Mathilde Chevin1, Clémence Guiraut2, Caroline Maurice-Gelinas3, Jessica Deslauriers4, Sylvain Grignon5, Guillaume Sébire6. 1. Département de Pédiatrie, Université de Sherbrooke, 3001- 12e avenue Nord, Sherbrooke (Quebec), J1H 5N4, Canada. Electronic address: Mathilde.Chevin@USherbrooke.ca. 2. Department of Pediatrics, McGill University, Research Institute of the McGill University Health Centre, 1001- Decarie boulevard, Montreal (Quebec), H4A 3J1, Canada. Electronic address: Clemence.Guiraut2@mail.mcgill.ca. 3. Département de Pharmacologie-physiologie, Université de Sherbrooke, 3001- 12e avenue Nord, Sherbrooke (Quebec), J1H 5N4, Canada. Electronic address: Caroline.Maurice-Gelinas@USherbrooke.ca. 4. Department of Psychiatry, University of California, 9500 Gilman Drive #0804 San Diego, (CA) La Jolla, 92093, United States. Electronic address: jdeslauriers@ucsd.edu. 5. Département de Psychiatrie, Université de Sherbrooke, 3001- 12e avenue Nord, Sherbrooke (Quebec), J1H 5N4, Canada. Electronic address: Sylvain.Grignon@USherbrooke.ca. 6. Département de Pédiatrie, Université de Sherbrooke, 3001- 12e avenue Nord, Sherbrooke (Quebec), J1H 5N4, Canada; Department of Pediatrics, McGill University, Research Institute of the McGill University Health Centre, 1001- Decarie boulevard, Montreal (Quebec), H4A 3J1, Canada. Electronic address: Guillaume.Sebire@mcgill.ca.
Abstract
BACKGROUND: Despite the recent introduction of hypothermia as a mandatory standard of care, the incidence of neonatal encephalopathy in full-term newborns and its devastating neuro-behavioral outcomes continues to be a major individual, familial and social issue. Neonatal encephalopathy is mainly due to the compounding and interacting effects of hypoxia-ischemia and inflammation resulting from placental and other perinatal infections. It is unclear why hypothermia is effective in alleviating neonatal encephalopathy in some, but not all, full-term newborns. However, newborns exposed to inflammatory-sensitized hypoxia-ischemia seem to have less therapeutic benefit from hypothermia than those exposed to hypoxia-ischemia alone. OBJECTIVES: To clarify this uncertainty, we tested the efficacy of hypothermia in a double-hit model of neonatal encephalopathy induced by inflammatory-sensitized hypoxia-ischemia. METHODS: Using a rat preclinical model of endotoxin plus hypoxia-ischemia-induced neonatal encephalopathy of term newborns, we assessed the following in pups exposed (or not) to hypothermia: the extent of brain injuries and the expressions of molecules implicated in neural cell death, namely: pro-inflammatory cytokines, matrix metalloproteinase-9, antioxidant enzymes, as well as receptor-interacting protein-3. RESULTS: Hypothermia was neuroprotective on inflammatory-sensitized hypoxia-ischemia-induced penumbra, but not core, brain injuries. This beneficial effect was associated with a hypothermia-induced increase of antioxidant enzymes (superoxide dismutase-1, glutathione peroxidase-1), but was not associated with any variations of the other inflammatory mediators tested, namely: interleukin-1β, interleukin-1 receptor antagonist, tumor necrosis factor-α and matrix metalloproteinase-9. CONCLUSION: Hypothermia is neuroprotective against inflammatory-sensitized hypoxia-ischemia possibly through a hypothermia-induced increase of antioxidant enzymes. This neuroprotective effect seems to be independent of the interleukin-1 system.
BACKGROUND: Despite the recent introduction of hypothermia as a mandatory standard of care, the incidence of neonatal encephalopathy in full-term newborns and its devastating neuro-behavioral outcomes continues to be a major individual, familial and social issue. Neonatal encephalopathy is mainly due to the compounding and interacting effects of hypoxia-ischemia and inflammation resulting from placental and other perinatal infections. It is unclear why hypothermia is effective in alleviating neonatal encephalopathy in some, but not all, full-term newborns. However, newborns exposed to inflammatory-sensitized hypoxia-ischemia seem to have less therapeutic benefit from hypothermia than those exposed to hypoxia-ischemia alone. OBJECTIVES: To clarify this uncertainty, we tested the efficacy of hypothermia in a double-hit model of neonatal encephalopathy induced by inflammatory-sensitized hypoxia-ischemia. METHODS: Using a rat preclinical model of endotoxin plus hypoxia-ischemia-induced neonatal encephalopathy of term newborns, we assessed the following in pups exposed (or not) to hypothermia: the extent of brain injuries and the expressions of molecules implicated in neural cell death, namely: pro-inflammatory cytokines, matrix metalloproteinase-9, antioxidant enzymes, as well as receptor-interacting protein-3. RESULTS:Hypothermia was neuroprotective on inflammatory-sensitized hypoxia-ischemia-induced penumbra, but not core, brain injuries. This beneficial effect was associated with a hypothermia-induced increase of antioxidant enzymes (superoxide dismutase-1, glutathione peroxidase-1), but was not associated with any variations of the other inflammatory mediators tested, namely: interleukin-1β, interleukin-1 receptor antagonist, tumor necrosis factor-α and matrix metalloproteinase-9. CONCLUSION:Hypothermia is neuroprotective against inflammatory-sensitized hypoxia-ischemia possibly through a hypothermia-induced increase of antioxidant enzymes. This neuroprotective effect seems to be independent of the interleukin-1 system.
Authors: Lauren E Adams; Hunter G Moss; Danielle W Lowe; Truman Brown; Donald B Wiest; Bruce W Hollis; Inderjit Singh; Dorothea D Jenkins Journal: Antioxidants (Basel) Date: 2021-03-20