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 (Ih) and a shift of the half-activation potential (V1/2) of Ih 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.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with motor dysfunction and neuropsychiatric symptoms, primarily characterized by the agedependent loss of dopaminergic projections in the nigrostriatal pathway [1,2]
We examined whether the CB2-selective agonist GW842166x protected against dopamine neuron loss in the substantia nigra pars compacta (SNc)
Tukey’s post hoc tests indicated that the 6-OHDA injection significantly reduced the number of tyrosine hydroxylase (TH)+ dopamine neurons in the SNc compared with the vehicle injection (p < 0.001; Figure 1c)
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with motor dysfunction and neuropsychiatric symptoms, primarily characterized by the agedependent loss of dopaminergic projections in the nigrostriatal pathway [1,2]. The classical motor symptoms of PD include bradykinesia, resting tremors, rigidity, and postural instability [2,3]. These symptoms arise from the progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc) and the reduction in dopamine release in the striatum. The identification of neuroprotective agents that can prevent or slow the death of dopamine neurons holds great promise for slowing disease progression and reducing the risk of onset in vulnerable individuals
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