WIN55,212‐2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mouse model of Parkinson’s disease

Abstract

Parkinson's disease (PD) is characterized by the progressive loss of nigrostriatal dopamine (DA) neurons leading to motor disturbances and cognitive impairment. Current pharmacotherapies relieve PD symptoms temporarily but fail to prevent or slow down the disease progression. In this study, we investigated the molecular mechanisms by which the non-selective cannabinoid receptor agonist WIN55,212-2 (WIN) protects mouse nigrostriatal neurons from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity and neuroinflammation. Stereological analyses showed that chronic treatment with WIN (4 mg/kg, i.p.), initiated 24 hr after MPTP administration, protected against MPTP-induced loss of tyrosine hydroxylase positive (TH + ) neurons in the substantia nigra pars compacta (SNc) independently of CB 1 cannabinoid receptor activation. The neuroprotective effect of WIN was accompanied by increased DA and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the SNc and dorsal striatum of MPTP-treated mice. Three days post-MPTP, we found significant microglial activation and up-regulation of CB 2 cannabinoid receptors in the ventral midbrain. Treatment with WIN or the CB 2 receptor agonist JWH015 (4 mg/kg, i.p.) reduced MPTP-induced microglial activation, whereas genetic ablation of CB 2 receptors exacerbated MPTP systemic toxicity. Furthermore, chronic WIN reversed MPTPassociated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults using the inverted grid test. In conclusion, our data indicate that agonism at CB 2 cannabinoid receptors protects against MPTP-induced nigrostriatal degeneration by inhibiting microglial activation/infiltration and suggest that CB 2 receptors represent a new therapeutic target to slow the degenerative process occurring in PD.

Cannabinoid Receptor Type 1 Protects Nigrostriatal Dopaminergic Neurons against MPTP Neurotoxicity by Inhibiting Microglial Activation

“…However, these results may be irrelevant for CB 1 receptor-independent neuroprotection in the MPTP model (42). WIN55,212-2 rescued nigrostriatal DA neurons and inhibited microglial activation in CB 1 receptor knockout mice treated with MPTP, indicating CB 1 receptor-independent activity.…”

“…The inconsistent experimental results between the two studies are probably a result of the different methods used for CB 1 receptor inhibition (genetic ablation of CB 1 receptor versus pharmacological inhibition) and varying drug doses (20 mg/kg versus 4 mg/kg) of WIN55,212-2. Alternatively, MPTP metabolism (conversion of MPTP into MPP + ) may be altered in CB 1 receptor knockout mice, compared with their wild-type counterparts, because MPTP-induced neurotoxicity is significantly lower in CB 1 receptor knockout mice (42).…”

Cannabinoids in Neurodegenerative Disorders and Stroke/Brain Trauma: From Preclinical Models to Clinical Applications

“…Neuroprotection has also been provided by synthetic cannabinoids such as the endocannabinoid transporter inhibitor/vanilloid agonist AM404 [110], or the CB 1 R/CB 2 R agonist CP55,940 [112], which are also antioxidant and also work through cannabinoid receptor-independent mechanisms in this case. In contrast, cannabinoids that selectively target the CB 2 R were also active against local inflammation and gliosis in models of mitochondrial dysfunction or LPS insult [111,113,114], a fact also supported by studies conducted with classic parkinsonian neurotoxins administered to mice with genetic deletion of the CB 2 R (greater vulnerability against the insult) or overexpressing these receptors (lower susceptibility against the insult) [111,115]. CB 1 R-activating compounds have also been studied, but with controversial results [110,116].…”

“…Again, these pharmacological effects may be influenced by the changes that the endocannabinoid system experienced in this disease, as revealed by the data collected in postmortem tissues and biological fluids [114,118,119], as well as those found in animal models [111,113,118,120]. They include: 1) the upregulation of CB 1 R in striatal neurons under the control of dopaminergic neurons that degenerate in PD, as observed in postmortem tissue from patients and in different experimental models of the disease (reviewed in [108]); 1) the elevation of CB 2 R in glia recruited to the lesion sites in the postmortem substantia nigra of patients with PD and in mice lesioned with MPTP or LPS [111,113,114]; and 3) the loss of neuronal CB 2 R in postmortem tissues of patients with PD due to the degeneration of nigrostriatal dopaminergic neurons [121,122].…”

“…They include: 1) the upregulation of CB 1 R in striatal neurons under the control of dopaminergic neurons that degenerate in PD, as observed in postmortem tissue from patients and in different experimental models of the disease (reviewed in [108]); 1) the elevation of CB 2 R in glia recruited to the lesion sites in the postmortem substantia nigra of patients with PD and in mice lesioned with MPTP or LPS [111,113,114]; and 3) the loss of neuronal CB 2 R in postmortem tissues of patients with PD due to the degeneration of nigrostriatal dopaminergic neurons [121,122].…”