Faculty Collaboration Database

The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson's Disease. Cells 2021 Dec 16;10(12)

Date

12/25/2021

Pubmed ID

34944056

Pubmed Central ID

PMC8700250

DOI

10.3390/cells10123548

Scopus ID

2-s2.0-85121121427 (requires institutional sign-in at Scopus site)   14 Citations

Abstract

Parkinson's disease (PD) is a chronic neurodegenerative disorder associated with dopamine neuron loss and motor dysfunction. Neuroprotective agents that prevent dopamine neuron death hold great promise for slowing the disease's progression. The activation of cannabinoid (CB) receptors has shown neuroprotective effects in preclinical models of neurodegenerative disease, traumatic brain injury, and stroke, and may provide neuroprotection against PD. Here, we report that the selective CB2 agonist GW842166x exerted protective effects against the 6-hydroxydopamine (6-OHDA)-induced loss of dopamine neurons and its associated motor function deficits in mice, as shown by an improvement in balance beam walking, pole, grip strength, rotarod, and amphetamine-induced rotation tests. The neuroprotective effects of GW842166x were prevented by the CB2 receptor antagonist AM630, suggesting a CB2-dependent mechanism. To investigate potential mechanisms for the neuroprotective effects of GW842166x, we performed electrophysiological recordings from substantia nigra pars compacta (SNc) dopamine neurons in ex vivo midbrain slices prepared from drug-naïve mice. We found that the bath application of GW842166x led to a decrease in action potential firing, likely due to a decrease in hyperpolarization-activated currents (I_h) and a shift of the half-activation potential (V_1/2) of I_h to a more hyperpolarized level. Taken together, the CB2 agonist GW842166x may reduce the vulnerability of dopamine neurons to 6-OHDA by decreasing the action potential firing of these neurons and the associated calcium load.

Author List

Yu H, Liu X, Chen B, Vickstrom CR, Friedman V, Kelly TJ, Bai X, Zhao L, Hillard CJ, Liu QS

Authors

Xiaowen Bai PhD Associate Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin
Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Disease Models, Animal
Dopaminergic Neurons
Humans
Mice
Neuroprotective Agents
Oxidopamine
Parkinson Disease
Parkinson Disease, Secondary
Pars Compacta
Pyrans
Pyrimidines
Receptor, Cannabinoid, CB2