Cannabinoid Type 2 (CB2) Receptors Activation Protects against Oxidative Stress and Neuroinflammation Associated Dopaminergic Neurodegeneration in Rotenone Model of Parkinson's Disease

Abstract

The cannabinoid type two receptors (CB2), an important component of the endocannabinoid system, have recently emerged as neuromodulators and therapeutic targets for neurodegenerative diseases including Parkinson's disease (PD). The downregulation of CB2 receptors has been reported in the brains of PD patients. Therefore, both the activation and the upregulation of the CB2 receptors are believed to protect against the neurodegenerative changes in PD. In the present study, we investigated the CB2 receptor-mediated neuroprotective effect of β-caryophyllene (BCP), a naturally occurring CB2 receptor agonist, in, a clinically relevant, rotenone (ROT)-induced animal model of PD. ROT (2.5 mg/kg BW) was injected intraperitoneally (i.p.) once daily for 4 weeks to induce PD in male Wistar rats. ROT injections induced a significant loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and DA striatal fibers, following activation of glial cells (astrocytes and microglia). ROT also caused oxidative injury evidenced by the loss of antioxidant enzymes and increased nitrite levels, and induction of proinflammatory cytokines: IL-1β, IL-6 and TNF-α, as well as inflammatory mediators: NF-κB, COX-2, and iNOS. However, treatment with BCP attenuated induction of proinflammatory cytokines and inflammatory mediators in ROT-challenged rats. BCP supplementation also prevented depletion of glutathione concomitant to reduced lipid peroxidation and augmentation of antioxidant enzymes: SOD and catalase. The results were further supported by tyrosine hydroxylase immunohistochemistry, which illustrated the rescue of the DA neurons and fibers subsequent to reduced activation of glial cells. Interestingly, BCP supplementation demonstrated the potent therapeutic effects against ROT-induced neurodegeneration, which was evidenced by BCP-mediated CB2 receptor activation and the fact that, prior administration of the CB2 receptor antagonist AM630 diminished the beneficial effects of BCP. The present study suggests that BCP has the potential therapeutic efficacy to elicit significant neuroprotection by its anti-inflammatory and antioxidant activities mediated by activation of the CB2 receptors.

Involvement of c-Abl Kinase in Microglial Activation of NLRP3 Inflammasome and Impairment in Autolysosomal System

“…Upon ROT administration, microglia-derived ROS such as superoxide, hydroxyl, and peroxynitrite has been shown to cause selective degeneration of SNc, owing to low levels of antioxidant defense and accompanying high levels of DA metabolism (Javed et al, 2016). More specifically, microglia derived ROS was found to be indispensable for ROT-induced DA degeneration (Gao et al, 2003).…”

Endocannabinoid system in neurodegenerative disorders

“…Similarly, the CB2R agonist β‐caryophyllene demonstrated neuroprotection by virtue of its anti‐inflammatory and antioxidant properties (Javed et al . ). Studies using leucine‐rich repeat kinase 2 (LRRK2)‐transgenic mice also demonstrated CB2 receptor as a potential pharmacological target to treat PD (Palomo‐Garo et al .…”

β-Caryophyllene/Hydroxypropyl-β-Cyclodextrin Inclusion Complex Improves Cognitive Deficits in Rats with Vascular Dementia through the Cannabinoid Receptor Type 2 -Mediated Pathway

“…Administration of CB2 agonist can reduce the infract size of the brain and motor functional deficits and restrain the production of adhesion factor and matrix metalloproteinases, inhibit the inflammatory response, and improve the microcirculation after cerebral ischemia (Fernández-Ruiz et al, 2007; Benito et al, 2008; Pini et al, 2012). The CB2 can be upregulated in multiple central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and stroke (Capettini et al, 2012; Javed et al, 2016). The CB2 signaling mechanism is associated with the activation of the phosphatidylinositol 3-kinase (PI3K–Akt) pathway (Molina-Holgado et al, 2002; Palazuelos et al, 2006; Fernández-Ruiz et al, 2007).…”