Novel peptidomimetic compounds attenuate hypoxic-ischemic brain injury in neonatal rats

• Published in: Experimental neurology 2025-01, p.115151, Article 115151
• Main Authors: Chen, Xiaodi F., Kroke, Brynn, Ni, Jun, Munoz, Christian, Appleman, Mark, Jacobs, Bryce, Tran, Tuong, Nguyen, Kevin V., Qiu, Chenxi, Stonestreet, Barbara, Marshall, John
• Format: Article
• Language: English
• Subjects: D-Syn3, hypoxic-ischemic brain injury; Neuroprotection; Newborn; Syn3
• ISSN: 0014-4886; 1090-2430; 1090-2430
• DOI: 10.1016/j.expneurol.2025.115151

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.