Therapeutic Role of <scp>l</scp>-Theanine in Mitigating Cognitive Dysfunction and Neuropathology in Scopolamine-Treated Mice

Abstract

Memory decline is a prominent hallmark of Alzheimer's disease (AD). Scopolamine-induced amnesia is a pharmacological paradigm in AD research to model these cognitive insults. AD represents the most prevalent type of dementia among the elderly, depicted by impaired cognition and memory. AD pathogenesis is an interplay among cholinergic signaling disruption, neuroinflammation, and oxidative stress. Recently, autophagy modulation has been proven to display a beneficial effect against several diseases. l-Theanine (LTA), found in green tea, possesses neuroprotective, anti-inflammatory, antioxidant, and antiaging properties. Hence, this study investigated LTA's potential to alleviate AD symptoms, elaborating the role of autophagy. 45 mice were classified into five groups: the control, where animals received phosphate-buffered saline, while the other groups received scopolamine (Scop; 1 mg/kg; i.p.), inducing amnesia; then they were categorized as follows: group II represented the model one, group III was treated with donepezil (DON; 5 mg/kg; p.o.), while group IV was treated with LTA (20 mg/kg; p.o.), and group V received chloroquine (CQ; 10 mg/kg; p.o.), an autophagy blocker, followed by LTA. LTA stimulated AMP-activated protein kinase (AMPK), microtubule-associated protein-1 light chain-3II (LC3II), and beclin 1 but lowered phosphorylated levels of protein kinase B (p-AKT) and mammalian target of rapamycin (p-mTOR). Furthermore, LTA elevated the brain-derived neurotrophic factor (BDNF) and downregulated caspase-3 expression. Noteworthily, LTA increased glutathione and reduced malondialdehyde and tumor necrosis factor-alpha levels. In conclusion, LTA ameliorated histopathological changes, reduced amyloid-β, and enhanced learning and memory performance in novel object recognition, Y-maze, and Morris water maze. LTA boosted autophagy, promoted neuronal survival, and attenuated oxidative stress. LTA almost displayed similar effects to the DON group, while CQ abolished LTA-enhanced memory via blocking autophagy. Consequently, LTA-mediated autophagy represents a promising approach to alleviating Scop-induced amnesia in mice.