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Background <p>Buyang Huanwu Decoction (BHD) is a classical Traditional Chinese Medicine (TCM) formula effective for treating Chronic Cerebral Ischemia with Qi Deficiency and Blood Stasis Syndrome (CCI<sub>QDBS</sub>), which is known to alleviate neuronal damage and improve cerebral blood flow. The use of a high dose of Astragalus (Huangqi) has been clinically emphasized as crucial to BHD's efficacy, yet the pharmacological basis for this requirement remains unelucidated.</p> Objective <p>This study aimed to compare the therapeutic efficacy of BHD with a high dose of Astragalus (120&#xa0;g, BHD<sub>HA</sub>) versus a low dose (30&#xa0;g, BHD<sub>LA</sub>) in treating CCI<sub>QDBS</sub> and to investigate the underlying mechanisms.</p> Methods <p>A mouse model of CCI<sub>QDBS</sub> was established by combining systemic hypotension with bilateral common carotid artery occlusion and sleep deprivation. The necessity of high-dose Astragalus in BHD was evaluated by assessing syndrome-specific symptoms, cognitive performance, and brain functional connectivity via functional magnetic resonance imaging (fMRI). Neurovascular coupling (NVC) function was visualized in real-time using two-photon in vivo microscopy. RNA sequencing and immunofluorescence were employed to explore the molecular mechanisms by which BHD<sub>HA</sub> improves NVC and mitigates brain injury. Finally, the role of nuclear Factor IA (NFIA) was validated through targeted gene silencing using an AAV-shRNA vector (pAVV-U6-sh<i>Nfia</i>).</p> Results <p>BHD<sub>HA</sub> demonstrated significantly superior therapeutic effects compared to BHD<sub>LA</sub>. It more effectively ameliorated CCI<sub>QDBS</sub>-induced deficits, including memory impairment and fatigue-like behaviors, and significantly enhanced brain functional connectivity. Mechanistically, BHD<sub>HA</sub> induced the morphological recovery of astrocytes, increased their perivascular coverage, and restored impaired NVC function. These beneficial effects were found to be dependent on the upregulation of NFIA. Silencing <i>Nfia</i> abolished the therapeutic advantages of BHD<sub>HA</sub> in improving NVC and cognitive function.</p> Conclusion <p>Our findings demonstrate that the high dose of Astragalus is essential for the therapeutic efficacy of BHD under the conditions of the present experimental model. BHD<sub>HA</sub> alleviates CCI<sub>QDBS</sub> by modulating NFIA to maintain the stability of the neurovascular unit (NUV), thereby improving neurovascular coupling, remodeling brain functional connectivity, and restoring cognitive function. This study provides a scientific basis for the high-dose application of Astragalus in this classical formula. This study provides a scientific basis for the high-dose application of Astragalus in the treatment of CCI<sub>QDBS</sub> using BHD.</p>

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Critical role of high-dose Astragalus in Buyang Huanwu Decoction for enhancing neurovascular coupling in a Qi Deficiency and Blood Stasis animal model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月18日

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  • Kaichao Hu,
  • Juxiang Yang,
  • Guining Wei,
  • Yaxian Zhao,
  • Shifeng Chu,
  • Liqing Li,
  • Shasha Wang,
  • Shanhe Qu,
  • Lixiang Chen,
  • Yuxin Zhang,
  • Xu Yan,
  • Zhao Zhang,
  • Naihong Chen,
  • Wenbin He

摘要

Background

Buyang Huanwu Decoction (BHD) is a classical Traditional Chinese Medicine (TCM) formula effective for treating Chronic Cerebral Ischemia with Qi Deficiency and Blood Stasis Syndrome (CCIQDBS), which is known to alleviate neuronal damage and improve cerebral blood flow. The use of a high dose of Astragalus (Huangqi) has been clinically emphasized as crucial to BHD's efficacy, yet the pharmacological basis for this requirement remains unelucidated.

Objective

This study aimed to compare the therapeutic efficacy of BHD with a high dose of Astragalus (120 g, BHDHA) versus a low dose (30 g, BHDLA) in treating CCIQDBS and to investigate the underlying mechanisms.

Methods

A mouse model of CCIQDBS was established by combining systemic hypotension with bilateral common carotid artery occlusion and sleep deprivation. The necessity of high-dose Astragalus in BHD was evaluated by assessing syndrome-specific symptoms, cognitive performance, and brain functional connectivity via functional magnetic resonance imaging (fMRI). Neurovascular coupling (NVC) function was visualized in real-time using two-photon in vivo microscopy. RNA sequencing and immunofluorescence were employed to explore the molecular mechanisms by which BHDHA improves NVC and mitigates brain injury. Finally, the role of nuclear Factor IA (NFIA) was validated through targeted gene silencing using an AAV-shRNA vector (pAVV-U6-shNfia).

Results

BHDHA demonstrated significantly superior therapeutic effects compared to BHDLA. It more effectively ameliorated CCIQDBS-induced deficits, including memory impairment and fatigue-like behaviors, and significantly enhanced brain functional connectivity. Mechanistically, BHDHA induced the morphological recovery of astrocytes, increased their perivascular coverage, and restored impaired NVC function. These beneficial effects were found to be dependent on the upregulation of NFIA. Silencing Nfia abolished the therapeutic advantages of BHDHA in improving NVC and cognitive function.

Conclusion

Our findings demonstrate that the high dose of Astragalus is essential for the therapeutic efficacy of BHD under the conditions of the present experimental model. BHDHA alleviates CCIQDBS by modulating NFIA to maintain the stability of the neurovascular unit (NUV), thereby improving neurovascular coupling, remodeling brain functional connectivity, and restoring cognitive function. This study provides a scientific basis for the high-dose application of Astragalus in this classical formula. This study provides a scientific basis for the high-dose application of Astragalus in the treatment of CCIQDBS using BHD.