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Vinpocetine attenuates methotrexate-induced hippocampal intoxication via Keap-1/Nrf2, NF-κB/AP-1, and apoptotic
Badrah Alghamdi1,2, Emad H M Hassanein3, Saif A Alharthy4,5
1Department of Physiology, Neuroscience Unit, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
Abstract:
Methotrexate (MTX) is an anti-folate chemotherapeutic commonly used to treat cancer and autoimmune diseases. Despite its widespread clinical use, MTX has been linked to serious neurotoxicity side effects. Vinpocetine (VNP) has been widely used clinically to treat many neurological conditions. This study was conducted to study the potential neuroprotective effects of VNP against MTX hippocampal intoxication in rats. Thirty-two rats were randomly allocated into 4 groups: (I) control (Vehicle); (II) VNP-treated group (20 mg/kg/day, p.o); (III) MTX-control (20 mg/kg/once, i.p.) group; and (IV) the VNP + MTX group. VNP was administered orally for 10 days, during which MTX was given intraperitoneally once at the end of day 5. Our data indicated that VNP administration significantly improved MTX-induced neuronal cell death, odema, vacuolation and degeneration. VNP attenuated oxidative injury mediated by significant upregulation of the Nrf2, HO-1, and GCLC genes, while the Keap-1 mRNA expression downregulated. Moreover, VNP suppressed cytokines release mediated by increasing IκB expression level while it caused a marked downregulation in NF-κB and AP-1 (C-FOS and C-JUN) levels. Additionally, VNP attenuated apoptosis by reducing hippocampal Bax levels while increasing Bcl2 levels in MTX-intoxicated rats. In conclusion, our results suggested that VNP significantly attenuated MTX hippocampal intoxication by regulating Keap-1/Nrf2, NF-κB/AP-1, and apoptosis signaling in these effects.
Insights
Vinpocetine (VNP) protects against methotrexate (MTX) neurotoxicity in rats. VNP reduced neuronal damage, oxidative stress, and inflammation, suggesting its neuroprotective potential for MTX-induced hippocampal injury.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- Methotrexate (MTX) is a chemotherapy drug with known neurotoxicity.
- Vinpocetine (VNP) is a drug used for neurological conditions.
- MTX-induced hippocampal neurotoxicity is a significant clinical concern.
Purpose of the Study:
- To investigate the neuroprotective effects of VNP against MTX-induced hippocampal toxicity in a rat model.
- To elucidate the molecular mechanisms underlying VNP's potential protective actions.
Main Methods:
- Rats were divided into four groups: control, VNP-treated, MTX-treated, and VNP + MTX-treated.
- VNP was administered orally, and MTX was given intraperitoneally.
- Histological examination and molecular analysis (gene and protein expression) were performed.
Main Results:
- VNP significantly reduced MTX-induced neuronal cell death, edema, vacuolation, and degeneration in the hippocampus.
- VNP attenuated oxidative stress by upregulating Nrf2, HO-1, and GCLC, and downregulating Keap-1.
- VNP suppressed inflammation by increasing IκB and decreasing NF-κB and AP-1.
- VNP modulated apoptosis by altering Bax and Bcl2 levels.
Conclusions:
- Vinpocetine demonstrates significant neuroprotective effects against methotrexate-induced hippocampal intoxication in rats.
- VNP's protective mechanisms involve regulating oxidative stress, inflammation, and apoptosis signaling pathways.
- These findings suggest VNP as a potential therapeutic agent to mitigate MTX neurotoxicity.
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