{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T07:38:36Z","timestamp":1774251516755,"version":"3.50.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T00:00:00Z","timestamp":1774224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"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>In recent years, significant attention has been directed toward the development of therapeutic agents targeting cognitive and motor dysfunction following ischemic stroke. Our research team synthesized SHPL-49, a salidroside derivative, which has demonstrated neuroprotective effects in rat models of ischemic stroke in prior studies. However, the underlying mechanisms remain poorly understood. This study aims to evaluate the therapeutic potential of orally administered SHPL-49 over a 28-day period in rats with bilateral common carotid artery occlusion (BCCAO), specifically focusing on improvements in cognitive and motor deficits, and to further elucidate its mechanism of action.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A BCCAO rat model was employed to investigate the effects of SHPL-49 on cognitive and motor functions following ischemic stroke. Behavioral performance was assessed using the Morris water maze, shuttle box, running wheel, gait analysis, and rotarod tests. Synaptic remodeling in the brain was evaluated through Golgi staining, Western blotting, and immunofluorescence.\n                      <jats:italic>In vitro<\/jats:italic>\n                      transcriptomic changes in PC-12 cells were analyzed by RNA sequencing to identify SHPL-49-regulated genes associated with synaptic remodeling. Furthermore, primary neurons exposed to oxygen-glucose deprivation\/reperfusion (OGD\/R) were utilized to validate the potential therapeutic targets of SHPL-49.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>SHPL-49 significantly ameliorated cognitive and motor impairments in BCCAO rats. SHPL-49 markedly increased dendritic spine density in brain tissue and promoted synaptic remodeling by upregulating the mRNA expression of synapse-related genes, including MAP-2, SYP, and \u03b2III-tubulin, as well as the expression of the key synaptic protein SYN1. Furthermore, transcriptomic analysis of SHPL-49-treated PC-12 cells suggested that SHPL-49 may regulate synaptic remodeling through CDK4 and CDK5 signaling. Subsequent experiments confirmed that SHPL-49 enhanced the expression of CDK5 and its activator p35 in both primary neurons and BCCAO rats, meanwhile inhibited the cleavage of p35 into p25 (a proteolytic event associated with dendritic spine atrophy and synaptic protein degradation).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In summary, SHPL-49 significantly improved memory and motor impairments in BCCAO rats, highlighting the role of synaptic remodeling in this therapeutic effect. The underlying mechanism is closely linked to the modulation of CDK5\/p35\/p25 signaling pathway. These findings provide important theoretical evidence supporting the potential for the long-term clinical oral application of SHPL-49 in treating ischemic stroke.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1727177","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T06:44:18Z","timestamp":1774248258000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Salidroside derivative SHPL-49 enhances synaptic remodeling in BCCAO rats via the CDK5\/p35\/p25 signaling pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Pei","family":"Zhang","sequence":"first","affiliation":[{"name":"The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Guo","sequence":"additional","affiliation":[{"name":"The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Shen","sequence":"additional","affiliation":[{"name":"The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruyi","family":"Wang","sequence":"additional","affiliation":[{"name":"The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoujiao","family":"Peng","sequence":"additional","affiliation":[{"name":"The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruixiang","family":"Li","sequence":"additional","affiliation":[{"name":"The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiange","family":"Zhang","sequence":"additional","affiliation":[{"name":"The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"951202","DOI":"10.3389\/fncel.2022.951202","article-title":"The role of Cdk5 in neurological disorders","volume":"16","author":"Ao","year":"2022","journal-title":"Front. 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