Tribulus terrestris L. (Tt) has been recently gaining attention for its pharmacological value, including its neuroprotective activities. In this study, we explore the neuroprotective effects of a Tribulus terrestris extract in a zebrafish (Danio rerio) model of scopolamine (SCOP)-induced memory impairment and brain oxidative stress. SCOP, an anticholinergic drug, was employed to replicate fundamental aspects of Alzheimer’s disease (AD) in animal models. The fish were treated with ethanolic leaf extract (ELE) from Tt (1, 3, and 6 mg/L) for 15 days. SCOP (100 µM) was administered 30 min before behavioral tests were conducted. Molecular interactions of the major compounds identified via UPLC-PDA/MS in Tt fractions with the active site of acetylcholinesterase (AChE) were explored via molecular docking analyses. Terrestrosin C, protodioscin, rutin, and saponin C exhibited the most stable binding. The spatial memory performance was assessed using the Y-maze test, and memory recognition was examined using a novel object recognition (NOR) test. Tt extract treatment reversed the altered locomotion patterns that were caused by SCOP administration. Biochemical analyses also verified Tt’s role in inhibiting AChE, improving antioxidant enzyme activities, and reducing oxidative stress markers. The present findings pave the way for future application of Tt as a natural alternative to treat cognitive disorders.

Plants of the genus Tribulus have been used in folk medicine for wound healing, alleviating liver, stomach, and rheumatism pains, and as cognitive enhancers, sedatives, antiseptics, tonics, and stimulants. The present work aimed to evaluate whether Tribulus terrestris (Tt) administered for 15 days attenuated cognitive deficits and exhibited anxiolytic and antidepressant profiles in scopolamine-induced amnesia in zebrafish. Animals were randomly divided into six groups (eight animals per group): (1)–(3) Tt treatment groups (1, 3 and 6 mg/L), (4) control, (5) scopolamine (SCOP, 0.7 mg/kg), and (6) galantamine (Gal, 1 mg/L). Exposure to SCOP (100 µM) resulted in anxiety in zebrafish, as assessed by the novel tank diving test (NTT) and novel approach test (NAT). When zebrafish were given SCOP and simultaneously given Tt (1, 3, and 6 mg/L once daily for 10 days), the deficits were averted. Molecular interactions of chemical compounds from the Tt fractions with the monoamine oxidase A (MAO-A) were investigated via molecular docking experiments. Using behavioral experiments, we showed that administration of Tt induces significant anxiolytic-antidepressant-like effects in SCOP-treated zebrafish. Our result indicated that flavonoids of Tt, namely kaempferol, quercetin, luteolin, apigetrin, and epigallocatechin, could act as promising phytopharmaceuticals for improving anxiety-related disorders.