Effects of a Sativex-Like Combination of Phytocannabinoids on Disease Progression in R6/2 Mice, an Experimental Model of Huntington's Disease.

Sara Valdeolivas,Miguel Pozo,Onintza Sagredo,Javier Fernández-Ruiz,Mercedes Delgado

doi:10.3390/ijms18040684

Abstract

Several cannabinoids afforded neuroprotection in experimental models of Huntington’s disease (HD). We investigated whether a 1:1 combination of botanical extracts enriched in either ∆9-tetrahydrocannabinol (∆9-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex®, is beneficial in R6/2 mice (a transgenic model of HD), as it was previously shown to have positive effects in neurotoxin-based models of HD. We recorded the progression of neurological deficits and the extent of striatal deterioration, using behavioral, in vivo imaging, and biochemical methods in R6/2 mice and their corresponding wild-type mice. The mice were daily treated, starting at 4 weeks after birth, with a Sativex-like combination of phytocannabinoids (equivalent to 3 mg/kg weight of pure CBD + ∆9-THC) or vehicle. R6/2 mice exhibited the characteristic deterioration in rotarod performance that initiated at 6 weeks and progressed up to 10 weeks, and elevated clasping behavior reflecting dystonia. Treatment with the Sativex-like combination of phytocannabinoids did not recover rotarod performance, but markedly attenuated clasping behavior. The in vivo positron emission tomography (PET) analysis of R6/2 animals at 10 weeks revealed a reduced metabolic activity in the basal ganglia, which was partially attenuated by treatment with the Sativex-like combination of phytocannabinoids. Proton nuclear magnetic resonance spectroscopy (H+-MRS) analysis of the ex vivo striatum of R6/2 mice at 12 weeks revealed changes in various prognostic markers reflecting events typically found in HD patients and animal models, such as energy failure, mitochondrial dysfunction, and excitotoxicity. Some of these changes (taurine/creatine, taurine/N-acetylaspartate, and N-acetylaspartate/choline ratios) were completely reversed by treatment with the Sativex-like combination of phytocannabinoids. A Sativex-like combination of phytocannabinoids administered to R6/2 mice at the onset of motor symptoms produced certain benefits on the progression of striatal deterioration in these mice, which supports the interest of this cannabinoid-based medicine for the treatment of disease progression in HD patients.

Highlights

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor alterations, and cognitive dysfunction and psychiatric symptoms [1]
We found that, using the Sativex-like combination of these two phytocannabinoids, striatal neurons were preserved against the 3-nitropropionic acid (3NP) intoxication and, again, we found that such a neuroprotective effect was CB1/CB2 receptor independent [18]
This loss of weight has been widely reported in R6/2 mice [9,10] and in other transgenic models of HD [27,28]

Summary

Introduction

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor alterations (chorea followed by akinesia), and cognitive dysfunction and psychiatric symptoms [1]. Continuing on from an extensive preclinical evaluation using different experimental models of HD, clinical tests are being performed with cannabinoids [4]. Such preclinical evaluation demonstrated preservation of striatal neurons by several cannabinoid agonists against different cytotoxic stimuli that operate in HD pathogenesis [5,6]. These beneficial effects were exerted through multiple mechanisms of action, some of which involve the activation of CB1 and/or CB2 receptors and others of which do not. Selective agonists of CB1 [10,13] and CB2 [11] receptors preserved striatal neurons in in vitro or in vivo excitotoxic models, whereas other authors did not find any beneficial effect in R6/1 mice using ∆9-THC, the synthetic agonist HU-210, and the inhibitor of the endocannabinoid metabolism URB597 [14]

Methods

Results

Discussion

Conclusion