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Harpagide attenuates cerebral ischemic injury by modulating mitochondrial calcium homeostasis associated with the

Ke Wang1, Huai-Yu Liu2, Yue Wang3

  • 1Department of Pharmacology, College of Medicine, Jiaxing University, Jiaxing, 314001, People's Republic of China. wangke@zjxu.edu.cn.

Scientific Reports
|June 1, 2026
PubMed

Insights

Harpagide protects brain cells from ischemic stroke by stabilizing mitochondrial calcium and energy production. This phytochemical shows promise for treating stroke by preserving mitochondrial function and reducing cell death.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Pharmacology

Background:

  • Mitochondrial calcium homeostasis is crucial for cellular function and may be a therapeutic target for ischemic stroke.
  • Harpagide is known to inhibit mitochondrial calcium uptake, but its precise mechanism of action is not fully understood.

Purpose of the Study:

  • To investigate the neuroprotective mechanisms of harpagide in an in vivo (pMCAO mouse model) and in vitro (OGD-treated cells) model of ischemic stroke.
  • To elucidate the role of harpagide in modulating mitochondrial calcium ([Ca2+]mito) overload, oxidative stress, and apoptosis.

Main Methods:

  • Utilized permanent middle cerebral artery occlusion (pMCAO) in mice and oxygen-glucose deprivation (OGD) in PC12 and SH-SY5Y cells.
  • Assessed neuroprotection via apoptosis, lactate dehydrogenase (LDH), superoxide dismutase (SOD), malondialdehyde (MDA), and ATP levels.
  • Analyzed mitochondrial function using JC-1 and Rhod-2A probes, and mitochondrial ultrastructure via transmission electron microscopy (TEM).
  • Investigated protein and gene expression of mitochondrial calcium uniporter (MCU) complex components, apoptosis-related factors (AIF, Endo G, Cyt C, Caspase-3), and AMPK using RT-qPCR and Western blot.

Main Results:

  • Harpagide significantly reduced OGD-induced cytotoxicity, evidenced by decreased LDH leakage and restored ATP levels.
  • Harpagide suppressed oxidative stress and alleviated mitochondrial calcium overload, improving mitochondrial ultrastructure.
  • Modulated expression of MCU complex components and apoptosis-related proteins was observed, linked to harpagide-mediated AMPK activation.

Conclusions:

  • Harpagide exhibits significant neuroprotective effects against ischemic stroke by preserving mitochondrial bioenergetics and calcium homeostasis.
  • The findings highlight the AMPK-MCU axis as a key pathway through which harpagide exerts its therapeutic benefits.
  • Harpagide represents a potential phytochemical therapeutic agent for ischemic stroke, meriting further research into its molecular interactions.
Keywords:
AMPKHarpagideIschemic strokeMCUMitochondrial calcium homeostasis

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