Eugenol mitigates schizophrenia-like behavioral deficits, oxidative stress, apoptosis, neuroinflammation, and cholinergic dysfunction in ketamine-induced mice.
Rotu Arientare Rume, Mega Obukowo Oyovwi, Rotu A Rotu, Benneth Ben-Azu, Esthinsheen Osirim
Daru April 27, 2026 DOI: 10.1007/s40199-026-00603-3 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Sample size | 10 |
| Population | Male C57BL/6 mice, 10 per group |
| Interventions | Ketamine Eugenol |
| Dose | Ketamine 30 mg/kg, i.p.; eugenol 50 and 100 mg/kg, p.o. |
| Duration | Ketamine for 7 consecutive days; eugenol co-administered daily |
| Measures | Locomotor activity, pre-pulse inhibition (PPI), novel object recognition (NOR), social interaction; MDA, GSH, SOD, CAT; Caspase-3, Bax, Bcl-2; TNF-α, IL-1β, IL-6; acetylcholinesterase (AChE) activity |
| Topics | Ketamine Esketamine |
| Keywords | Hippocampus Prefrontal cortex Animals Mice, inbred c57bl Disease models, animal Eugenol Acetylcholinesterase Cytokines Behavior, animal Schizophrenia Apoptosis Oxidative stress Male Neuroinflammatory diseases Neuroinflammation |
| Key findings | Ketamine induced schizophrenia-like behavioral deficits and biochemical changes in prefrontal cortex and hippocampus. Eugenol, particularly at 100 mg/kg, significantly ameliorated these behavioral deficits and reversed oxidative stress, apoptosis, neuroinflammation, and increased acetylcholinesterase activity. The authors suggest eugenol may be a promising adjuvant therapeutic for schizophrenia. |
Abstract
Schizophrenia, a severe neurodevelopmental disorder, is influenced by oxidative stress, neuroinflammation, apoptosis, and cholinergic system dysfunction. Given the multifactorial nature of schizophrenia, targeting multiple pathological pathways simultaneously may offer superior therapeutic benefits compared to single-target approaches, particularly for refractory symptoms. Eugenol, a natural phenylpropanoid in clove oil, was investigated for potential therapeutic effects on schizophrenia-like behaviors in mice. Male C57BL/6 mice (n = 10 per group) were administered ketamine (30 mg/kg, i.p.) for 7 consecutive days to induce schizophrenia-like phenotypes. Eugenol (50 and 100 mg/kg, p.o.) was co-administered daily with ketamine. Behavioral assessments, including locomotor activity, pre-pulse inhibition (PPI), novel object recognition (NOR), and social interaction, were performed. Following behavioral tests, brain tissues (prefrontal cortex and hippocampus) were collected for biochemical analyses. Oxidative stress markers (MDA, GSH, SOD, CAT), apoptotic markers (Caspase-3, Bax, Bcl-2), neuroinflammatory cytokines (TNF-α, IL-1β, IL-6), and acetylcholinesterase (AChE) activity were quantified using spectrophotometric and ELISA methods. Ketamine administration significantly induced hyperactivity (p < 0.001), impaired PPI (p < 0.01), reduced NOR (p < 0.001), and decreased social interaction (p < 0.001). Biochemically, ketamine increased MDA, Caspase-3, Bax, TNF-α, IL-1β, IL-6, and AChE activity (p < 0.05 to p < 0.001), while decreasing GSH, SOD, CAT, and Bcl-2 in both prefrontal cortex and hippocampus (p < 0.05–p < 0.001). Eugenol treatment, particularly at 100 mg/kg, significantly ameliorated these behavioral deficits and biochemical alterations (all p < 0.05 vs. ketamine group). Eugenol reversed ketamine-induced oxidative stress by reducing lipid peroxidation and enhancing antioxidant defenses. It attenuated apoptosis by modulating Caspase-3, Bax, and Bcl-2 levels. Furthermore, eugenol suppressed neuroinflammation by reducing pro-inflammatory cytokine levels and restored cholinergic balance by inhibiting AChE activity. These findings suggest that eugenol holds significant promise as a potential adjuvant therapeutic agent for schizophrenia, attributable to its multifaceted neuroprotective effects against oxidative stress, apoptosis, neuroinflammation, and cholinergic dysfunction.