Effective action of silymarin against ketamine-induced schizophrenia in male mice: Insight into the biochemical and molecular mechanisms of action.
Benneth Ben-Azu, Aliance R Fokoua, Olajide S Annafi, Olusegun G Adebayo, Elisabetta C. del Re, Nneka Okuchukwu, Gbemileke J Aregbesola, Akpor-Esiri C Ejenavi, David M Isiwele, Arausi J Efezino, Ifelunwa D Okpu
Journal of Psychiatric Research November 1, 2024 DOI: 10.1016/j.jpsychires.2024.09.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preventive-reversal model in mice Peer reviewed |
|---|---|
| Sample size | 54 |
| Population | Mice |
| Interventions | Silymarin Risperidone Ketamine |
| Dose | silymarin 50 and 100 mg/kg/p.o.; risperidone 0.5 mg/kg/p.o.; ketamine 20 mg/kg/i.p. |
| Duration | 14 days |
| Topics | Esketamine Ketamine |
| Keywords | Antipsychotics Negative symptoms Neuropharmacology Psychosis Antipsychotic therapy Plant-based treatment Phytotherapy Neuroinflammation brain inflammation Neuroimmunology Schizophrenia |
| Citations | 24 |
| Key points | Silymarin prevented and reversed ketamine-induced schizophrenia-like behavioral, neurochemical, inflammatory, and oxidative stress changes in mice, suggesting an antipsychotic effect linked to normalization of neurochemical and neurotrophic alterations. |
Abstract
Neurochemical dysregulations resulting from N-methyl-D-aspartate hypofunction (NMDA), are exacerbated by neuroimmune and oxidative stress and are known risk factors for neuropsychiatric disorders like schizophrenia-like diseases. Here, we investigate the protective and curative effects, and mechanisms of silymarin, a polyphenolic flavonoid with neuroprotective functions in preventive-reversal model of ketamine, an NMDA antagonist in mice. Mice were grouped into 6 cohorts (n = 9). In the pre-treatment, groups 1 and 2 received saline (10 mL/kg/p.o.), groups 3 and 4 (silymarin, 50 and 100 mg/kg/p.o.), and group 5 (risperidone, 0.5 mg/kg/p.o.) consecutively for 14 days, then combined with ketamine (20 mg/kg/i.p.) injection in groups 2-5 from days 8-14. However, mice in reversal study received intraperitoneal injection of ketamine for 14 days before silymarin (50 and 100 mg/kg, p.o) and risperidone (0.5 mg/kg, p.o.) treatment between days 8-14. The consequences on schizophrenia-like behavior, neurochemistry, inflammation, and oxidative/nitrergic stress markers were evaluated in critical brain regions of the disease. Silymarin prevented and reversed ketamine-induced increase in dopamine, 5-hydroxyltryptamine, acetylcholinesterase, malondialdehyde and nitrite levels in the striatum, prefrontal-cortex and hippocampus. These were accompanied by improvement in hyperlocomotion, stereotypy, memory, and social impairments, notably devoid of cataleptogenic potential. Complementarily, silymarin reduced myeloperoxidase, tumor-necrosis factor-α, and interleukin-6 concentrations relative to the ketamine group. Moreover, ketamine-induced decreased brain-derived neurotrophic factor, glutathione, catalase, superoxide-dismutase levels were normalized by silymarin in the brain regions relative to ketamine. Overall, these findings suggest that silymarin's antipsychotic effect might be primarily associated, among other mechanisms, with the normalization of neurochemical and neurotrophic changes in the mice brains.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 3
- Inhibition of oxidative stress, neuroinflammatory cytokines, and protein expressions contributes to the antipsychotic effects of geraniol in mice with ketamine-induced schizophrenia. Journal of Neuroimmune Pharmacology July 3, 2025
- Antipsychotic-like Effects of Jobelyn® in Ketamine-induced Psychosis in Mice Emerging Frontiers in Translational Biomedicine and Health Sciences July 10, 2026
- Sabinene's neuroprotective effect reverses ketamine-induced experimental schizophrenia in mice through enhancement of cholinergic, antioxidant, and anti-inflammatory mechanisms. Journal of Psychiatric Research March 5, 2026
Cites 6
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia JAMA Network Open May 1, 2020
- Prevention and reversal of ketamine-induced schizophrenia related behavior by minocycline in mice: Possible involvement of antioxidant and nitrergic pathways Journal of Psychopharmacology September 17, 2013
- Antipsychotic effect of diosgenin in ketamine-induced murine model of schizophrenia: Involvement of oxidative stress and cholinergic transmission IBRO Neuroscience Reports January 3, 2024
- Neuroprotective effect of hesperidin and its combination with coenzyme Q10 on an animal model of ketamine-induced psychosis: behavioral changes, mitochondrial dysfunctions, and oxidative stress Future Journal of Pharmaceutical Sciences January 15, 2022
and 1 more in the library