Instituto Universitario de Investigación en Neuroquímica, Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Biomed Pharmacother. 2024 May;174:116473. doi: 10.1016/j.biopha.2024.116473. Epub 2024 Mar 24.
The elevation of endocannabinoid levels through inhibiting their degradation afforded neuroprotection in CaMKIIα-TDP-43 mice, a conditional transgenic model of frontotemporal dementia. However, which cannabinoid receptors are mediating these benefits is still pending to be elucidated.
We have investigated the involvement of the CB and the CB receptor using chronic treatments with selective ligands in CaMKIIα-TDP-43 mice, analysis of their cognitive deterioration with the Novel Object Recognition test, and immunostaining for neuronal and glial markers in two areas of interest in frontotemporal dementia.
Our results confirmed the therapeutic value of activating either the CB or the CB receptor, with improvements in the animal performance in the Novel Object Recognition test, preservation of pyramidal neurons, in particular in the medial prefrontal cortex, and attenuation of glial reactivity, in particular in the hippocampus. In addition, the activation of both CB and CB receptors reduced the elevated levels of TDP-43 in the medial prefrontal cortex of CaMKIIα-TDP-43 mice, an effect exerted by mechanisms that are currently under investigation.
These data reinforce the notion that the activation of CB and CB receptors may represent a promising therapy against TDP-43-induced neuropathology in frontotemporal dementia. Future studies will have to confirm these benefits, in particular with one of the selective CB agonists used here, which has been thoroughly characterized for clinical development.
通过抑制内源性大麻素的降解来提高其水平，为 CaMKIIα-TDP-43 小鼠（额颞叶痴呆的条件性转基因模型）提供了神经保护。然而，哪种大麻素受体介导了这些益处仍有待阐明。
我们使用选择性配体对 CaMKIIα-TDP-43 小鼠进行慢性治疗，研究了 CB 和 CB 受体的参与情况，通过新物体识别测试分析其认知恶化情况，并对额颞叶痴呆两个感兴趣区域的神经元和神经胶质标志物进行免疫染色。
我们的结果证实了激活 CB 或 CB 受体的治疗价值，在新物体识别测试中改善了动物的表现，保留了锥体神经元，特别是在额前皮质，同时减轻了神经胶质反应，特别是在海马体中。此外，激活 CB 和 CB 受体均可降低 CaMKIIα-TDP-43 小鼠额前皮质中 TDP-43 的升高水平，这种作用是通过目前正在研究的机制发挥的。
这些数据强化了这样一种观点，即激活 CB 和 CB 受体可能代表了针对额颞叶痴呆中 TDP-43 诱导的神经病理学的一种有前途的治疗方法。未来的研究将不得不确认这些益处，特别是使用这里使用的一种选择性 CB 激动剂，该激动剂已为临床开发进行了彻底的表征。
