Delta-9-tetrahydrocannabinol ameliorates oxidative stress, mitochondrial redox state, and neuroinflammation induced by high-fructose diet.

Toprak M.; Coskun Yazici Z.; Yanar K.; Bolkent S. · Naunyn-Schmiedeberg's archives of pharmacology · 2026

**Background & Methods** This preclinical study examined whether delta-9-tetrahydrocannabinol (THC) could attenuate neuroinflammation and oxidative stress induced by high-fructose diet (HFD) in 32 Sprague-Dawley rats divided into four groups: control, HFD alone, THC alone, and HFD+THC combination. Rats consumed 10% fructose in drinking water for 12 weeks, with THC administered during the final 4 weeks, and brain tissue was analyzed for oxidative stress biomarkers and inflammatory gene expression. **Key Findings** • High-fructose diet significantly increased multiple markers of oxidative damage in brain tissue, including advanced protein oxidation (AOPP, DT, KYN, AGE), lipid peroxidation (MDA), elevated NADH and FAD fluorescence (indicating mitochondrial redox imbalance), and decreased antioxidant defenses (total thiol content). • THC treatment substantially reduced HFD-induced oxidative stress, normalized mitochondrial redox state, and significantly decreased mRNA expression of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) and NF-κB pathway activation in brain tissue. • Strong positive correlations were observed between pro-inflammatory cytokine mRNA expression and oxidative stress markers, suggesting interconnected mechanisms of HFD-induced neurochemical damage that were simultaneously ameliorated by THC administration. **Dosage & Administration** Delta-9-tetrahydrocannabinol was administered at 1.5 mg/kg daily for 4 weeks via unspecified route (presumed intraperitoneal or oral based on rodent standard practice, but not explicitly stated in abstract). **Safety & Adverse Effects** Not reported. The abstract does not discuss adverse effects, behavioral changes, or safety parameters associated with THC administration. **Evidence Quality** This is a preclinical animal study with significant limitations for clinical translation. The study design is robust for mechanistic investigation but represents early-stage evidence. Key limitations include: small sample size (n=32 across four groups), single animal model (Sprague-Dawley rats), short intervention period (4 weeks THC), lack of behavioral or functional outcome measures, and absence of dose-response analysis. Results cannot be directly extrapolated to humans without further clinical investigation. The study provides mechanistic insight into potential neuroprotective pathways but requires validation in human trials before clinical application can be considered.

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