Phosphocreatine Mitigates Doxorubicin-Induced Neurotoxicity in Rats by Regulating Mitochondrial Function and Apoptosis via the NF-κB/PGC-1α Pathway.

Doxorubicin (DOX) is an effective chemotherapeutic agent, but its clinical utility is limited by its neurotoxic side effects. This study investigates the neuroprotective effects of phosphocreatine (PCr) against DOX-induced neurotoxicity in Sprague-Dawley rats. Forty rats were randomly assigned to four groups: control, DOX (2 mg/kg), DOX + PCr (20 mg/kg), and DOX + PCr (50 mg/kg). Parameters assessed included body weight, oxidative stress markers (MDA, SOD, GSH), and neurofunctional indicators (nNOS, BDNF). Mitochondrial respiration was evaluated using high-resolution respirometry, measuring state 3 and state 4 respiration, the respiratory control ratio (RCR), and ADP/O ratio. Western blotting was used to analyze apoptosis-related proteins (Bax, Bcl-2, cleaved caspase-3, pro-caspase-3, pro-caspase-9, cytochrome c) and signaling molecules (NF-κB, PGC-1α). PCr treatment significantly reduced oxidative stress, as evidenced by lower MDA levels and elevated GSH and SOD. It also modulated apoptotic signaling by decreasing pro-apoptotic proteins (Bax, cleaved caspase-3) and increasing anti-apoptotic Bcl-2. Moreover, PCr enhanced mitochondrial function and biogenesis, while attenuating neuroinflammation through regulation of the NF-κB/PGC-1α pathway. These findings suggest that PCr protects against DOX-induced neurotoxicity by improving mitochondrial bioenergetics, reducing oxidative damage, and inhibiting neuronal apoptosis. PCr may represent a promising therapeutic strategy to mitigate chemotherapy-associated neurotoxicity.