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Background <p>Chronic methylphenidate (MPH) use causes neurological and behavioral problems. Aprepitant (APR) has demonstrated neuroprotective effects.</p> Objectives <p>This research investigated APR’s neuroprotective effects against MPH-induced biochemical, mitochondrial, motor, and mood disturbances in rats.</p> Method <p>Forty-eight male Wistar rats were divided into six groups to receive treatment for 21 days with saline, MPH, or different doses of APR combined with MPH. Behavioral tests included OFT, EPM, and FST; biochemical assessments focused on hippocampal inflammation, oxidative stress, and apoptosis pathways.</p> Results <p>APR dose-dependently mitigated the MPH-induced disruptions in motor activity and mood, and increased activities of glutathione peroxidase (GPx), glutathione reductase (GR), and superoxide dismutase (SOD), along with levels of mitochondrial membrane potential (ΔΨm = MMP), reduced glutathione (GSH), total antioxidant capacity (TAC), adenosine triphosphate (ATP), and unphosphorylated Bcl-2. In MPH-treated rats, APR decreased tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), oxidized glutathione (GSSG), reactive oxygen species (ROS), malondialdehyde (MDA), and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>), and reduced both forms of JNK, Bax, Beclin-1, and phosphorylated Bcl-2.</p> Conclusion <p>APR dose-dependently alleviated MPH-induced anxiety and depression-like behaviors, restored redox and mitochondrial homeostasis, suppressed MPH-induced neuroinflammation and neuronal apoptosis, and influenced Beclin, a key regulator of autophagosome nucleation.</p> Graphical abstract <p></p>

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Aprepitant’s neuroprotective effects on methylphenidate-induced biochemical/mitochondrial dysfunction, neuroinflammation, and mood-related behavior alterations

  • 期刊论文

  • 发表日期：

    2026年6月24日

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  • Ladan Akbarpournikghalb,
  • Parisa Pourdehghan Shahrestani,
  • Mahnaz Gomi,
  • A. Wallace Hayes,
  • Mahdieh Gholami,
  • Majid Motaghinejad

摘要

Background

Chronic methylphenidate (MPH) use causes neurological and behavioral problems. Aprepitant (APR) has demonstrated neuroprotective effects.

Objectives

This research investigated APR’s neuroprotective effects against MPH-induced biochemical, mitochondrial, motor, and mood disturbances in rats.

Method

Forty-eight male Wistar rats were divided into six groups to receive treatment for 21 days with saline, MPH, or different doses of APR combined with MPH. Behavioral tests included OFT, EPM, and FST; biochemical assessments focused on hippocampal inflammation, oxidative stress, and apoptosis pathways.

Results

APR dose-dependently mitigated the MPH-induced disruptions in motor activity and mood, and increased activities of glutathione peroxidase (GPx), glutathione reductase (GR), and superoxide dismutase (SOD), along with levels of mitochondrial membrane potential (ΔΨm = MMP), reduced glutathione (GSH), total antioxidant capacity (TAC), adenosine triphosphate (ATP), and unphosphorylated Bcl-2. In MPH-treated rats, APR decreased tumor necrosis factor-α (TNF-α), interleukin-1 beta (IL-1β), oxidized glutathione (GSSG), reactive oxygen species (ROS), malondialdehyde (MDA), and hydrogen peroxide (H2O2), and reduced both forms of JNK, Bax, Beclin-1, and phosphorylated Bcl-2.

Conclusion

APR dose-dependently alleviated MPH-induced anxiety and depression-like behaviors, restored redox and mitochondrial homeostasis, suppressed MPH-induced neuroinflammation and neuronal apoptosis, and influenced Beclin, a key regulator of autophagosome nucleation.

Graphical abstract