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<p>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&#xa0;mg/kg), DOX + PCr (20&#xa0;mg/kg), and DOX + PCr (50&#xa0;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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年8月4日

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  • Eskandar Qaed,
  • Waleed Aldahmash,
  • Mueataz A. Mahyoub,
  • Dalal Sanad Al-Mutairi,
  • Zeyao Tang,
  • Marwan Almoiliqy

摘要

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.