Valdeolivas Sara, Sagredo Onintza, Delgado Mercedes, Pozo Miguel A, Fernández-Ruiz Javier
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28040 Madrid, Spain.
Int J Mol Sci. 2017 Mar 23;18(4):684. doi: 10.3390/ijms18040684.
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 ∆⁸-tetrahydrocannabinol (∆⁸-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 + ∆⁸-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/-acetylaspartate, and -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.
几种大麻素在亨廷顿舞蹈病（HD）的实验模型中具有神经保护作用。我们研究了富含Δ⁸-四氢大麻酚（Δ⁸-THC）或大麻二酚（CBD）的植物提取物按1:1比例组合（这两种成分是大麻类药物萨替维克斯的主要成分）对R6/2小鼠（一种HD转基因模型）是否有益，因为先前已证明其在基于神经毒素的HD模型中具有积极作用。我们使用行为学、体内成像和生化方法，记录了R6/2小鼠及其相应野生型小鼠神经功能缺损的进展情况以及纹状体退化的程度。从出生后4周开始，小鼠每天接受一次植物大麻素的萨替维克斯样组合治疗（相当于3mg/kg体重的纯CBD + Δ⁸-THC）或赋形剂。R6/2小鼠在6周时开始出现特征性的转棒试验性能恶化，并持续进展至10周，同时反映肌张力障碍的抱握行为增加。植物大麻素的萨替维克斯样组合治疗并未恢复转棒试验性能，但明显减轻了抱握行为。对10周龄的R6/2动物进行的体内正电子发射断层扫描（PET）分析显示，基底神经节的代谢活性降低，而植物大麻素的萨替维克斯样组合治疗可部分减轻这种降低。对12周龄的R6/2小鼠离体纹状体进行的质子核磁共振波谱（H⁺-MRS）分析显示，各种预后标志物发生了变化，这些变化反映了HD患者和动物模型中常见的事件，如能量衰竭、线粒体功能障碍和兴奋性毒性。其中一些变化（牛磺酸/肌酸、牛磺酸/N-乙酰天门冬氨酸和N-乙酰天门冬氨酸/胆碱比值）通过植物大麻素的萨替维克斯样组合治疗完全逆转。在运动症状出现时给R6/2小鼠施用植物大麻素的萨替维克斯样组合，对这些小鼠纹状体退化的进展产生了一定益处，这支持了这种基于大麻素的药物在治疗HD患者疾病进展方面的应用价值。
