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.
Highlights
The endocannabinoid system, consisting of cannabinoid receptors type 1 and 2 (CB1 and cannabinoid receptor type 2 (CB2)), their endogenous ligands, and the enzymes for synthesis, reuptake and metabolism of the endocannabinoids, has emerged as an important neuromodulator system for many brain functions such as learning, memory, mood, addiction, and reward processing (Hill et al, 2009; Zanettini et al, 2011)
We observed that AM630 administration to ROT-injected rats did not cause any change in the expression of CB2 receptors when compared to ROT-injected rats (63.28 vs. 62.56%)
The control group (CONT) and AM630-only groups of rats did not show any marked differences in the expression level of CB2 receptors (98.19 vs. 100% control)
Summary
The endocannabinoid system, consisting of cannabinoid receptors type 1 and 2 (CB1 and CB2), their endogenous ligands, and the enzymes for synthesis, reuptake and metabolism of the endocannabinoids, has emerged as an important neuromodulator system for many brain functions such as learning, memory, mood, addiction, and reward processing (Hill et al, 2009; Zanettini et al, 2011). Β-caryophyllene (BCP) generated enormous therapeutic interest due to its noteworthy identification as a fully selective agonist of CB2 receptors, its affinity and binding with CB2, receptors along with favorable physicochemical and pharmacokinetic properties (Figure 1; Gertsch et al, 2008). It is one of the widely available dietary phytocannabinoids and is commonly used as a preservative, additive, and flavoring in food and cosmetics. The identification and participation of CB2 receptors in mediating neuroprotection has driven special interest in the pharmacological investigation of BCP for neurodegenerative disorders including PD
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