TY - JOUR

T1 - The cannabinoid antagonist, AM251 attenuates ataxia related deficiencies in a cerebellar ataxic model

AU - Ranjbar, Hoda

AU - Soti, Monavareh

AU - Kohlmeier, Kristi A.

AU - Sheibani, Vahid

AU - Ahmadi-Zeidabadi, Meysam

AU - Rafiepour, Kiana

AU - Shabani, Mohammad

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

KW - Ataxia

KW - cerebellum

KW - cannabinoid antagonist

KW - neuroprotective

KW - SEX-DIFFERENCES

KW - MOUSE MODEL

KW - RECEPTOR

KW - MOTOR

KW - CB1

KW - HIPPOCAMPUS

KW - DYSFUNCTION

KW - EXPOSURE

KW - SYSTEM

U2 - 10.1080/00207454.2022.2126771

DO - 10.1080/00207454.2022.2126771

M3 - Journal article

C2 - 36120979

VL - 134

SP - 522

EP - 529

JO - International Journal of Neuroscience

JF - International Journal of Neuroscience

SN - 0020-7454

IS - 5

ER -