The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson’s Disease
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 neur...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Online Access: | https://www.mdpi.com/2073-4409/10/12/3548 |
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| author | Hao Yu Xiaojie Liu Bixuan Chen Casey R. Vickstrom Vladislav Friedman Thomas J. Kelly Xiaowen Bai Li Zhao Cecilia J. Hillard Qing-Song Liu |
| author_facet | Hao Yu Xiaojie Liu Bixuan Chen Casey R. Vickstrom Vladislav Friedman Thomas J. Kelly Xiaowen Bai Li Zhao Cecilia J. Hillard Qing-Song Liu |
| author_sort | Hao Yu |
| collection | DOAJ |
| description | 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<sub>h</sub>) and a shift of the half-activation potential (<i>V</i><sub>1/2</sub>) of I<sub>h</sub> 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. |
| first_indexed | 2024-03-10T04:24:58Z |
| format | Article |
| id | doaj.art-959db8bfb1994f41bedb4f7528603162 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T04:24:58Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-959db8bfb1994f41bedb4f75286031622023-11-23T07:39:19ZengMDPI AGCells2073-44092021-12-011012354810.3390/cells10123548The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson’s DiseaseHao Yu0Xiaojie Liu1Bixuan Chen2Casey R. Vickstrom3Vladislav Friedman4Thomas J. Kelly5Xiaowen Bai6Li Zhao7Cecilia J. Hillard8Qing-Song Liu9Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USADepartment of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USADepartment of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USADepartment of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USADepartment of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USADepartment of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USADepartment of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USADepartment of Exercise Physiology, Beijing Sport University, Beijing 100084, ChinaDepartment of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USADepartment of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USAParkinson’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<sub>h</sub>) and a shift of the half-activation potential (<i>V</i><sub>1/2</sub>) of I<sub>h</sub> 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.https://www.mdpi.com/2073-4409/10/12/3548Parkinson’s disease6-OHDAGW842166xdopamine neuronmotor functionI<sub>h</sub> |
| spellingShingle | Hao Yu Xiaojie Liu Bixuan Chen Casey R. Vickstrom Vladislav Friedman Thomas J. Kelly Xiaowen Bai Li Zhao Cecilia J. Hillard Qing-Song Liu The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson’s Disease Cells Parkinson’s disease 6-OHDA GW842166x dopamine neuron motor function I<sub>h</sub> |
| title | The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson’s Disease |
| title_full | The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson’s Disease |
| title_fullStr | The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson’s Disease |
| title_full_unstemmed | The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson’s Disease |
| title_short | The Neuroprotective Effects of the CB2 Agonist GW842166x in the 6-OHDA Mouse Model of Parkinson’s Disease |
| title_sort | neuroprotective effects of the cb2 agonist gw842166x in the 6 ohda mouse model of parkinson s disease |
| topic | Parkinson’s disease 6-OHDA GW842166x dopamine neuron motor function I<sub>h</sub> |
| url | https://www.mdpi.com/2073-4409/10/12/3548 |
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