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Novel peptidomimetic compounds attenuate hypoxic-ischemic brain injury in neonatal rats
Hypoxic-ischemic (HI) brain injury is a common neurological problem in neonates. The postsynaptic density protein-95 (PSD-95) is an excitatory synaptic scaffolding protein that regulates synaptic function, and represents a potential therapeutic target to attenuate HI brain injury. Syn3 and d-Syn3 ar...
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Published in: | Experimental neurology 2025-04, Vol.386, p.115151, Article 115151 |
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description | Hypoxic-ischemic (HI) brain injury is a common neurological problem in neonates. The postsynaptic density protein-95 (PSD-95) is an excitatory synaptic scaffolding protein that regulates synaptic function, and represents a potential therapeutic target to attenuate HI brain injury. Syn3 and d-Syn3 are novel high affinity cyclic peptides that bind the PDZ3 domain of PSD-95. We investigated the neuroprotective efficacy of Syn3 and d-Syn3 after exposure to HI in neonatal rodents. Postnatal (P) day-7 rats were treated with Syn3 and d-Syn3 at zero, 24, and 48-h after carotid artery ligation and 90-min of 8 % oxygen. Hemispheric volume atrophy and Iba-1 positive microglia were quantified by cresyl violet and immunohistochemical staining. Treatment with Syn3 and d-Syn3 reduced tissue volume loss by 47.0 % and 41.0 % in the male plus female, and by 42.1 % and 65.0 % in the male groups, respectively. Syn3 reduced tissue loss by 52.3 % in females. D-Syn3 reduced Iba-1 positive microglia/DAPI ratios in the pooled group, males, and females. Syn3 effects were observed in the pooled group and females. Changes in Iba-1 positive microglia/DAPI cellular ratios correlated directly with reduced hemispheric volume loss, suggesting that Syn3 and d-Syn3 provide neuroprotection in part by their effects on Iba-1 positive microglia. The pathogenic cis phosphorylated Thr231 in Tau (cis P-tau) is a marker of neuronal injury. Cis P-tau was induced in cortical cells of the placebo-treated pooled group, males and females after HI, and reduced by treatment with d-Syn3. Therefore, treatment with these peptidomimetic agents exert neuroprotective effects after exposure of neonatal subjects to HI related brain injury.
[Display omitted]
•Syn3 and d-Syn3 reduce brain volume loss in neonatal rats after exposure to HI.•Syn3 and d-Syn3 reduce the increased number of Iba-1 positive microglia after HI.•Iba-1 positive microglia correlate directly with reduced brain volume loss.•d-Syn3 reduces cis P-tau induction in neonatal rats after HI. |
doi_str_mv | 10.1016/j.expneurol.2025.115151 |
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[Display omitted]
•Syn3 and d-Syn3 reduce brain volume loss in neonatal rats after exposure to HI.•Syn3 and d-Syn3 reduce the increased number of Iba-1 positive microglia after HI.•Iba-1 positive microglia correlate directly with reduced brain volume loss.•d-Syn3 reduces cis P-tau induction in neonatal rats after HI.</description><identifier>ISSN: 0014-4886</identifier><identifier>ISSN: 1090-2430</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2025.115151</identifier><identifier>PMID: 39832663</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>D-Syn3, hypoxic-ischemic brain injury ; Neuroprotection ; Newborn ; Syn3</subject><ispartof>Experimental neurology, 2025-04, Vol.386, p.115151, Article 115151</ispartof><rights>2024</rights><rights>Copyright © 2024. Published by Elsevier Inc.</rights><rights>Copyright © 2025. Published by Elsevier Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c247t-456115fc60a15b639d7d3ceebcb0e17edb85cfe262efa2cc1e3cebf4d7a996873</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27898,27899</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39832663$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chen, Xiaodi F.</creatorcontrib><creatorcontrib>Kroke, Brynn</creatorcontrib><creatorcontrib>Ni, Jun</creatorcontrib><creatorcontrib>Munoz, Christian</creatorcontrib><creatorcontrib>Appleman, Mark</creatorcontrib><creatorcontrib>Jacobs, Bryce</creatorcontrib><creatorcontrib>Tran, Tuong</creatorcontrib><creatorcontrib>Nguyen, Kevin V.</creatorcontrib><creatorcontrib>Qiu, Chenxi</creatorcontrib><creatorcontrib>Stonestreet, Barbara S.</creatorcontrib><creatorcontrib>Marshall, John</creatorcontrib><title>Novel peptidomimetic compounds attenuate hypoxic-ischemic brain injury in neonatal rats</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>Hypoxic-ischemic (HI) brain injury is a common neurological problem in neonates. The postsynaptic density protein-95 (PSD-95) is an excitatory synaptic scaffolding protein that regulates synaptic function, and represents a potential therapeutic target to attenuate HI brain injury. Syn3 and d-Syn3 are novel high affinity cyclic peptides that bind the PDZ3 domain of PSD-95. We investigated the neuroprotective efficacy of Syn3 and d-Syn3 after exposure to HI in neonatal rodents. Postnatal (P) day-7 rats were treated with Syn3 and d-Syn3 at zero, 24, and 48-h after carotid artery ligation and 90-min of 8 % oxygen. Hemispheric volume atrophy and Iba-1 positive microglia were quantified by cresyl violet and immunohistochemical staining. Treatment with Syn3 and d-Syn3 reduced tissue volume loss by 47.0 % and 41.0 % in the male plus female, and by 42.1 % and 65.0 % in the male groups, respectively. Syn3 reduced tissue loss by 52.3 % in females. D-Syn3 reduced Iba-1 positive microglia/DAPI ratios in the pooled group, males, and females. Syn3 effects were observed in the pooled group and females. Changes in Iba-1 positive microglia/DAPI cellular ratios correlated directly with reduced hemispheric volume loss, suggesting that Syn3 and d-Syn3 provide neuroprotection in part by their effects on Iba-1 positive microglia. The pathogenic cis phosphorylated Thr231 in Tau (cis P-tau) is a marker of neuronal injury. Cis P-tau was induced in cortical cells of the placebo-treated pooled group, males and females after HI, and reduced by treatment with d-Syn3. Therefore, treatment with these peptidomimetic agents exert neuroprotective effects after exposure of neonatal subjects to HI related brain injury.
[Display omitted]
•Syn3 and d-Syn3 reduce brain volume loss in neonatal rats after exposure to HI.•Syn3 and d-Syn3 reduce the increased number of Iba-1 positive microglia after HI.•Iba-1 positive microglia correlate directly with reduced brain volume loss.•d-Syn3 reduces cis P-tau induction in neonatal rats after HI.</description><subject>D-Syn3, hypoxic-ischemic brain injury</subject><subject>Neuroprotection</subject><subject>Newborn</subject><subject>Syn3</subject><issn>0014-4886</issn><issn>1090-2430</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><recordid>eNqFkD1PwzAQhi0EglL4C5CRJcUfiZ2MFeJLqmABMVqOfVFdJXGwHUT_Pa5aWJGHG_zc3XsPQtcELwgm_HazgO9xgMm7bkExLReElOkdoRnBNc5pwfAxmmFMiryoKn6GzkPYYIzrgopTdMbqilHO2Qx9vLgv6LIRxmiN620P0epMu35002BCpmKEYVIRsvV2dN9W5zboNfQJaryyQ2aHzeS3qWQDuEFF1WVexXCBTlrVBbg81Dl6f7h_u3vKV6-Pz3fLVa5pIWJelDwlbzXHipQNZ7URhmmARjcYiADTVKVugXIKraJaE0i_TVsYoeqaV4LN0c1-7ujd5wQhyj4FhK5TKc4UJCOlKEtWCZJQsUe1dyF4aOXoba_8VhIsd1blRv5ZlTurcm81dV4dlkxND-av71djApZ7ANKpXxa8DNrCoMFYDzpK4-y_S34AU1eQIg</recordid><startdate>20250401</startdate><enddate>20250401</enddate><creator>Chen, Xiaodi F.</creator><creator>Kroke, Brynn</creator><creator>Ni, Jun</creator><creator>Munoz, Christian</creator><creator>Appleman, Mark</creator><creator>Jacobs, Bryce</creator><creator>Tran, Tuong</creator><creator>Nguyen, Kevin V.</creator><creator>Qiu, Chenxi</creator><creator>Stonestreet, Barbara S.</creator><creator>Marshall, John</creator><general>Elsevier Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20250401</creationdate><title>Novel peptidomimetic compounds attenuate hypoxic-ischemic brain injury in neonatal rats</title><author>Chen, Xiaodi F. ; Kroke, Brynn ; Ni, Jun ; Munoz, Christian ; Appleman, Mark ; Jacobs, Bryce ; Tran, Tuong ; Nguyen, Kevin V. ; Qiu, Chenxi ; Stonestreet, Barbara S. ; Marshall, John</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c247t-456115fc60a15b639d7d3ceebcb0e17edb85cfe262efa2cc1e3cebf4d7a996873</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><topic>D-Syn3, hypoxic-ischemic brain injury</topic><topic>Neuroprotection</topic><topic>Newborn</topic><topic>Syn3</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chen, Xiaodi F.</creatorcontrib><creatorcontrib>Kroke, Brynn</creatorcontrib><creatorcontrib>Ni, Jun</creatorcontrib><creatorcontrib>Munoz, Christian</creatorcontrib><creatorcontrib>Appleman, Mark</creatorcontrib><creatorcontrib>Jacobs, Bryce</creatorcontrib><creatorcontrib>Tran, Tuong</creatorcontrib><creatorcontrib>Nguyen, Kevin V.</creatorcontrib><creatorcontrib>Qiu, Chenxi</creatorcontrib><creatorcontrib>Stonestreet, Barbara S.</creatorcontrib><creatorcontrib>Marshall, John</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chen, Xiaodi F.</au><au>Kroke, Brynn</au><au>Ni, Jun</au><au>Munoz, Christian</au><au>Appleman, Mark</au><au>Jacobs, Bryce</au><au>Tran, Tuong</au><au>Nguyen, Kevin V.</au><au>Qiu, Chenxi</au><au>Stonestreet, Barbara S.</au><au>Marshall, John</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel peptidomimetic compounds attenuate hypoxic-ischemic brain injury in neonatal rats</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2025-04-01</date><risdate>2025</risdate><volume>386</volume><spage>115151</spage><pages>115151-</pages><artnum>115151</artnum><issn>0014-4886</issn><issn>1090-2430</issn><eissn>1090-2430</eissn><abstract>Hypoxic-ischemic (HI) brain injury is a common neurological problem in neonates. The postsynaptic density protein-95 (PSD-95) is an excitatory synaptic scaffolding protein that regulates synaptic function, and represents a potential therapeutic target to attenuate HI brain injury. Syn3 and d-Syn3 are novel high affinity cyclic peptides that bind the PDZ3 domain of PSD-95. We investigated the neuroprotective efficacy of Syn3 and d-Syn3 after exposure to HI in neonatal rodents. Postnatal (P) day-7 rats were treated with Syn3 and d-Syn3 at zero, 24, and 48-h after carotid artery ligation and 90-min of 8 % oxygen. Hemispheric volume atrophy and Iba-1 positive microglia were quantified by cresyl violet and immunohistochemical staining. Treatment with Syn3 and d-Syn3 reduced tissue volume loss by 47.0 % and 41.0 % in the male plus female, and by 42.1 % and 65.0 % in the male groups, respectively. Syn3 reduced tissue loss by 52.3 % in females. D-Syn3 reduced Iba-1 positive microglia/DAPI ratios in the pooled group, males, and females. Syn3 effects were observed in the pooled group and females. Changes in Iba-1 positive microglia/DAPI cellular ratios correlated directly with reduced hemispheric volume loss, suggesting that Syn3 and d-Syn3 provide neuroprotection in part by their effects on Iba-1 positive microglia. The pathogenic cis phosphorylated Thr231 in Tau (cis P-tau) is a marker of neuronal injury. Cis P-tau was induced in cortical cells of the placebo-treated pooled group, males and females after HI, and reduced by treatment with d-Syn3. Therefore, treatment with these peptidomimetic agents exert neuroprotective effects after exposure of neonatal subjects to HI related brain injury.
[Display omitted]
•Syn3 and d-Syn3 reduce brain volume loss in neonatal rats after exposure to HI.•Syn3 and d-Syn3 reduce the increased number of Iba-1 positive microglia after HI.•Iba-1 positive microglia correlate directly with reduced brain volume loss.•d-Syn3 reduces cis P-tau induction in neonatal rats after HI.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>39832663</pmid><doi>10.1016/j.expneurol.2025.115151</doi></addata></record> |
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subjects | D-Syn3, hypoxic-ischemic brain injury Neuroprotection Newborn Syn3 |
title | Novel peptidomimetic compounds attenuate hypoxic-ischemic brain injury in neonatal rats |
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