Vinpocetine mitigates methotrexate-induced duodenal intoxication by modulating NF-κB, JAK1/STAT-3, and...

Area of Science:

• Pharmacology
• Gastroenterology
• Toxicology

Background:

• Methotrexate (MTX) is a crucial antimetabolite for treating cancers and autoimmune conditions.
• MTX-induced intestinal toxicity is a significant clinical challenge, often linked to inflammation and oxidative stress.
• Vinpocetine (VNP), a vincamine derivative, exhibits known anti-inflammatory and antioxidant properties.

Purpose of the Study:

• To investigate the protective effects of Vinpocetine (VNP) against Methotrexate (MTX)-induced intestinal injury in a rat model.
• To evaluate VNP's capacity to attenuate the histological, oxidative, inflammatory, and necroptotic damage caused by MTX in the intestine.

Main Methods:

• Rats were administered MTX (20 mg/kg, intraperitoneal) to induce intestinal toxicity.
• Vinpocetine (VNP) was administered orally at a dose of 20 mg/kg to assess its protective effects.
• Histological examination, assessment of oxidative stress markers (Nrf2, HO-1), inflammatory mediators (MPO, NO2-, TNF-α, IL-1β), and necroptosis-related proteins (RIPK1, RIPK3, MLKL, caspase-8) were performed.

Main Results:

• VNP administration preserved intestinal histology, preventing MTX-induced villus and crypt damage.
• VNP significantly reduced oxidative stress by upregulating Nrf2 and HO-1 expression.
• VNP attenuated inflammation and necroptosis by modulating key signaling pathways including NF-κB, JAK/STAT, and necroptotic effectors.

Conclusions:

• Vinpocetine demonstrates significant protective effects against MTX-induced intestinal toxicity in rats.
• VNP mitigates damage through antioxidant, anti-inflammatory, and anti-necroptotic mechanisms.
• VNP shows promise as a therapeutic agent to reduce MTX-related intestinal side effects in patients.