Abstract
Cerebellar ataxia is a neurodegenerative disorder leading to severe motor incoordination. Recently, it has been suggested that cannabinoids play a role in modulating ataxic symptoms. To understand the possible therapeutic effect of cannabinoids for the management of cerebellar ataxia, we used cannabinoid agonist/antagonists to target the cannabinoid type 1 receptor (CB1R) in the 3 acetyl pyridine (3AP) rat model of ataxia. The role of the CB1R was examined using three different doses of the CB1R agonist, WIN-55,212–2 (WIN; 0.1, 0.5, 1 mg/kg) administrated 30 min prior to 3AP (55 mg/kg, i.p.) which leads to motor impairment through destruction of the inferior olive. In some groups, the CB1R antagonist AM251 (1 mg/kg) was given in combination with WIN. Locomotor activity and motor coordination were impaired by 3AP, and the application of WIN did not ameliorate this effect. However, the abnormal gait, rearing and grooming caused by 3AP were prevented by co-administration of AM251 with WIN. While the addition of the CB1R antagonist improved some ataxic symptoms, there was no effect of AM251 on balance or locomotor activity when co-administrated with WIN. Behavioral testing indicated that not only did WIN fail to exert any protective effect on ataxic symptoms; it exacerbated ataxic symptoms, suggesting that CB1R agonists may not be the ideal therapeutic drug in this disorder. When taken together, the findings from the present study indicate that cannabinoid modulation of ataxia symptoms may not act solely through CB1Rs and other cannabinoid receptors should be considered in future studies.
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The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.
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The authors thank Dr. Moazamehosadat Razavinasab for helping in the illustration provided in this article.
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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. MJ, KAK, and VS have critically reviewed the manuscript for its content, originality, usage of English language, and accuracy of interpreted data. MA carried out the immunohistochemistry experiment and preformed statistical analysis. 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.
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Communicated by Sreedharan Sajikumar.
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Ranjbar, H., Soti, M., Janahmadi, M. et al. Modulation of the CB1 cannabinoid receptor has potential therapeutic utility in the 3-acetylpyridine cerebellar ataxia rat model. Exp Brain Res 240, 2339–2348 (2022). https://doi.org/10.1007/s00221-022-06415-6
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DOI: https://doi.org/10.1007/s00221-022-06415-6