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Updated: Jul 5, 2025
A Piglet Model of Neonatal Hypoxic-Ischemic Encephalopathy
Published on: May 16, 2015
Intranasal insulin attenuates hypoxia-ischemia-induced short-term sensorimotor behavioral disturbances, neuronal
Chirag P Talati1, Jonathan W Lee1, Silu Lu1,2
1Department of Pediatrics, Division of Newborn Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
Insights
Intranasal insulin shows neuroprotective effects in neonatal rats with Hypoxic-ischemic encephalopathy (HIE). This non-invasive treatment reduced brain damage and improved neurobehavioral outcomes in a preclinical model.
Area of Science:
- Neuroscience
- Neonatal Medicine
- Pharmacology
Background:
- Hypoxic-ischemic encephalopathy (HIE) in newborns requires improved therapeutic options.
- Emerging evidence suggests insulin possesses neuroprotective properties.
Purpose of the Study:
- To investigate the efficacy of intranasal insulin in mitigating brain damage and neurobehavioral deficits caused by HI in neonatal rats.
- To explore the underlying cellular mechanisms of insulin's neuroprotection.
Main Methods:
- Neonatal rats (P10) underwent HI or sham procedures, followed by intranasal administration of insulin or vehicle.
- Brain tissue was analyzed for neuronal degeneration, apoptosis markers, and signaling pathway activation (Akt/PI3K).
- Sensorimotor behaviors were assessed post-treatment.
Main Results:
- Intranasal insulin administration successfully delivered insulin to the brain, activating the Akt/PI3K pathway in neurons.
- Insulin treatment significantly reduced HI-induced sensorimotor deficits, neuronal degeneration (Fluoro-Jade C+), apoptosis (cleaved caspase 3+), and brain volume loss.
- No sex-specific differences in response to HI or insulin were observed.
Conclusions:
- Intranasal insulin demonstrates significant neuroprotection against HI-induced brain injury in a neonatal rat model.
- The protective effects are associated with the activation of neuronal cell survival signaling pathways.
- Intranasal insulin presents a promising, non-invasive therapeutic strategy for HIE, warranting further investigation for long-term benefits.
Abstract:
There is a significant need for additional therapy to improve outcomes for newborns with acute Hypoxic-ischemic (HI) encephalopathy (HIE). New evidence suggests that insulin could be neuroprotective. This study aimed to investigate whether intranasal insulin attenuates HI-induced brain damage and neurobehavioral dysfunction in neonatal rats. Postnatal day 10 (P10), Sprague-Dawley rat pups were randomly divided into Sham + Vehicle, Sham + Insulin, HI + Vehicle, and HI + Insulin groups with equal male-to-female ratios. Pups either had HI by permanent ligation of the right common carotid artery followed by 90 min of hypoxia (8% O2) or sham surgery followed by room air exposure. Immediately after HI or Sham, pups were given fluorescence-tagged insulin (Alex-546-insulin)/vehicle, human insulin (25 μg), or vehicle in each nare under anesthesia. Shortly after administration, widespread Alex-546-insulin-binding cells were detected in the brain, primarily co-localized with neuronal nuclei-positive neurons on double-immunostaining. In the hippocampus, phospho-Akt was activated in a subset of Alex-546-insulin double-labeled cells, suggesting activation of the Akt/PI3K pathway in these neurons. Intranasal insulin (InInsulin) reduced HI-induced sensorimotor behavioral disturbances at P11. InInsulin prevented HI-induced increased Fluoro-Jade C+ degenerated neurons, cleaved caspase 3+ neurons, and volume loss in the ipsilateral brain at P11. There was no sex-specific response to HI or insulin. The findings confirm that intranasal insulin provides neuroprotection against HI brain injury in P10 rats associated with activation of intracellular cell survival signaling. If further pre-clinical research shows long-term benefits, intranasal insulin has the potential to be a promising non-invasive therapy to improve outcomes for newborns with HIE.
