Trans-anethole attenuates streptozotocin-induced cognitive dysfunction by modulating oxidative stress and cholinergic activity

Abstract

Cognitive impairment is a neurological disorder defined as an inability to learn, think, judge, remember, and make decisions. The primary cause of chronic, age- related cognitive decline is Alzheimer’s disease (AD), which is frequently studied as a representative model. The current therapies for AD provide only symptomatic relief, which necessitates the need for safer, multi-target treatments. Trans- anethole, the primary constituent of Illicium verum , Pimpinella anisum , and Foeniculum vulgare , is an aromatic molecule that possesses several pharmacological activities, including anti-inflammatory and antioxidant effects, which may have neuroprotective benefits. The current study integrated in silico , in vitro , and in vivo approaches to examine the neuroprotective potential of trans- anethole. In silico studies were carried out to find out the potential molecular targets and pathways associated with the effects of trans-anethole against AD- related cognitive dysfunction. Cytotoxicity, antioxidant activity, and cholinesterase inhibition were assessed in vitro on BV2 cells. Intracerebroventricular (ICV) administration of streptozotocin (STZ: 3 mg/kg) in rats induces an insulin-resistant brain state leading to progressive cognitive and memory impairment, a condition that closely relates to sporadic Alzheimer’s disease. ICV-STZ-induced Wistar rats were used to assess the effect of trans- anethole on AD-related cognitive dysfunction through behavioral, biochemical, and histopathological assessments. A total of 174 common targets were identified, enriching pathways including apoptosis, AGE-RAGE, TNF, and PI3K- Akt signaling. Stable interactions were observed in molecular docking and molecular dynamics simulations. Trans-anethole demonstrates moderate cholinesterase inhibition and antioxidant activity in BV2 cells. Comparing STZ- treated rats to disease control, trans-anethole at doses of 100 mg/kg and 400 mg/kg significantly reduced lipid peroxidation, restored antioxidant enzyme levels, and attenuated cholinergic dysfunction. Histopathological findings showed qualitative preservation of hippocampal neuronal morphology. Overall, these findings suggest that trans-anethole may represent a potential neuroprotective preclinical candidate for further investigation in Alzheimer’s disease-related cognitive dysfunction.