Neuroprotective effects of hypothermia in inflammatory-sensitized hypoxic-ischemic encephalopathy.
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Département de Pédiatrie, Université de Sherbrooke, 3001- 12e avenue Nord, Sherbrooke (Quebec), J1H 5N4, Canada. Electronic address: Mathilde.Chevin@USherbrooke.ca.
Mathilde
M
Chevin
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.
Clémence
C
Guiraut
Département de Pharmacologie-physiologie, Université de Sherbrooke, 3001- 12e avenue Nord, Sherbrooke (Quebec), J1H 5N4, Canada. Electronic address: Caroline.Maurice-Gelinas@USherbrooke.ca.
Caroline
C
Maurice-Gelinas
Department of Psychiatry, University of California, 9500 Gilman Drive #0804 San Diego, (CA) La Jolla, 92093, United States. Electronic address: jdeslauriers@ucsd.edu.
Jessica
J
Deslauriers
Département de Psychiatrie, Université de Sherbrooke, 3001- 12e avenue Nord, Sherbrooke (Quebec), J1H 5N4, Canada. Electronic address: Sylvain.Grignon@USherbrooke.ca.
Sylvain
S
Grignon
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.
Guillaume
G
Sébire
D000818:Animals; D000831:Animals, Newborn; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D002374:Catalase / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D005979:Glutathione Peroxidase / Q000378:metabolism; D007036:Hypothermia, Induced / Q000379:methods*; D020925:Hypoxia-Ischemia, Brain / Q000150:complications* / Q000628:therapy*; D007249:Inflammation / Q000139:chemically induced / Q000150:complications*; D008070:Lipopolysaccharides / Q000633:toxicity; D051381:Rats; D011917:Rats, Inbred Lew; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000378:metabolism; D013997:Time Factors; D000094765:Glutathione Peroxidase GPX1
D016207:Cytokines; D008070:Lipopolysaccharides; D002374:Catalase; D005979:Glutathione Peroxidase; C000606292:Sod1 protein, rat; D000072105:Superoxide Dismutase-1; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C582791:Ripk3 protein, rat; D000094765:Glutathione Peroxidase GPX1; C000722069:Gpx1 protein, rat
Hypothermia; Inflammation; Neonatal encephalopathy; Neuroprotection