Prevention and reversal of ketamine-induced experimental psychosis in mice by the neuroactive flavonoid, hesperidin: the role of oxidative and cholinergic mechanisms.
I. Ishola, Benneth Ben-Azu, Oluwatosin A. Adebayo, A. Ajayi, I. Omorodion, K. E. Edje, O. Adeyemi
Brain Research Bulletin October 1, 2021 DOI: 10.1016/j.brainresbull.2021.10.007 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Peer reviewed |
|---|---|
| Sample size | 48 |
| Population | Male Swiss mice |
| Interventions | Hesperidin Ketamine |
| Dose | Hesperidin 100 mg/kg/p.o./day; ketamine 20 mg/kg/i.p./day |
| Duration | 14 days (hesperidin days 1-14; ketamine days 8-14 in preventive study; ketamine pretreatment 14 days with hesperidin days 8-14 in reversal study) |
| Measures | Open-field test, Y-maze test, social interaction test, glutathione, superoxide dismutase, malondialdehyde, nitrite, acetylcholinesterase |
| Topics | Esketamine Ketamine |
| Key findings | Hesperidin prevented and reversed ketamine-induced schizophrenia-like behaviors (hyperactivity, social withdrawal, cognitive impairment) in mice and normalized markers of oxidative/nitrergic stress and acetylcholinesterase activity across prefrontal cortex, striatum, and hippocampus. The authors propose hesperidin dietary supplementation as a potential natural nutritional intervention for schizophrenia. |
Abstract
Currently, prevailing evidence have identified cholinergic and oxidative pathways as important therapeutic targets for abating ketamine-induced schizophrenia-like behavior. Thus, this study evaluated the ability of hesperidin, a naturally occurring antioxidant and neuroprotective flavonoid, to prevent and reverse ketamine-induced schizophrenia-like behaviors and changes in cholinergic, oxidative and nitrergic status in mice. Forty-eight male Swiss mice were allotted into the preventive and reversal studies with 4 groups (n = 6) each. In the preventive study, groups 1 and 2 received vehicle (10mL/kg/p.o./day), while groups 3 and 4 had hesperidin (100mg/kg/p.o./day) for 14 days, but ketamine (20mg/kg/i.p./day) was concurrently given to groups 2 and 4 from days 8-14. In the reversal study, groups 1 and 3 received vehicle, groups 2 and 4 were pretreated with ketamine for 14 days. Nevertheless, groups 3 and 4 additionally received hesperidin from days 8-14. Thereafter, schizophrenia-like behavior from exploratory activity, open-field (positive symptoms), Y-maze (cognitive symptoms) and social interaction (negative symptoms) tests were evaluated. Brain levels of oxidative/nitrergic (glutathione, superoxide-dismutase, malondialdehyde and nitrite levels) and cholinergic (acetylcholinesterase activity) markers were measured in the prefrontal-cortex, striatum and hippocampus. Hesperidin prevents and reverses ketamine-induced hyperactivities, social withdrawal and cognitive impairment. Also, hesperidin prevented and reversed ketamine-induced decrease in glutathione and superoxide-dismutase levels in the prefrontal-cortical, striatal and hippocampal brain regions in mice. Consequently, hesperidin attenuated ketamine-induced increase in malondialdehyde, nitrite levels and acetylcholinesterase activities in the prefrontal-cortex, striatum and hippocampus, respectively. The study showed that hesperidin prevents and reverses ketamine-induced schizophrenia-like behavior through inhibition of oxidative/nitrergic stress and acetylcholinesterase activity in mice brains. Therefore, these findings suggest that hesperidin dietary supplementation could provide natural nutritional intervention to protect against epigenetic-induced mental ill-health like schizophrenia, and thus serve as an important agent for nutritional psychiatry.
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 5
- Effective action of silymarin against ketamine-induced schizophrenia in male mice: Insight into the biochemical and molecular mechanisms of action. Journal of Psychiatric Research November 1, 2024
- 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
- Ketamine-dependent patients with persistent psychosis have higher neurofilament light chain levels than patients with schizophrenia. Asian Journal of Psychiatry October 1, 2024
- 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
- Antipsychotic effect of diosgenin in ketamine-induced murine model of schizophrenia: Involvement of oxidative stress and cholinergic transmission IBRO Neuroscience Reports January 3, 2024
Cites 2
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- 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