Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain.
Institut d'Investigacions Biomèdiques de Barcelona (IIBB-CSIC), 08036 Barcelona, Spain; Department of Biomedicine, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, 28029 Madrid, Spain; Universitat de Vic-Universitat Central de Catalunya (UVic-UCC), Institut de Recerca i Innovació en Ciències de la Vida i de la Salut a la Catalunya Central (IRIS-CC), 08500 Vic, Spain.
Neurotherapeutics. 2024 Sep;21(5):e00439. doi: 10.1016/j.neurot.2024.e00439. Epub 2024 Sep 3.
A combination of Δ-tetrahydrocannabinol (Δ-THC) and cannabidiol (CBD) at non-psychoactive doses was previously demonstrated to reduce cognitive decline in APP/PS1 mice, an animal model of Alzheimer's disease (AD). However, the neurobiological substrates underlying these therapeutic properties of Δ-THC and CBD are not fully understood. Considering that dysregulation of glutamatergic activity contributes to cognitive impairment in AD, the present study evaluates the hypothesis that the combination of these two natural cannabinoids might reverse the alterations in glutamate dynamics within the hippocampus of this animal model of AD. Interestingly, our findings reveal that chronic treatment with Δ-THC and CBD, but not with any of them alone, reduces extracellular glutamate levels and the basal excitability of the hippocampus in APP/PS1 mice. These effects are not related to significant changes in the function and structure of glutamate synapses, as no relevant changes in synaptic plasticity, glutamate signaling or in the levels of key components of these synapses were observed in cannabinoid-treated mice. Our data instead indicate that these cannabinoid effects are associated with the control of glutamate uptake and/or to the regulation of the hippocampal network. Taken together, these results support the potential therapeutic properties of combining these natural cannabinoids against the excitotoxicity that occurs in AD brains.
先前的研究表明，低浓度的Δ-四氢大麻酚（Δ-THC）和大麻二酚（CBD）联合使用可以减少 APP/PS1 小鼠（阿尔茨海默病的动物模型）的认知能力下降。然而，Δ-THC 和 CBD 的这些治疗特性的神经生物学基础尚不完全清楚。鉴于谷氨酸能活动的失调会导致 AD 中的认知障碍，本研究评估了这样一个假设，即这两种天然大麻素的组合可能会逆转 AD 动物模型中海马内谷氨酸动力学的改变。有趣的是，我们的研究结果表明，Δ-THC 和 CBD 的慢性治疗（但不是单独使用它们中的任何一种）可以降低 APP/PS1 小鼠中海马体的细胞外谷氨酸水平和基础兴奋性。这些作用与谷氨酸突触的功能和结构的显著变化无关，因为在大麻素处理的小鼠中没有观察到突触可塑性、谷氨酸信号或这些突触的关键成分水平的任何相关变化。相反，我们的数据表明，这些大麻素的作用与控制谷氨酸摄取和/或调节海马网络有关。综上所述，这些结果支持联合使用这些天然大麻素来对抗 AD 大脑中发生的兴奋性毒性的潜在治疗特性。
