---
title: "Tanshinone IIA improves cognition in vascular dementia rats by modulating copper homeostasis"
id: "plos-one-5-tanshinone-iia-attenuates-cognitive-impairment-in-vascular-dementia-rats-by"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-5-tanshinone-iia-attenuates-cognitive-impairment-in-vascular-dementia-rats-by"
content_type: "clinical_feed_article"
specialty: "Neurology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885"
published_at: "2026-08-24T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Tanshinone IIA improves cognition in vascular dementia rats by modulating copper homeostasis
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-5-tanshinone-iia-attenuates-cognitive-impairment-in-vascular-dementia-rats-by
- **Specialty:** [Neurology](https://medichelpline.com/clinical-feed/neurology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885)
- **Published At:** 2026-08-24T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The study tested **Tanshinone IIA (TSA)**, a liposoluble component of Salvia miltiorrhiza, for neuroprotective effects in a rat model of **vascular dementia (VaD)**. - VaD was induced by permanent bilateral common carotid artery ligation (2-VO) to model chronic cerebral hypoperfusion and cognitive impairment. - Cognitive function was assessed using the Morris water maze; neuronal injury was evaluated by HE and Nissl staining and mitochondrial ultrastructure by transmission electron microscopy (TEM). - The investigation focused on the novel regulated cell-death pathway **cuproptosis**, which is driven by copper overload, mitochondrial dysfunction, and aggregation of lipoylated proteins. - Key cuproptosis-related proteins measured by Western blot included **SLC31A1**, **FDX1**, LIAS and DLAT; SLC31A1 mediates copper influx and FDX1 is a central regulator that reduces Cu2+ to Cu+ and affects lipoylation. - In vivo, TSA treatment markedly alleviated spatial learning and memory deficits and reduced neuronal damage in the hippocampus of VaD rats, and reversed abnormal changes in cuproptosis-related protein expression. - In vitro, TSA protected HT-22 hippocampal cells subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) by improving cell viability, lowering intracellular reactive oxygen species (ROS), and reducing copper accumulation (measured with Coppersensor-1). - TSA-associated effects included attenuation of copper overload and preservation of mitochondrial integrity, suggesting neuroprotection is at least partially mediated via modulation of the **SLC31A1/FDX1** axis and suppression of cuproptosis. - The authors conclude TSA may offer a new mechanistic target for VaD therapy by regulating copper-dependent cytotoxic stress; the study provides preclinical evidence supporting cuproptosis-targeted strategies. - Details on dose regimens, statistical values, and full experimental parameters are reported in the manuscript and supporting information; no competing interests were declared by the authors.
## Clinical Analysis & Structured Key Points
[ Skip to main content ](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#main-content) Advertisement * [plos.org](https://plos.org/) * [Create account](https://community.plos.org/registration/new) * [Sign in](https://journals.plos.org/user/secure/login?page=%2Fplosone%2Farticle%3Fid%3D10.1371%2Fjournal.pone.0356885) * * About * Browse * Publish * [](https://journals.plos.org/plosone/ "PLOS One") * Search [advanced search](https://journals.plos.org/plosone/search) * [Browse Topics](https://journals.plos.org/plosone/subjectAreaBrowse) Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click [here](https://github.com/PLOS/plos-thesaurus/blob/master/README.md "Link opens in new window"). [](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885) [](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885) * 0 [Save](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356885#savedHeader) [Total Mendeley and Citeulike bookmarks.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356885#savedHeader) * 0 [Citation](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356885#citedHeader) [Paper's citation count computed by Dimensions.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356885#citedHeader) * 31 [View](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356885#viewedHeader) [PLOS views and downloads.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356885#viewedHeader) * 0 [Share](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356885#discussedHeader) [Sum of Facebook, Twitter, Reddit and Wikipedia activity.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356885#discussedHeader) Open Access Peer-reviewed Research Article # Tanshinone IIA attenuates cognitive impairment in vascular dementia rats by modulating copper homeostasis via the SLC31A1/FDX1 axis * Hongxiao Lv, Roles Conceptualization, Data curation, Writing – original draft, Writing – review & editing Affiliation Hebei University of Chinese Medicine, Shijiazhuang, China ⨯ * Xinyu Yang, Roles Formal analysis, Methodology Affiliation Hebei University of Chinese Medicine, Shijiazhuang, China ⨯ * Yutong Liu, Roles Data curation Affiliation Hebei University of Chinese Medicine, Shijiazhuang, China ⨯ * Junwei Zhou , Roles Funding acquisition * E-mail: yuwentao@hebcm.edu.cn (WTY); 13691113555@163.com (JWZ) Affiliation Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China ⨯ * Wentao Yu Roles Funding acquisition, Visualization * E-mail: yuwentao@hebcm.edu.cn (WTY); 13691113555@163.com (JWZ) Affiliations Hebei University of Chinese Medicine, Shijiazhuang, China, Hebei International Joint Research Center for Dominant Diseases in Chinese Medicine and Acupuncture, Shijiazhuang, China, Hebei Key Laboratory of Chinese Medicine Research on Cardio-Cerebrovascular Diseases, Shijiazhuang, China [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0009-0009-0369-5032 ](https://orcid.org/0009-0009-0369-5032 "ORCID Registry") ⨯ # Tanshinone IIA attenuates cognitive impairment in vascular dementia rats by modulating copper homeostasis via the SLC31A1/FDX1 axis * Hongxiao Lv, * Xinyu Yang, * Yutong Liu, * Junwei Zhou, * Wentao Yu ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: August 24, 2026 * * [Article](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885) * [Authors](https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0356885) * [Metrics](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356885) * [Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0356885) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pone.0356885) * [Abstract](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#abstract0) * [1. Introduction](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#sec005) * [2. Materials and methods](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#sec006) * [3. Results](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#sec019) * [4. Discussion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#sec025) * [5. Discussion-Limitations](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#sec026) * [Supporting information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#sec027) * [References](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#references) * [Reader Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0356885) * [Figures](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885) ## Abstract ### Background Tanshinone IIA (TSA) is the core liposoluble active component of _Salvia miltiorrhiza_ , a traditional Chinese medicine, and exhibits multiple pharmacological activities including anti-inflammation, anti-oxidation, anti-apoptosis and mitochondrial function improvement. Studies have confirmed that TSA can ameliorate cognitive function in rats with vascular dementia (VaD) by alleviating cerebral ischemic injury, inhibiting neuroinflammation, protecting the blood-brain barrier and other pathways. However, it has not been reported whether TSA exerts its neuroprotective effect by regulating the cuproptosis pathway. Focusing on cuproptosis, this study investigated the effects of TSA on cognitive impairment, neuronal injury and cuproptosis-related mechanisms in a rat model of VaD. ### Methods A rat model of VaD was established by permanent bilateral common carotid artery ligation (2-VO), and the model rats were treated with TSA. The cognitive impairment of VaD rats was evaluated by the Morris water maze test. Hematoxylin-eosin (HE) staining and Nissl staining were used to detect neuronal injury and loss in the hippocampus of VaD rats. Transmission electron microscopy (TEM) was performed to observe the ultrastructure of mitochondria in the hippocampus; Western blot (WB) assay was adopted to detect the expression levels of cuproptosis-related proteins, including solute carrier family 31 member 1 (SLC31A1), ferredoxin 1 (FDX1), lipoic acid synthetase (LIAS) and dihydrolipoamide transacetylase (DLAT).In vitro, an oxygen-glucose deprivation/reoxygenation (OGD/R) model was established in HT-22 cells to evaluate the effects of TSA on cell viability (CCK-8), intracellular reactive oxygen species (ROS) levels, and copper accumulation (Coppersensor-1 staining), further validating the involvement of copper homeostasis in TSA-mediated neuroprotection. ### Results The results revealed that TSA markedly alleviated cognitive dysfunction and neuronal damage in VaD rats. It also reversed the cuproptosis-related abnormal changes in the brain of VaD rats, and modulated the expression of SLC31A1/FDX1 pathway proteins. In vitro, TSA protected HT-22 cells from OGD/R-induced injury by reducing oxidative stress and copper accumulation.These changes were associated with amelioration of copper overload and mitochondrial damage, suggesting that TSA may exert neuroprotection partially through the regulation of cuproptosis-related pathways. ### Conclusion TSA effectively alleviated cognitive impairment and neuronal injury in VaD rats, and exerted neuroprotective effects both in vivo and in vitro by attenuating copper-dependent cytotoxic stress, preserving mitochondrial integrity, and modulating the SLC31A1/FDX1 axis. This study provides a new perspective and theoretical basis for the future development of targeted drugs for VaD. ## Figures ![Fig 4](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g004) ![Fig 5](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g005) ![Fig 6](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g006) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g003) ![Fig 4](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g004) ![Fig 5](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g005) ![Fig 6](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g006) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356885.g003) **Citation:** Lv H, Yang X, Liu Y, Zhou J, Yu W (2026) Tanshinone IIA attenuates cognitive impairment in vascular dementia rats by modulating copper homeostasis via the SLC31A1/FDX1 axis. PLoS One 21(8): e0356885. https://doi.org/10.1371/journal.pone.0356885 **Editor:** Vincenzo Lionetti, Scuola Superiore Sant'Anna, ITALY **Received:** March 12, 2026; **Accepted:** August 10, 2026; **Published:** August 24, 2026 **Copyright:** © 2026 Lv et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** All relevant data are within the manuscript and its [Supporting information](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#sec027) files. **Funding:** This study was supported by Hebei Province Natural Science Foundation Project (H2020423042);Hebei Provincial Administration of Traditional Chinese Medicine Science and Technology Plan Project (2022090);Hebei Provincial Administration of Traditional Chinese Medicine Research Project (B2025067).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study. **Competing interests:** NO authors have competing interests Enter: The authors have declared that no competing interests exist. Authors with competing interests Enter competing interest details beginning with this statement: I have read the journal’s policy and the authors of this manuscript have the following competing interests: [insert competing interests here]. ## 1. Introduction Vascular dementia (VaD) is a cognitive impairment syndrome caused by cerebrovascular diseases or vascular risk factors. It is the second most common type of dementia worldwide after Alzheimer’s disease, accounting for approximately 15%–20% of all dementia cases [[1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref001)]. Its core pathological basis is neuronal loss and brain function degeneration induced by chronic cerebral hypoperfusion and cerebrovascular injury [[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref002)]. The clinical manifestations include memory decline, inattention, executive dysfunction, etc., which seriously affect the quality of life of patients and impose a heavy medical burden on families and society [[3](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref003)]. Although some understanding of the pathological mechanisms of VaD has been achieved, there are still no specific therapeutic drugs. Clinical interventions are mostly limited to controlling risk factors and alleviating symptoms, which cannot effectively delay disease progression. Therefore, further revealing its novel pathological mechanisms and developing targeted therapeutic strategies on this basis is of great clinical significance and scientific value for improving the prognosis of patients. VaD is pathologically heterogeneous, encompassing multiple subtypes including subcortical ischemic vascular dementia (SIVD), multi-infarct dementia, and strategic single-infarct dementia [[4](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref004)]. Neuropathologically, VaD is characterized by multifocal and/or diffuse lesions, ranging from lacunar infarcts and microinfarcts to diffuse white matter changes involving myelin loss and axonal abnormalities, often affecting subcortical structures, basal ganglia, thalamus, and white matter tracts [[5](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref005),[6](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref006)]. Among these, chronic cerebral hypoperfusion (CCH) is recognized as a primary driver of vascular cognitive impairment, with cerebral blood flow typically falling below 24–45 mL/100 g/min (normal: 50–60 mL/100 g/min) [[7](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref007)]. To investigate the pathophysiology of VaD and evaluate potential therapeutic interventions, several animal models of chronic cerebral hypoperfusion have been developed. Among these, the permanent bilateral common carotid artery occlusion (2-VO) model in rats is one of the most widely used and well-characterized approaches [[8](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref008),[9](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref009)]. The 2-VO model exhibits characteristic features of subcortical ischemic VaD, including white matter damage, neuronal shrinkage in the cerebral cortex and hippocampus, and cognitive impairments in spatial learning and memory tasks [[10](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref010)]. Importantly, the 2-VO rat model has been validated as a useful tool for investigating the pathophysiology of human dementia and for elucidating the therapeutic potential of candidate drugs [[9](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref009)]. However, this model also possesses inherent limitations: cerebral blood flow drops sharply and substantially after acute ligation of the common carotid arteries, and the model lacks concomitant vascular risk factors (e.g., hypertension, diabetes) and causative small vessel changes that typically characterize human VaD [[11](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref011)]. Despite these limitations, the 2-VO model remains a standard and reproducible approach for initial mechanistic screening of neuroprotective agents in VaD, given its well-defined timeline of pathological progression, established cognitive endpoints, and extensive historical data for cross-study comparison [[8](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref008),[9](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref009)]. Dysregulated cell death modalities play a pivotal role in the pathological progression of VaD. In recent years, cuproptosis has been identified as a novel regulated form of cell death, characterized by mitochondrial dysfunction, abnormal aggregation of lipoylated proteins and loss of iron-sulfur cluster proteins triggered by aberrant copper ion accumulation, ultimately leading to proteotoxic stress and cell death [[12](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref012)]. As an essential trace element in the organism, copper homeostasis relies on the precise regulation of transporters. Among these, SLC31A1 mediates the intracellular influx of copper ions. FDX1, as a core regulatory factor of the cuproptosis pathway, not only reduces Cu²⁺ to the more toxic Cu ⁺ , but also modulates the post-translational modification of downstream lipoylated proteins (e.g., dihydrolipoamide transacetylase, DLAT), thereby directly driving the onset and progression of cuproptosis [[13](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref013)]. Recent studies have indicated a close association between the cuproptotic mechanism and neurological disorders [[14](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref014)]. In VaD models, cerebral vascular injury can induce copper homeostasis imbalance, exacerbate neuronal damage by activating the cuproptosis pathway, and inhibition of cuproptosis is promising to ameliorate neurological deficits, suggesting that cuproptosis may serve as a potential therapeutic target for VaD. Furthermore, the SLC31A1/FDX1 signaling pathway, as the core axis regulating cuproptosis, has been proven to be abnormally activated and involved in the pathological processes of various diseases [[15](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref015)]. Downregulation of this pathway can effectively inhibit copper ion accumulation and the transduction of downstream death signals, providing a well-defined molecular target for cuproptosis-targeted therapy [[16](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref016)]. TSA is the major liposoluble active component of Salvia miltiorrhiza, a traditional Chinese medicine. It exhibits prominent anti-inflammatory, antioxidant, mitochondrial protective and neuroprotective effects, and has been widely used in the basic research and clinical treatment of cardio-cerebrovascular diseases [[17](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref017)]. Studies have confirmed that TSA can significantly alleviate cognitive impairment in animal models of VaD through mechanisms such as improving cerebral perfusion, inhibiting oxidative stress and reducing neuronal apoptosis [[18](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356885#pone.0356885.ref018)]. However, it remains unclear whether its protective effects are associated with the regulation of cuproptosis. Considering the potential of TSA in regulating intracellular homeostasis and the pathological role of cuproptosis in VaD, we hypothesize that TSA may exert its therapeutic effects on VaD by modulating the key pathways of cuproptosis. Against this backdrop, the present study aimed to investigate the therapeutic effects of TSA on VaD and its association with cuproptosis, with a focus on clarifying whether it inhibits cuproptosis by downregulating the SLC31A1/FDX1 signaling pathway, thereby attenuating neuronal injury and ameliorating cognitive function. This study will provide experimental evidence for uncovering the novel mechanism underlying TSA in the treatment of VaD, and meanwhile offer new strategies and insights for the development of targeted therapy for VaD. ## 2. Materials and methods ### 2.1 Experimental design The overall experimental design is illustrated in [Fig 1](https://journals.plos.org/plos
## Related Clinical Research

- [Updated 2026 Migraine Prevention Guidelines Reflect Expanded Treatment Options](https://medichelpline.com/clinical-feed/stat-news-0-new-guidelines-on-migraine-prevention-reflect-increasing-options-for-patients.md)
- [Diet and Alzheimer’s risk: Why no single best diet fits everyone](https://medichelpline.com/clinical-feed/medical-news-today-0-is-there-a-best-diet-to-help-lower-alzheimer-s-risk.md)
- [Prevalence of cognitive impairment in older Palestinian adults in community and nursing homes](https://medichelpline.com/clinical-feed/plos-one-16-prevalence-of-cognitive-impairment-among-older-adult-palestinians-in-community.md)
- [Pre-diagnostic 1-year prevalence of polypharmacy and PIMcog in Norwegian outpatients with MCI or d](https://medichelpline.com/clinical-feed/plos-one-14-one-year-pre-diagnostic-prevalence-and-associated-factors-of-polypharmacy-and.md)
- [Estrogen-only menopausal therapy associated with reduced Alzheimer’s biomarkers](https://medichelpline.com/clinical-feed/medical-news-today-0-estrogen-only-therapy-after-menopause-linked-to-reduced-alzheimer-s-biomarkers.md)

## Navigation
- [← Back to Neurology Feed](https://medichelpline.com/clinical-feed/neurology.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.