A Systematic Review of Preclinical Studies Investigating the Effects of Pharmacological Agents on Learning and Memory in Prolonged Aluminum-Exposure-Induced Neurotoxicity

Background: Aluminum accumulation in the brain causes cognitive deficits. No comprehensive synthesis of pharmacological treatments against aluminum neurotoxicity has been conducted, which led us to systematically review the effects of various pharmacological agents against aluminum-induced neurotoxicity, primarily addressing learning and memory after chronic aluminum exposure (≥2 months) in rodent models. Methods: A literature search was performed in PubMed, Google Scholar, Science Direct, and Scopus for studies published between 2000 and 2023. A total of 45 studies were selected according to the inclusion criteria. Primary outcomes focused on assessing learning and memory, with 39 different pharmacological agents evaluated explicitly for their effects against aluminum-induced neurotoxicity. Meta-analysis and subgroup analysis were performed to evaluate cognitive improvement in the Morris water maze (MWM) for learning and memory, and oxidative stress parameters were evaluated through superoxide dismutase (SOD) and catalase (CAT) in aluminum-induced neurotoxicity models. Results: According to the systematic analysis, most treatments significantly improve learning and memory, except for insulin and melatonin. According to the MWM analysis, Memantine, Hypericum perforatum extract, Bennincasa hespidia, and, based on the biochemical analysis, Chrysin showed better results. The meta-analysis (random effects) revealed reduced escape latency (SMD = 0.97, 95% CI: 0.74 to 1.19) and increased SOD (SMD = −0.54, 95% CI: −0.79 to −0.29) and CAT levels (SMD = −0.50, 95% CI: −0.73 to −0.27) in treated groups versus aluminum. Egger’s regression tests showed no strong evidence of publication bias. Conclusions: This study effectively synthesized preclinical evidence, identifying promising pharmacological agents for mitigating aluminum-induced cognitive deficits. These findings offer a scientific basis for future experimental studies and therapeutic development targeting aluminum neurotoxicity.