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A Piglet Model of Neonatal Hypoxic-Ischemic Encephalopathy
Published on: May 16, 2015
Novel peptidomimetic compounds attenuate hypoxic-ischemic brain injury in neonatal rats
Xiaodi F Chen1, Brynn Kroke2, Jun Ni3
1Department of Pediatrics, Women & Infants Hospital of RI, The Alpert Medical School of Brown University, Providence, RI, USA.
Insights
Novel peptides Syn3 and d-Syn3 show neuroprotective effects in neonatal rodent models of hypoxic-ischemic brain injury. These treatments reduced brain tissue loss and inflammation, offering potential therapeutic strategies for neonatal brain damage.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Hypoxic-ischemic (HI) brain injury is a significant cause of neurological deficits in neonates.
- Postsynaptic density protein-95 (PSD-95) is a key regulator of synaptic function and a potential therapeutic target for HI brain injury.
- Syn3 and d-Syn3 are novel cyclic peptides designed to bind the PDZ3 domain of PSD-95.
Purpose of the Study:
- To investigate the neuroprotective efficacy of Syn3 and d-Syn3 in a neonatal rodent model of HI brain injury.
- To assess the impact of Syn3 and d-Syn3 on brain tissue loss, microglial activation, and tau phosphorylation after HI.
- To explore the therapeutic potential of PSD-95 targeting peptides in neonatal neurological conditions.
Main Methods:
- Neonatal (P7) rats were subjected to HI injury (carotid artery ligation and 90-min hypoxia).
- Rats received Syn3 or d-Syn3 at 0, 24, and 48 hours post-injury.
- Neuroprotection was evaluated by quantifying hemispheric volume loss (cresyl violet staining) and Iba-1 positive microglia (immunohistochemistry).
- Pathogenic cis phosphorylated Tau (cis P-tau) levels were assessed as a marker of neuronal injury.
Main Results:
- Syn3 and d-Syn3 significantly reduced hemispheric volume loss in both sexes (41-65% reduction).
- D-Syn3 treatment decreased Iba-1 positive microglia in all groups, while Syn3 showed effects in females and pooled groups.
- Reduced microglial activation correlated with decreased tissue volume loss.
- D-Syn3 treatment reduced the induction of pathogenic cis P-tau in cortical cells.
Conclusions:
- Syn3 and d-Syn3 demonstrate significant neuroprotective effects against HI brain injury in neonatal rodents.
- These peptides appear to exert their effects, in part, by modulating microglial activation.
- Targeting PSD-95 with peptidomimetics like Syn3 and d-Syn3 represents a promising therapeutic approach for neonatal HI brain injury.
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.
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