Mechanisms of the inotropic actions of MPTP and MPP+ on isolated atria of rat

Wilson, James S.; Shearer, Danny T.; Adelakun, Akintoye K.; Carpentier, Robert

doi:10.1016/0041-008x(91)90133-y

Cited by 3 publications

(2 citation statements)

References 39 publications

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“…The effects of the CB 1 receptor antagonist AM251 on WIN‐induced neuroprotection could not be studied, as all MPTP‐treated animals injected with AM251 alone or in combination with WIN died within 48 h. Although the precise cause of this mortality remains unknown, it may be contingent upon side‐effects exerted by MPTP in addition to its well‐known toxicity on DA neurons (Przedborski et al. , 2001), such as hypothermia and disruption of cardiac function (Wilson et al. , 1991; Moy et al.…”

Section: Discussionmentioning

confidence: 99%

“…The effects of the CB 1 receptor antagonist AM251 on WIN-induced neuroprotection could not be studied, as all MPTP-treated animals injected with AM251 alone or in combination with WIN died within 48 h. Although the precise cause of this mortality remains unknown, it may be contingent upon side-effects exerted by MPTP in addition to its well-known toxicity on DA neurons , such as hypothermia and disruption of cardiac function (Wilson et al, 1991;Moy et al, 1998). These effects may have been further exacerbated by the administration of cannabinoid agents, which, in turn, affect body temperature and cardiovascular function (Hillard, 2000).…”

Section: Discussionmentioning

confidence: 99%

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WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease

Price

Bahillo

Seillier

et al. 2009

Eur J of Neuroscience

214

185

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Parkinson's disease (PD) is characterized by the progressive loss of nigrostriatal dopamine (DA) neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non-selective cannabinoid receptor agonist WIN55,212-2 (WIN) protects mouse nigrostriatal neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, i.p.), initiated 24 hr after MPTP administration, protected against MPTP-induced loss of tyrosine hydroxylase positive (TH + ) neurons in the substantia nigra pars compacta (SNc) independently of CB 1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the SNc and dorsal striatum of MPTP-treated mice. Three days post-MPTP, we found significant microglial activation and up-regulation of CB 2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB 2 receptor agonist JWH015 (4 mg/kg, i.p.) reduced MPTP-induced microglial activation, whereas genetic ablation of CB 2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTPassociated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB 2 cannabinoid receptors protects against MPTP-induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB 2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease

Price

Bahillo

Seillier

et al. 2009

Eur J of Neuroscience

214

185

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Strategic Approaches to in Vitro Neurotoxicology

Campbell

Abdulla

1995

Neurotoxicology

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Acute Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or Paraquat on Core Temperature in C57BL/6J Mice

Jiao

Dou

Lockwood

et al. 2015

Journal of Parkinson’s Disease

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Background: MPTP and paraquat are two compounds that have been used to model Parkinson’s disease in mice. Previous studies in two non-traditional strains of mice have shown that a single dose of MPTP can induce changes in body temperature, while the effects of paraquat have not been examined. Examination of body temperature is important since small fluctuations in an animal’s core temperature can significantly affect drug metabolism, and if significant enough can even culminate in an animal’s death.Objective: To determine how external heating can alter the survival of C57BL/6J mice following MPTP administration.Methods: In this study, we examine the effects of MPTP (4×20 mg/kg, 2 hours apart) and paraquat (2×10 mg/kg/week for 3 weeks) on core temperature of C57BL/6J mice. Correlations of purine and catecholamine levels were also done in mice treated with MPTP.Results: We find that MPTP induces a significant hypothermia in C57BL/6J mice that reduces their core temperature below the limit of fatal hypothermia. Unlike MPTP, paraquat did not induce a significant hypothermia. Placement of animals on heating pads significantly abrogates the loss of core temperature. In both heated and non-heated conditions, mice treated with MPTP showed a significant depletion of ATP within 2 hours of administration in both striatum and SN that started to recover 2 hours after MPTP administration was complete. Striatal DA and DOPAC are significantly reduced starting 4–6 hours after MPTP.Conclusions: The fatal hypothermic effects of MPTP can be abrogated through use of external heating.

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Mechanisms of the inotropic actions of MPTP and MPP+ on isolated atria of rat

Cited by 3 publications

References 39 publications

WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease

WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease

Strategic Approaches to in Vitro Neurotoxicology

Acute Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or Paraquat on Core Temperature in C57BL/6J Mice

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