The cannabinoid antagonist, AM251 attenuates ataxia related deficiencies in a cerebellar ataxic model

Abstract

Aim: Disruption in cerebellar inputs, as well as dysfunction of Purkinje cells (PCs), causes a change in the timing of electrical signaling in the cerebellum resulting in disorders such as cerebellar ataxia. Although much clinical and molecular genetics research has been conducted to understand this disorder, there is no specific treatment for cerebellar ataxia. As cannabinoid type 1 receptors (CB1Rs) are highly expressed in the cerebellum and have been suggested as a therapeutic strategy, we determined whether AM251, a cannabinoid receptor antagonist, was neuroprotective of PCs in a rat cerebellar ataxic model.Materials and methods: To this end, we conducted behavioral and histological tests in the 3-acetylpyridine (3AP) rat cerebellar ataxia model, to explore whether AM251 was protective against induction of ataxia and cell death.Results: Rats with chemical degeneration of the inferior olive induced by 3AP (55 mg/kg, i.p.) clearly showed cerebellar ataxic symptoms. The locomotor activity and motor coordination of the ataxic animals were clearly disrupted compared to the control group. Further, histological analysis showed cell death and PCs degenerated with loss of cell membrane integrity associated with 3AP. Pre-treatment by AM251 improved the locomotor activity of the ataxic animals, and AM251 almost prevented PCs neuronal degeneration.Conclusion: Our data which show protection of cerebellar PCs and motor improvement in the ataxic rat model by treatment with AM251 suggests that targeting cannabinoid receptors should be considered for therapeutic intervention in cerebellar ataxia.

HIGHLIGHTS:

• AM251 was protective against induction of ataxia and cell death.

• CBR antagonist typically ameliorated 3AP induced Ataxia.

• AM251 affected explorative and gait disturbances induced by 3AP.

• CBR antagonist improved impairments of anxiety-like behaviors following 3AP

Keywords:

• Ataxia
• cerebellum
• cannabinoid antagonist
• neuroprotective

Author contribution

HR and MS have conceived and designed the concept and road map of the study, searched the literature, designed the concept map and figures, and drafted the manuscript. KAK, VSH MA and KR have critically reviewed the manuscript for its content, originality, usage of English language, and accuracy of interpreted data. MSH designed the study, helped in manuscript preparation, and critically reviewed the manuscript. MSH is the archival author and attests to the integrity of the original data and the analysis reported in this manuscript. All authors have made substantive contribution and attest to approving the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Code availability

All software applications used are included in this article.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Consent to participate

The protocol was established, according to the ethical guidelines of the Helsinki Declaration, and was approved by the Institutional Ethics Committee of of Kerman University of Medical Sciences.

Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Disclosure statement

No potential conflict of interest was reported by the authors.

Ethics approval

All procedures performed in studies were in accordance with the ethical standards of the ethical committee of Kerman University of Medical Sciences (Ethical approval number: IR.KMU.REC.1398.012, Reg. No. 97000860).

Additional information

Funding

Funding for this study was provided by Kerman University of Medical Sciences as a grant for the PhD thesis conducted by Hoda Ranjbar.