Neuroprotective potential of chrysin against ketamine-induced neurotoxicity: Effects on behavioral changes, oxidative stress, and neuroinflammation.
Onur Karaca, Özge Kandemir, Hasan Şimşek, Nurhan Akaras, Şeyda Öte Karaca, Fatih Mehmet Kandemir
Neurotoxicology and Teratology September 18, 2026 DOI: 10.1016/j.ntt.2026.107720 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled experimental animal study Peer reviewed |
|---|---|
| Sample size | 35 |
| Population | Adult male Wistar rats |
| Interventions | Ketamine Chrysin |
| Dose | Ketamine 30 mg/kg i.p.; Chrysin 25 or 50 mg/kg p.o. |
| Duration | 10-day treatment regimen |
| Measures | Morris Water Maze test, MDA, GSH, SOD, CAT, GPx, NF-κB, TNF-α, iNOS, Bax, Caspase-3, Bcl-2, CaMKII, GFAP |
| Topics | Ketamine Esketamine |
| Keywords | Oxidative stress Neurotoxicity Neuroinflammation Chrysin |
| Key findings | Ketamine given for 10 days increased oxidative stress, neuroinflammation, and apoptotic markers and produced neuronal degeneration, necrosis, and vascular hyperemia in rat cerebral cortex and hippocampus. Chrysin, particularly at 50 mg/kg, reduced these histopathological changes and lowered GFAP and Caspase-3 expression, suggesting it may be a promising adjunctive neuroprotective agent. |
Abstract
Aim: Ketamine (KTM) is widely used in clinical settings for its anesthetic, analgesic, and antidepressant properties. However, prolonged or repeated KTM exposure can induce neurotoxicity through oxidative stress, neuroinflammation, and apoptotic mechanisms. This study investigated the neuroprotective effects of Chrysin (CHR), a natural flavonoid with potent antioxidant and anti-inflammatory properties, against KTM-induced neurotoxicity in rats.
Methods: Adult male Wistar rats were divided into five groups (n = 7): Control, KTM, CHR KTM + CHR25 and KTM + CHR50. Following a 10-day treatment regimen (KTM:30 mg/kg, i.p.; CHR: 25 or 50 mg/kg, p.o.) cognitive function was assessed using the Morris Water Maze test.
Results: Biochemical analyses revealed that KTM significantly increased MDA levels while decreasing GSH levels and antioxidant enzyme (SOD,CAT,GPx) activities in brain and hippocampus tissues. KTM also upregulated pro-inflammatory (NF-κB,TNF-α,iNOS) and pro-apoptotic (Bax,Caspase-3) markers while downregulating anti-apoptotic Bcl-2 and CaMKII isoforms. Histopathological examination showed that KTM induced neuronal degeneration, necrosis, and vascular hyperemia in cerebral cortex and hippocampus, while immunohistochemical analysis revealed increased GFAP and Caspase-3 immunopositivity. CHR treatment, particularly at the higher dose, significantly ameliorated these histopathological alterations and reduced GFAP and Caspase-3 expression.
Conclusion: These findings suggest that CHR represents a promising adjunctive neuroprotective agent that could mitigate KTM-associated neurotoxicity while preserving its therapeutic applications.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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State of the evidence: Ketamine Supports
Chrysin appeared to protect against ketamine-induced neurotoxicity by reducing behavioral changes, oxidative stress, and neuroinflammation.
Synthesized
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 |