Thymoquinone-loaded solid lipid nanoparticles mitigate 3-Nitropropionic acid-induced mitochondrial dysfunction and oxidative damage via regulating PGC-1α/Nrf2 pathway

Abstract

3-Nitropropionic acid (3-NP) is a mitochondrial toxin which causes bilateral striatal lesions in experimental animals, mimicking Huntington’s disease (HD) pathology. The molecular mechanisms underlying 3-NP-induced neuronal death involve mitochondrial dysfunction, transcriptional dysregulation, and impaired antioxidant defense systems. This study investigated the effects of thymoquinone (TQ) encapsulated in solid lipid nanoparticles (NanoTQ), on mitochondrial biogenesis in 3-NP-induced neurotoxicity in the striatum of male Wistar rats. Systemic administration of 3-NP (10 mg/kg) for 14 days inhibited mitochondrial complex enzymes and increased mitochondrial membrane permeability in the striatum. 3-NP exposure significantly altered the translational level of PGC-1α by modifying the expression of p-CREB/TORC1/SIRT1/PPARγ. Additionally, 3-NP exposure significantly reduced striatal levels of BDNF, GDNF, and their downstream effectors. Treatment with NanoTQ (10 and 20 mg/kg) and TQ (80 mg/kg) significantly (P < 0.01) increased mitochondrial complex enzyme activity compared to TQ (40 mg/kg). NanoTQ also significantly (P < 0.01) regulated the expression of regulatory proteins, promoting PGC-1α mediated mitochondrial biogenesis. Furthermore, NanoTQ restored BDNF and GDNF signaling and enhanced the antioxidant defense mechanism by increasing Nrf-2 and HO-1 expression while reducing Keap1 levels in the striatum. In conclusion, NanoTQ effectively mitigated 3-NP-induced neurotoxicity by regulating the mitochondrial biogenesis, neurotrophic factors, and antioxidant defense system, thereby preventing HD-like symptoms in rats.