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

Abstract

This study examined whether the cannabinoid receptor type 1 (CB1) receptor contributes to the survival of nigrostriatal dopaminergic (DA) neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson’s disease. MPTP induced significant loss of nigrostriatal DA neurons and microglial activation in the substantia nigra (SN), visualized with tyrosine hydroxylase or macrophage Ag complex-1 immunohistochemistry. Real-time PCR, ELISA, Western blotting, and immunohistochemistry disclosed upregulation of proinflammatory cytokines, activation of microglial NADPH oxidase, and subsequent reactive oxygen species production and oxidative damage of DNA and proteins in MPTP-treated SN, resulting in degeneration of DA neurons. Conversely, treatment with nonselective cannabinoid receptor agonists (WIN55,212-2 and HU210) led to increased survival of DA neurons in the SN, their fibers and dopamine levels in the striatum, and improved motor function. This neuroprotection by cannabinoids was accompanied by suppression of NADPH oxidase reactive oxygen species production and reduced expression of proinflammatory cytokines from activated microglia. Interestingly, cannabinoids protected DA neurons against 1-methyl-4-phenyl-pyridinium neurotoxicity in cocultures of mesencephalic neurons and microglia, but not in neuron-enriched mesencephalic cultures devoid of microglia. The observed neuroprotection and inhibition of microglial activation were reversed upon treatment with CB1 receptor selective antagonists AM251 and/or SR14,716A, confirming the involvement of the CB1 receptor. The present in vivo and in vitro findings clearly indicate that the CB1 receptor possesses anti-inflammatory properties and inhibits microglia-mediated oxidative stress. Our results collectively suggest that the cannabinoid system is beneficial for the treatment of Parkinson’s disease and other disorders associated with neuroinflammation and microglia-derived oxidative damage.

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

“…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]. Nevertheless, a neuroprotective strategy based on targeting CB 1 R might have some disadvantages in PD as the hypokinetic effects of CB 1 R may worsen bradykinesia and other parkinsonian symptoms [108], whereas the blockade of these receptors may reduce parkinsonian akinesia [117].…”

Cannabis users have higher premorbid IQ than other patients with first onset psychosis

“…A second possible explanation, based on research into animal models of Parkinson's disease and Alzheimer's disease (Ramirez et al, 2005;Chung et al, 2011;Martìn-Moreno et al, 2011), suggests that some cannabinoids have a neuroprotective action which may help to prevent psychosis-related cognitive decline (Jockers-Scherübl et al, 2007;Løberg and Hugdahl, 2009).…”

Exposure of Adolescent Mice to Delta-9-Tetrahydrocannabinol Induces Long-Lasting Modulation of Pro- and Anti-Inflammatory Cytokines in Hypothalamus and Hippocampus Similar to that Observed for Peripheral Macrophages

“…Depending on the model or the duration of treatment, THC has been shown to either inhibit (Chung et al 2011;Aso et al 2013) or induce neuroinflammation (Cutando et al 2013) as well as switch microglia Bon^or Boff^ (Fraga et al 2011;Cutando et al 2013;Suárez-Pinilla et al 2014). For these reasons, in the present work we investigated whether acute or chronic THC treatment exerts a similar regulation of pro-and anti-inflammatory cytokines in peripheral macrophages and in brain regions rich in cannabinoid receptors (CBRs), such as the hypothalamus and hippocampus (Herkenham et al 1990).…”