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<p>Diabetes mellitus is frequently associated with cognitive dysfunction, primarily attributed to impaired hippocampal neurogenesis, oxidative stress, inflammation, and pyroptosis. Caffeic acid (CA), a dietary polyphenol, has demonstrated antioxidant and neuroprotective effects. This study evaluated the protective role of CA under diabetic-like conditions using an in vitro glucolipotoxicity model in HT-22 hippocampal neurons exposed to high glucose and oleic acid (HG + OA). CA was administered at low (5 µM) and high (25 µM) concentrations prior to HG + OA treatment. CA significantly enhanced neuronal viability and restored the expression of neurogenesis markers (Nestin, DCX, NeuN) and synaptic proteins (PSD-95, Synaptophysin). Furthermore, CA elevated antioxidant enzyme levels (Nrf2, catalase, SOD-1), regulated apoptosis through increased Bcl-2 and decreased BAX expression, and attenuated inflammatory responses. Pyroptosis was also suppressed, as evidenced by reduced gasdermin D (GSDMD) expression. These findings suggest that CA confers multifactorial neuroprotection against glucolipotoxic injury, and may serve as a dietary modulator for mitigating diabetes-associated cognitive decline in vitro.</p> Graphical abstract <p>CA promotes adult hippocampal neurogenesis (AHN) through activation of the BDNF/TrkB/Akt/mTOR/CREB signaling pathway. In addition, CA reduces oxidative stress by activating the Nrf2-mediated antioxidant response and suppresses inflammation and pyroptosis through inhibition of the NF-κB/NLRP3 signaling pathway, thereby protecting neuronal function and improving cognitive performance.</p> <p></p>

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Caffeic acid restores neurogenesis and synaptic integrity under glucolipotoxic stress by suppressing inflammation and pyroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月28日

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  • I-Ning Tsai,
  • Xiang-Ning Xie,
  • Ping-En Ko,
  • Yung-Che Tsai,
  • Ching-Chun Chen,
  • Li-Sung Hsu,
  • Chau-Jong Wang

摘要

Diabetes mellitus is frequently associated with cognitive dysfunction, primarily attributed to impaired hippocampal neurogenesis, oxidative stress, inflammation, and pyroptosis. Caffeic acid (CA), a dietary polyphenol, has demonstrated antioxidant and neuroprotective effects. This study evaluated the protective role of CA under diabetic-like conditions using an in vitro glucolipotoxicity model in HT-22 hippocampal neurons exposed to high glucose and oleic acid (HG + OA). CA was administered at low (5 µM) and high (25 µM) concentrations prior to HG + OA treatment. CA significantly enhanced neuronal viability and restored the expression of neurogenesis markers (Nestin, DCX, NeuN) and synaptic proteins (PSD-95, Synaptophysin). Furthermore, CA elevated antioxidant enzyme levels (Nrf2, catalase, SOD-1), regulated apoptosis through increased Bcl-2 and decreased BAX expression, and attenuated inflammatory responses. Pyroptosis was also suppressed, as evidenced by reduced gasdermin D (GSDMD) expression. These findings suggest that CA confers multifactorial neuroprotection against glucolipotoxic injury, and may serve as a dietary modulator for mitigating diabetes-associated cognitive decline in vitro.

Graphical abstract

CA promotes adult hippocampal neurogenesis (AHN) through activation of the BDNF/TrkB/Akt/mTOR/CREB signaling pathway. In addition, CA reduces oxidative stress by activating the Nrf2-mediated antioxidant response and suppresses inflammation and pyroptosis through inhibition of the NF-κB/NLRP3 signaling pathway, thereby protecting neuronal function and improving cognitive performance.