The cannabinoid receptor agonist WIN 55,212-2 attenuates the effects induced by quinolinic acid in the rat striatum

Abstract

The cannabinoid receptor agonist WIN 55,212-2 attenuates the effects induced by quinolinic acid in the rat striatum AbstractThe ability of CB 1 receptors to regulate the release of glutamate in the striatum, together with the finding that, in experimental models of Huntington disease (HD), both endocannabinoid levels and CB 1 receptor densities are reduced, has prompted the investigation on the neuroprotective role of the cannabinoids in HD. Quinolinic acid (QA) is an excitotoxin that, when injected in the rat striatum reproduces many features of HD and that acts by stimulating glutamate outflow. The aim of the present study was to test the ability of the cannabinoid receptor agonist WIN 55,212-2 to prevent the effects induced by QA in the rat striatum. In microdialysis experiments, probe perfusion with WIN 55,212-2 significantly and dose-dependently prevented the increase in extracellular glutamate induced by QA. In electrophysiological recordings in corticostriatal slices, the application of WIN 55,212-2 prevented QA-induced reduction of the field potential amplitude. Both effects of WIN 55,212-2 were prevented by the CB 1 receptor antagonist AM 251. In in vivo experiments, intrastriatal WIN 55,212-2 significantly attenuated the striatal damage induced by QA, although no significant effects were observed on a behavioural ground.These data demonstrate that the stimulation of CB 1 receptors might lead to neuroprotective effects against excitotoxic striatal toxicity.

Type 1 cannabinoid receptor mapping with [18F]MK-9470 PET in the rat brain after quinolinic acid lesion: a comparison to dopamine receptors and glucose metabolism

“…In experimental and human HD, corticostriatal glutamatergic transmission is severely impaired (for review see [36]), and QA lesions result in a secondary dying back of these terminals [37]. Relative upregulation of this CB 1 receptor population could conceivably represent a compensatory response, damping the excessive corticostriatal glutamatergic drive that results from QA infusion [38] and reducing the excitotoxic mechanisms underlying HD [39]. However, within the caudate-putamen, CB 1 receptors are also expressed on striatal GABAergic interneurons that are labelled with parvalbumin and a few interneurons of the cholinergic population [40], from which their contribution to the observed effect cannot be excluded.…”

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

“…This was supported by an exhaustive preclinical work with positive results in a broad spectrum of animal models of HD (e.g., R6/2 mice, quinolinate-lesioned mice, 3-nitropropionate-or malonate-lesioned rats), which confirmed the benefits of cannabinoids against most of the cytotoxic stimuli acting in this disease (reviewed in [1,2,131]). For example, compounds targeting the CB 1 R preserved striatal neurons in studies conducted in a rat model that relies on quinolinate-induced excitotoxic damage [132]. The relevance of these receptors in HD was also demonstrated in a genetic model of the disease, R6/2 mice, in which CB 1 R activation again preserved striatal neurons from death, whereas striatal damage was aggravated in R6/2 mice having a genetic deficiency in CB 1 R [133].…”

“…This may explain why an early stimulation of these receptors may dampen their impairment, thereby maintaining their capacity to inhibit the excitotoxic events that initiate the damage to striatal neurons [132], although such an approach is unlikely to work at later symptomatic stages that are characterized by an important loss of CB 1 R-containing striatal neurons [117]. However, as recent study unequivocally demonstrated that CB 1 R-dependent neuroprotective activity in HD is predominantly derived from a restricted population of these receptors on cortical glutamatergic neurons that project to the striatum and that are preserved during the progression of HD rather than from the CB 1 R located on striatal projection γ-aminobutyric acid (GABA)-ergic neurons that are progressively lost during disease progression [142], supporting the relevance of these receptors as potential targets for a neuroprotective therapy with cannabinoids in HD.…”

Neuroprotective Properties of Cannabigerol in Huntington's Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice

“…Importantly, following on from an extensive preclinical evaluation using different experimental models of HD (reviewed in [4] and [5]), clinical tests are now being performed with cannabinoids. Using experimental models that reproduce different cytotoxic stimuli that operate in HD pathogenesis, for example rodents treated with mitochondrial toxins (e.g., inhibitors of mitochondrial complex II), quinolinate-lesioned mice, or transgenic mice bearing mutated forms of human huntingtin, preclinical studies with cannabinoids demonstrated preservation of striatal neurons [6][7][8][9][10][11]. The beneficial effects of cannabinoids were exerted through multiple mechanisms of action, including cannabinoid receptor type 1 (CB 1 ) activation (e.g., excitotoxic models [8,11]), cannabinoid receptor type 2 (CB 2 ) activation (e.g., inflammatory models [10]), and CB 1 /CB 2 -independent mechanisms.…”