Solanum macrocarpon L. Ethanolic Leaf Extract Exhibits Neuroprotective and Anxiolytic Effects in Scopolamine-Induced Amnesic Zebrafish Model

<b>Background/Objectives</b>: <i>Solanum macrocarpon</i> L. has been studied for its neuroprotective potential and memory-enhancing properties. Research suggests that bioactive compounds, including flavonoids, alkaloids, and phenolics, contribute to its cognitive benefits. These compounds may help protect against oxidative stress, neuroinflammation, and cholinergic dysfunction factors in memory impairment. This study was undertaken to investigate the effects of <i>S. macrocarpon</i> ethanolic leaf extract (SMEE) on the memory, anxiety-like behavior, and brain antioxidant status of scopolamine (SCOP, 100 μM)-induced amnesic zebrafish (<i>Danio rerio</i>) and thus to understand its possible mechanism of action. <b>Methods</b>: Adult zebrafish (<i>n</i> = 100) were divided into two cohorts (±SCOP) of five experimental groups: (I) control; (II) galantamine (GAL, 1 mg/L), serving as a positive control for both behavioral and biochemical assessments; (III-V) three groups treated with SMEE (1, 3, and 6 mg/L); (VI) scopolamine (SCOP, 100 μM); (VII) SCOP (100 μM) combined with GAL (1 mg/L); and (VIII-X) three groups treated with SCOP (100 μM) plus SMEE (1, 3, and 6 mg/L). The treatment lasted 23 days and amnesia was induced by a single dose of SCOP (100 μM) before testing. <b>Results</b>: The phenolic characterization from the samples was performed by using HPLC-PDA chromatography. Following HPLC analysis, an in silico pharmacokinetic evaluation was conducted using the ADMET model to investigate the pharmacological and toxicological profiles of the identified compounds. Spatial memory was evaluated through the Y-maze and novel object recognition (NOR) tests, while anxiety-like behavior was assessed using the novel tank diving test (NTT), novel approach test (NAT), and light-dark test (LDT). The zebrafish were euthanized, and homogenates of isolated brain samples were assayed for acetylcholinesterase (AChE) activity and brain antioxidant markers. The HPLC analysis revealed that the main major compounds in the extract were chlorogenic acid and rutin, both recognized for their significant antioxidant properties. <b>Conclusions</b>: SMEE enhanced memory by inhibiting AChE, alleviated SCOP-induced anxiety-like behavior, and significantly decreased oxidative stress markers. These findings support the potential role of SMEE in counteracting SCOP-induced cognitive and behavioral dysfunctions, related to dementia conditions.