ABSTRACT
Therapeutic hypothermia is the standard of care for hypoxic-ischemic (HI) encephalopathy. Inter-alpha Inhibitor Proteins (IAIPs) attenuate brain injury after HI in neonatal rats. Human (h) IAIPs (60 âmg/kg) or placebo (PL) were given 15 âmin, 24 and 48 âh to postnatal (P) day-7 rats after carotid ligation and 8% oxygen for 90 âmin with (30 â°C) and without (36 â°C) exposure to hypothermia 1.5 âh after HI for 3 âh. Hemispheric volume atrophy (P14) and neurobehavioral tests including righting reflex (P8-P10), small open field (P13-P14), and negative geotaxis (P14) were determined. Hemispheric volume atrophy in males was reduced (P â< â0.05) by 41.9% in the normothermic-IAIP and 28.1% in the hypothermic-IAIP compared with the normothermic-PL group, and in females reduced (P â< â0.05) by 30.3% in the normothermic-IAIP, 45.7% in hypothermic-PL, and 55.2% in hypothermic-IAIP compared with the normothermic-PL group after HI. Hypothermia improved (P â< â0.05) the neuroprotective effects of hIAIPs in females. The neuroprotective efficacy of hIAIPs was comparable to hypothermia in female rats (P â= â0.183). Treatment with hIAIPs, hypothermia, and hIAIPs with hypothermia decreased (P â< â0.05) the latency to enter the peripheral zone in the small open field test in males. We conclude that hIAIPs provide neuroprotection from HI brain injury that is comparable to the protection by hypothermia, hypothermia increases the effects of hIAIPs in females, and hIAIPs and hypothermia exhibit some sex-related differential effects.
Subject(s)
Alpha-Globulins , Hypothermia, Induced , Hypoxia-Ischemia, Brain , Neuroprotective Agents , Animals , Female , Humans , Male , Rats , Alpha-Globulins/metabolism , Alpha-Globulins/pharmacology , Animals, Newborn , Hypothermia, Induced/methods , Hypoxia-Ischemia, Brain/therapy , Hypoxia-Ischemia, Brain/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Rats, Sprague-DawleyABSTRACT
Microvasculature develops during early brain development. Hypoxia-ischemia (HI) and hypoxia (H) predispose to brain injury in neonates. Inter-alpha inhibitor proteins (IAIPs) attenuate injury to the neonatal brain after exposure to HI. However, the effects of IAIPs on the brain microvasculature after exposure to HI have not been examined in neonates. Postnatal day-7 rats were exposed to sham treatment or right carotid artery ligation and 8% oxygen for 90 min. HI comprises hypoxia (H) and ischemia to the right hemisphere (HI-right) and hypoxia to the whole body, including the left hemisphere (H-left). Human IAIPs (hIAIPs, 30 mg/kg) or placebo were injected immediately, 24 and 48 h after HI/H. The brains were analyzed 72 h after HI/H to determine the effects of hIAIPs on the microvasculature by laminin immunohistochemistry and calculation of (1) the percentage area stained by laminin, (2) cumulative microvessel length, and (3) density of tunneling nanotubes (TNTs), which are sensitive indicators of the earliest phases of neo-vascularization/collateralization. hIAIPs mainly affected the percent of the laminin-stained area after HI/H, cumulative vessel length after H but not HI, and TNT density in females but not males. hIAIPs modify the effects of HI/H on the microvasculature after brain injury in neonatal rats and exhibit sex-related differential effects. Our findings suggest that treatment with hIAIPs after exposure to H and HI in neonatal rats affects the laminin content of the vessel basal lamina and angiogenic responses in a sex-related fashion.
