Regulatory role of the endocannabinoid system on glial cells toward cognitive function in Alzheimer’s disease: A systematic review and meta-analysis of animal studies

Abstract

Objective: Over the last decade, researchers have sought to develop novel medications against dementia. One potential agent under investigation is cannabinoids. This review systematically appraised and meta-analyzed published pre-clinical research on the mechanism of endocannabinoid system modulation in glial cells and their effects on cognitive function in animal models of Alzheimer’s disease (AD).Methods: A systematic review complying with PRISMA guidelines was conducted. Six databases were searched: EBSCOHost, Scopus, PubMed, CINAHL, Cochrane, and Web of Science, using the keywords AD, cannabinoid, glial cells, and cognition. The methodological quality of each selected pre-clinical study was evaluated using the SYRCLE risk of bias tool. A random-effects model was applied to analyze the data and calculate the effect size, while I2 and p-values were used to assess heterogeneity.Results: The analysis included 26 original articles describing (1050 rodents) with AD-like symptoms. Rodents treated with cannabinoid agonists showed significant reductions in escape latency (standard mean difference [SMD] = −1.26; 95% confidence interval [CI]: −1.77 to −0.76, p < 0.00001) and ability to discriminate novel objects (SMD = 1.40; 95% CI: 1.04 to 1.76, p < 0.00001) compared to the control group. Furthermore, a significant decrease in Aβ plaques (SMD = −0.91; 95% CI: −1.55 to −0.27, p = 0.006) was observed in the endocannabinoid-treated group compared to the control group. Trends were observed toward neuroprotection, as represented by decreased levels of glial cell markers including glial fibrillary acid protein (SMD = −1.47; 95% CI: −2.56 to −0.38, p = 0.008) and Iba1 (SMD = −1.67; 95% CI: −2.56 to −0.79, p = 0.0002). Studies on the wild-type mice demonstrated significantly decreased levels of pro-inflammatory markers TNF-α, IL-1, and IL-6 (SMD = −2.28; 95% CI: −3.15 to −1.41, p = 0.00001). Despite the non-significant decrease in pro-inflammatory marker levels in transgenic mice (SMD = −0.47; 95% CI: −1.03 to 0.08, p = 0.09), the result favored the endocannabinoid-treated group over the control group.Conclusion: The revised data suggested that endocannabinoid stimulation promotes cognitive function via modulation of glial cells by decreasing pro-inflammatory markers in AD-like rodent models. Thus, cannabinoid agents may be required to modulate the downstream chain of effect to enhance cognitive stability against concurrent neuroinflammation in AD. Population-based studies and well-designed clinical trials are required to characterize the acceptability and real-world effectiveness of cannabinoid agents.Systematic Review Registration: [https://inplasy.com/inplasy-2022-8-0094/], identifier [Inplasy Protocol 3770].

Exploring Cannabinoids with Enhanced Binding Affinity for Targeting the Expanded Endocannabinoid System: A Promising Therapeutic Strategy for Alzheimer’s Disease Treatment

“…This interaction is especially significant, particularly in the early stages of the disease, such as during the upregulation of CB2 receptor expression involved in the development of neuroinflammation [ 34 ]. However, targeting the ECS is not without its challenges, as CB1 and CB2 receptors serve as essential regulators of neuronal function, exerting varied effects on neuronal responses [ 35 ].…”

Sex-Dependent Altered Expression of Cannabinoid Signaling in Hippocampal Astrocytes of the Triple Transgenic Mouse Model of Alzheimer’s Disease: Implications for Controlling Astroglial Activity

“…Numerous studies have shown the great potential of ECS to control degenerative diseases such as AD, due to its anti-inflammatory and neuroprotective properties that involve astrocyte engagements. Interestingly, cannabinoid signaling in glial cells essential has this function, since neuroimmunomodulation of glial cells by exogenous cannabinoid treatment enhances behavioral and cognitive responses, resulting in improved learning and memory-related symptoms in AD (for review see [ 29 ]).…”