{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:11:56Z","timestamp":1792512716695,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:00:00Z","timestamp":1777420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004829","name":"Science and Technology Department of Sichuan Province","doi-asserted-by":"publisher","award":["2022NSSC1417 2022 \u5e74 NSSC1417"],"award-info":[{"award-number":["2022NSSC1417 2022 \u5e74 NSSC1417"]}],"id":[{"id":"10.13039\/501100004829","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Vascular dementia (VaD) is the second most common type of dementia after Alzheimer\u2019s disease. Puerarin (PUE) is a natural compound isolated from\n                      <jats:italic>Puerariae Lobatae Radix<\/jats:italic>\n                      , plays an important role in treating neurodegenerative and neurovascular diseases. Studies have confirmed that Puerarin can reduce neuroinflammation and protect the blood-brain barrier (BBB). However, the precise mechanism by which PUE treats VaD remains to be elucidated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate the therapeutic effect of Puerarin on VaD and its underlying molecular mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>Cognitive performance was assessed using the behavioral testing. Hematoxylin and Eosin staining (H&amp;amp;E) and Nissl staining were employed to assess neuronal morphology in the hippocampus. Additionally, network pharmacology (NP) was used to identify putative bioactive compounds in PUE and candidate targets associated with VaD. Transmission electron microscopy (TEM), enzyme-linked immunosorbent assay (ELISA), quantitative PCR (qPCR), and Western blotting were used for experimental validation. To further interrogate pathway involvement, lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, was administered, followed by repeated behavioral testing and molecular analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Behavioral testing showed that PUE mitigated two-vessel occlusion (2VO)-induced cognitive deficits and reduced hippocampal neuronal injury. NP identified 17 putative active compounds and 100 overlapping targets between PUE and VaD. GO and KEGG enrichment analyses indicated that these targets were enriched in Toll-like receptor and NF-\u03baB signaling, implicating an anti-neuroinflammatory mechanism. Experimental assays showed that PUE reduced TLR4 and myeloid differentiation primary response 88 (MyD88) expression, decreased nuclear factor-kappa-B p65 (NF-\u03baB p65) phosphorylation, and lowered pro-inflammatory mediator levels. Importantly, the administration of the TLR4 agonist LPS effectively counteracted the therapeutic effects of Puerarin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Puerarin improves learning and cognitive abilities in VaD rats by inhibiting the TLR4\/MyD88\/NF-\u03baB signaling pathway, thereby attenuating pathological alterations in the hippocampus, protecting the BBB integrity from cerebral ischemic damage, and exerting anti-neuroinflammatory effects.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1796295","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T05:52:11Z","timestamp":1777441931000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Investigating the therapeutic mechanism of Puerarin in vascular dementia: an integrated approach combining network pharmacology and experimental validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Hongmei","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Neurology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjiao","family":"Li","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Pu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingxue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunfang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University","place":["Luzhou, Sichuan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"102516","DOI":"10.1016\/j.mex.2023.102516","article-title":"Rodent brain extraction and dissection: a comprehensive approach","volume":"12","author":"Aboghazleh","year":"2024","journal-title":"MethodsX"},{"key":"B2","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/s41531-022-00297-9","article-title":"Effect of LRRK2 protein and activity on stimulated cytokines in human monocytes and macrophages","volume":"8","author":"Ahmadi","year":"2022","journal-title":"NPJ Parkinson's Disease"},{"key":"B3","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1007\/s11655-021-3350-5","article-title":"Electroacupuncture attenuates immune-inflammatory response in hippocampus of rats with vascular dementia by inhibiting TLR4\/MyD88 signaling pathway","volume":"28","author":"Bu","year":"2022","journal-title":"Chin. 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