual nigral cell loss was less than 50% ([11]r = −0.83, p < 0.001) but spanned a broad range with near complete striatal dopamine depletion, when nigral cell loss was greater than 50%. Our data indicate that residual striatal dopamine may not reflect dystonia severity. We speculate on mechanisms of transient dystonia followed by parkinsonism that may be studied using this particular NHP MPTP model to better understand relationships of transient dystonia to nigrostriatal injury and parkinsonism.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Transient dystonia correlates with parkinsonism after 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine in non- human primates

Norris¹,

Tian²,

Williams³

et al. 2023

Dystonia

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A primate nigrostriatal atlas of neuronal vulnerability and resilience in a model of Parkinson’s disease

Tang,

Xu,

Huang

et al. 2023

Nat Commun

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The degenerative process in Parkinson’s disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in neuronal susceptibility warrants an amenable PD model that, in comparison to post-mortem human specimens, controls for environmental and genetic differences in PD pathogenesis. Here we generated high-quality profiles for 250,173 cells from the substantia nigra (SN) and putamen (PT) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian macaques and matched controls. Our primate model of parkinsonism recapitulates important pathologic features in nature PD and provides an unbiased view of the axis of neuronal vulnerability and resistance. We identified seven molecularly defined subtypes of nigral DaNs which manifested a gradient of vulnerability and were confirmed by fluorescence-activated nuclei sorting. Neuronal resilience was associated with a FOXP2-centered regulatory pathway shared between PD-resistant DaNs and glutamatergic excitatory neurons, as well as between humans and nonhuman primates. We also discovered activation of immune response common to glial cells of SN and PT, indicating concurrently activated pathways in the nigrostriatal system. Our study provides a unique resource to understand the mechanistic connections between neuronal susceptibility and PD pathophysiology, and to facilitate future biomarker discovery and targeted cell therapy.

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Severe acute neurotoxicity reflects absolute intra-carotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine dose in non-human primates

Cited by 2 publications

References 31 publications

Transient dystonia correlates with parkinsonism after 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine in non- human primates

Transient dystonia correlates with parkinsonism after 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine in non- human primates

A primate nigrostriatal atlas of neuronal vulnerability and resilience in a model of Parkinson’s disease

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