Cannabinoids and Neuroprotection in Basal Ganglia Disorders

Abstract

Cannabinoids have been proposed as clinically promising neuroprotective molecules, as they are capable to reduce excitotoxicity, calcium influx, and oxidative injury. They are also able to decrease inflammation by acting on glial processes that regulate neuronal survival and to restore blood supply to injured area by reducing the vasoconstriction produced by several endothelium-derived factors. Through one or more of these processes, cannabinoids may provide neuroprotection in different neurodegenerative disorders including Parkinson's disease and Huntington's chorea, two chronic diseases that are originated as a consequence of the degeneration of specific nuclei of basal ganglia, resulting in a deterioration of the control of movement. Both diseases have been still scarcely explored at the clinical level for a possible application of cannabinoids to delay the progressive degeneration of the basal ganglia. However, the preclinical evidence seems to be solid and promising. There are two key mechanisms involved in the neuroprotection by cannabinoids in experimental models of these two disorders: first, a cannabinoid receptor-independent mechanism aimed at producing a decrease in the oxidative injury and second, an induction/upregulation of cannabinoid CB2 receptors, mainly in reactive microglia, that is capable to regulate the influence of these glial cells on neuronal homeostasis. Considering the relevance of these preclinical data and the lack of efficient neuroprotective strategies in both disorders, we urge the development of further studies that allow that the promising expectatives generated for these molecules progress from the present preclinical evidence till a real clinical application.

Reversal effect of simvastatin on the decrease in cannabinoid receptor 1 density in 6-hydroxydopamine lesioned rat brains

“…Among these previous studies, the evidence revealing an elevation in CB1 receptor expression is supportive of a view that a general overactivity of CB1 receptors and their endocannabinoids are an event that develops when the degeneration of nigral dopaminergic neurons has progressed to a certain degree and that major parkinsonian symptoms are already evident [13]. Furthermore, as for our study, the present findings of [ 3 H] SR141716A binding down-regulation with 6-OHDA lesion are likely an event that occurs during the early phases of the PD rodent model [13,42]. Previous studies (7) 6-OHDA treated with high simvastatin have identified that the dopaminergic dysfunction rather than cell death occurs at the same time as CB1 receptors malfunction, which is likely due to the close interactions between dopaminergic and cannabinergic system that are manifested.…”

Anti-neuroinflammatory Activity of a Novel Cannabinoid Derivative by Inhibiting the NF-κB Signaling Pathway in Lipopolysaccharide-Induced BV-2 Microglial Cells

“…Targeting of the CB1 receptor is useful for reducing bradykinesia and delaying L-dopa-induced dyskinesia (52). Various studies have reported the anti-inflammatory activity of CB1-receptor antagonists (53 -55) in animal models but the anti-neuroinflammatory activity of these molecules has not been evaluated with respect to neuroinflammatory disorders.…”

Oxidation of the Endogenous Cannabinoid Arachidonoyl Ethanolamide by the Cytochrome P450 Monooxygenases: Physiological and Pharmacological Implications

“…Use of anti-inflammatory therapy for reducing the harmful effects of microglia has been proposed based on numerous studies (Craft et al, 2005;Skaper, 2007). Selective CB2 receptor agonists, which lack psychotropic properties, are one class of anti-inflammatory agents that have therapeutic potential in reducing inflammation associated with chronic conditions such as Alzheimer's disease and multiple sclerosis, as well as acute CNS injury such as OXIDATIVE METABOLISM OF ANANDAMIDE BY CYTOCHROME P450S stroke and trauma (Carrier et al, 2004;Maresz et al, 2005;Ortega-Gutiérrez et al, 2005;Ramírez et al, 2005;Fernández-Ruiz et al, 2007;Sagredo et al, 2007). The anandamide product 5,6-EET-EA could be an endogenously produced mediator that can alter microglial activity.…”