AUTHOR=Kamaruzzaman Mohd Amir , Romli Muhammad Hibatullah , Abas Razif , Vidyadaran Sharmili , Hidayat Baharuldin Mohamad Taufik , Nasaruddin Muhammad Luqman , Thirupathirao Vishnumukkala , Sura Sreenivasulu , Warsito Kabul , Mohd Nor Nurul Huda , Azwaruddin Muhammad Amsyar , Alshawsh Mohammed Abdullah , Mohd Moklas Mohamad Aris 

TITLE=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

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1053680

DOI=10.3389/fphar.2023.1053680

ISSN=1663-9812

ABSTRACT=<p><bold>Objective:</bold> 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).</p><p><bold>Methods:</bold> 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 I<sup>2</sup> and <italic>p</italic>-values were used to assess heterogeneity.</p><p><bold>Results:</bold> 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, <italic>p</italic> &lt; 0.00001) and ability to discriminate novel objects (SMD = 1.40; 95% CI: 1.04 to 1.76, <italic>p</italic> &lt; 0.00001) compared to the control group. Furthermore, a significant decrease in Aβ plaques (SMD = −0.91; 95% CI: −1.55 to −0.27, <italic>p</italic> = 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, <italic>p</italic> = 0.008) and Iba1 (SMD = −1.67; 95% CI: −2.56 to −0.79, <italic>p</italic> = 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, <italic>p</italic> = 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, <italic>p</italic> = 0.09), the result favored the endocannabinoid-treated group over the control group.</p><p><bold>Conclusion:</bold> The revised data suggested that endocannabinoid stimulation promotes cognitive function <italic>via</italic> 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.</p><p><bold>Systematic Review Registration:</bold> [<ext-link ext-link-type="uri" xlink:href="https://inplasy.com/inplasy-2022-8-0094/" xmlns:xlink="http://www.w3.org/1999/xlink">https://inplasy.com/inplasy-2022-8-0094/</ext-link>], identifier [Inplasy Protocol 3770].</p>