Fernández-Ruiz Javier, Sagredo Onintza, Gómez-Ruiz María, de Lago Eva
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.
Curr Top Behav Neurosci. 2025 Jul 25. doi: 10.1007/7854_2025_597.
Numerous studies carried out in the last 30-40 years have strongly demonstrated that the endocannabinoid system exerts important modulatory functions in the central nervous system (CNS). These neuromodulatory functions encompass the whole life of animals, with specific activities during neurodevelopment (prenatal, postnatal and adolescent periods), adulthood and possibly senescence too. However, this is the life stage less investigated in relation with the endocannabinoid system to date. In the aged brain, the activity of this system appears to be altered, which contributes to subtle impairments that typically occur during ageing in learning and memory, motor behaviour, social behaviour and other neurobiological functions. Some of the changes in endocannabinoid activity may represent a process to attenuate ageing-related impairment in the brain function, which is consistent with its role as a pro-homeostatic system. An important observation is that these alterations become extreme when normal brain ageing acquires pathological characteristics, as happens in chronic neurodegenerative disorders. This includes the cannabinoid type-1 (CB) receptor downregulation or impairment in its signalling and the increase in endocannabinoid-inactivating enzymes, both hypothesised to contribute to pathogenic events. By contrast, elevated levels of endocannabinoids due to a reduced Fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MAGL) expression and the upregulation of cannabinoid type-2 (CB) receptors may in turn serve as endogenous pro-homeostatic adaptations against brain impairment. This review synthesises information on: (i) subtle alterations in the endocannabinoid system in the senescent brain in the absence of pathology, with the purpose of demonstrating that these alterations are representative of the extreme changes experienced by this system in the brain pathological ageing; and (ii) the development of neuroprotective therapies based on the pharmacological management of specific endocannabinoid targets to combat neurodegenerative pathologies. Together, research in this area comes at a critical time as global lifespan is increasing, incidence of age-related neurodegenerative disorders is expanding, and the unmet need for efficacious neuroprotective treatments is a public health necessity.
过去30至40年进行的大量研究有力地证明，内源性大麻素系统在中枢神经系统（CNS）中发挥着重要的调节功能。这些神经调节功能贯穿动物的整个生命周期，在神经发育（产前、产后和青少年期）、成年期甚至可能在衰老期都有特定的活动。然而，这是迄今为止与内源性大麻素系统相关研究较少的生命阶段。在老年大脑中，该系统的活性似乎发生了改变，这导致了衰老过程中通常会出现的学习和记忆、运动行为、社会行为及其他神经生物学功能的细微损害。内源性大麻素活性的一些变化可能代表了一种减轻大脑功能衰老相关损伤的过程，这与其作为促稳态系统的作用相一致。一个重要的观察结果是，当正常的大脑衰老具有病理特征时，这些改变会变得更加极端，慢性神经退行性疾病中就是如此。这包括1型大麻素（CB）受体下调或其信号传导受损，以及内源性大麻素失活酶增加，这两者都被认为与致病事件有关。相比之下，由于脂肪酸酰胺水解酶（FAAH）和单酰甘油脂肪酶（MAGL）表达降低导致内源性大麻素水平升高，以及2型大麻素（CB）受体上调，可能反过来作为针对脑损伤的内源性促稳态适应机制。本综述综合了以下信息：（i）在无病理状态下衰老大脑中内源性大麻素系统的细微改变，目的是证明这些改变代表了该系统在大脑病理衰老过程中所经历的极端变化；（ii）基于对特定内源性大麻素靶点的药理管理来对抗神经退行性疾病的神经保护疗法的发展。随着全球寿命的增加、与年龄相关的神经退行性疾病发病率的扩大以及对有效神经保护治疗的未满足需求成为公共卫生必需，该领域的研究恰逢关键时期。
