Cell Journal (Yakhteh) · 4 authors, 4 centres
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Curcumin nanoparticles (CN) given orally to rats before and after cerebral ischemia-reperfusion injury reduced oxidative stress, increased antioxidant enzyme activity, and upregulated pERK/ERK and TFEB protein expression, indicating neuroprotection. CN showed higher brain bioavailability than free curcumin, with effects lasting up to 72 hours. These findings suggest CN may be a promising adjuvant therapy for stroke.
**Background:** Cerebral ischemia-reperfusion injury (IRI) exacerbates cellular damage after blood flow restoration, largely due to oxidative stress. Curcumin has antioxidant and neuroprotective properties but limited brain bioavailability. Nanoparticle formulations may enhance brain delivery. This study investigated the effects of curcumin nanoparticle (CN) pretreatment on oxidative stress, mitochondrial function, and the ERK and TFEB signaling pathways in a rat model of cerebral IRI.
**Methods:** 48 male Wistar rats were divided into 5 groups: healthy control (n=9), sham surgery (n=9), cerebral IRI (n=10), cerebral IRI + free curcumin (FC, 25 mg/kg/day, n=10), and cerebral IRI + CN (25 mg/kg/day, n=10). Treatments were given orally by gavage starting 5 days before bilateral common carotid artery occlusion (BCCAO) and continued for 3 days after. Brains were collected after 72 hours of reperfusion. Measurements included: brain curcumin bioavailability by HPLC; oxidative stress markers (ROS, MDA); antioxidant enzymes (catalase, SOD, GSH); mitochondrial enzymes (SDH, MDH, LDH); and pERK/ERK and TFEB protein expression by Western blot. Statistical analysis used one-way ANOVA with Tukey's post hoc test (P<0.05).
**Key Results:** CN showed significantly higher brain bioavailability than FC, with peak concentration at 24 hours (14.75 ± 0.93 µg/g) and detectable levels up to 72 hours, whereas FC was undetectable after 48 hours. Cerebral IRI significantly increased ROS (274 ± 18 vs 106 ± 5 in control, P=0.0008) and lipid peroxidation (6.23 ± 0.78 vs 3.23 ± 0.56 µM), and decreased antioxidant enzymes: CAT (P<0.001), SOD (P<0.001), GSH (P<0.001). Mitochondrial enzyme activities (SDH, MDH, LDH) were also reduced. CN pretreatment significantly reversed these changes: ROS decreased to 131 ± 14 (not significantly different from control), lipid peroxidation to 3.65 ± 0.53 µM, and SDH, MDH, LDH activities recovered to near-control levels. CN also restored antioxidant enzyme activities and GSH content to levels comparable to controls. pERK/ERK expression ratio was significantly reduced in IRI rats (P=0.002) but increased with CN treatment (P=0.243 vs control, not significant). TFEB protein expression was significantly downregulated in IRI (P=0.005) and upregulated by CN to levels not significantly different from control.
**Clinical Implications:** CN demonstrates neuroprotective effects against cerebral IRI by reducing oxidative stress, preserving mitochondrial function, and upregulating pERK/ERK and TFEB signaling pathways. The enhanced brain bioavailability and sustained release of CN compared to FC suggest that nanoparticle formulation may overcome the blood-brain barrier limitation of curcumin. These findings support CN as a potential adjuvant therapy for stroke, though clinical studies are needed to confirm efficacy and safety in humans.