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Objective <p>To investigate the neuroprotective effects and underlying mechanisms of transcranial direct current stimulation (tDCS) combined with 6-Gingerol (6G) in a rat model of traumatic brain injury (TBI) complicated by copper overload, with particular emphasis on microglial polarization and mGluR1 signaling.</p> Methods <p>A controlled cortical impact (CCI) was used to establish TBI in rats, followed by induction of copper overload via oral administration of copper sulfate. Animals were randomly assigned to sham, TBI, copper-overloaded TBI, and copper-overloaded TBI treated with 6G, tDCS, or their combination, with or without the mGluR1 inhibitor LY367385. Neurological function and cognition were evaluated using the modified neurological severity score (mNSS) and Morris water maze. Brain copper content, oxidative stress markers, and neuronal apoptosis were assessed by biochemical assays, Western blotting, and TUNEL staining. Microglial polarization was examined by immunofluorescence and qRT-PCR, and the involvement of mGluR1 signaling was verified pharmacologically.</p> Results <p>Combined tDCS and 6G treatment significantly improved neurological function and spatial learning compared with monotherapy or untreated copper-overloaded TBI. This combination reduced cerebral copper accumulation, attenuated oxidative stress, and decreased neuronal apoptosis. Furthermore, it promoted microglial polarization toward the anti-inflammatory M2 phenotype while suppressing M1-associated inflammatory markers. Inhibition of mGluR1 partially abolished these neuroprotective effects, indicating a critical role of mGluR1 signaling.</p> Conclusion <p>tDCS combined with 6G provides enhanced neuroprotection in copper-overloaded TBI by regulating copper homeostasis, suppressing oxidative stress, promoting microglial M2 polarization, and engaging mGluR1-dependent signaling pathways. These findings suggest a promising combinational therapeutic strategy for TBI complicated by metal dysregulation.</p> Clinical trial number <p>Not applicable.</p>

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Enhanced neuroprotection effects of transcranial direct current stimulation combined with 6-Gingerol in copper-overloaded traumatic brain injury via mGluR1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月4日

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  • Bo Zhang,
  • Jiawei Zhou,
  • Fengkai Liu,
  • Dayong Cui,
  • Xinyu Liu,
  • Dan Wang

摘要

Objective

To investigate the neuroprotective effects and underlying mechanisms of transcranial direct current stimulation (tDCS) combined with 6-Gingerol (6G) in a rat model of traumatic brain injury (TBI) complicated by copper overload, with particular emphasis on microglial polarization and mGluR1 signaling.

Methods

A controlled cortical impact (CCI) was used to establish TBI in rats, followed by induction of copper overload via oral administration of copper sulfate. Animals were randomly assigned to sham, TBI, copper-overloaded TBI, and copper-overloaded TBI treated with 6G, tDCS, or their combination, with or without the mGluR1 inhibitor LY367385. Neurological function and cognition were evaluated using the modified neurological severity score (mNSS) and Morris water maze. Brain copper content, oxidative stress markers, and neuronal apoptosis were assessed by biochemical assays, Western blotting, and TUNEL staining. Microglial polarization was examined by immunofluorescence and qRT-PCR, and the involvement of mGluR1 signaling was verified pharmacologically.

Results

Combined tDCS and 6G treatment significantly improved neurological function and spatial learning compared with monotherapy or untreated copper-overloaded TBI. This combination reduced cerebral copper accumulation, attenuated oxidative stress, and decreased neuronal apoptosis. Furthermore, it promoted microglial polarization toward the anti-inflammatory M2 phenotype while suppressing M1-associated inflammatory markers. Inhibition of mGluR1 partially abolished these neuroprotective effects, indicating a critical role of mGluR1 signaling.

Conclusion

tDCS combined with 6G provides enhanced neuroprotection in copper-overloaded TBI by regulating copper homeostasis, suppressing oxidative stress, promoting microglial M2 polarization, and engaging mGluR1-dependent signaling pathways. These findings suggest a promising combinational therapeutic strategy for TBI complicated by metal dysregulation.

Clinical trial number

Not applicable.