Metab Brain Dis. 2026 Aug 29;41(1):194. doi: 10.1007/s11011-026-01957-y.
ABSTRACT
Therapeutic hypothermia (TH) is the standard treatment to reduce mortality and neurological impairments after neonatal hypoxia-ischemia (HI). However, TH does not fully suppress neuroinflammation, leading to persistent neuroinflammatory responses that may exacerbate brain injury and limit TH efficacy. In addition, the influence of sexual dimorphism on these outcomes remains poorly understood. We investigated short- and long-term microglial and astrocytic reactivity in male and female neonatal rats following HI and TH treatment. At postnatal day 7 (PND7), male and female pups underwent right common carotid occlusion followed by exposure to hypoxia (8% O). TH was induced by reducing body temperature to 32°C for 5 h. Brains were collected at PND8 or PND21 to assess brain injury volume, brain water content, and microglial and astrocytic reactivity based on Iba-1 and GFAP mean fluorescence intensity. Behavioral impairments were evaluated using negative geotaxis, olfactory discrimination, and cylinder tests. TH did not reduce injury volume but attenuated neuronal cell loss in males and reduced brain edema in females. In males, microglial reactivity was reduced by TH at PND8 and PND21 and astrocytic reactivity only at PND8. Olfactory discrimination was impaired in females and prevented by TH, whereas motor performance deficits and developmental impairments were not prevented by TH. Our results reinforce that the neuroprotective efficacy of TH is limited in severe HI injury and that, despite reducing early neuroinflammation, TH fails to prevent long-term neuroinflammatory responses. Notably, the early anti-inflammatory effects were only observed in males, underscoring the need for additional therapeutic strategies, particularly for females.
PMID:42667339 | DOI:10.1007/s11011-026-01957-y