Analysis of neuronal, glial, endothelial, axonal and apoptotic markers following moderate therapeutic hypothermia and anesthesia in the developing piglet brain.
Hypothermia (HT) by whole body (WBC) or selective head cooling (SHC) reduces hypoxic-ischemic (HI) brain injury; however, whether prolonged hypothermia and/or anesthesia disrupts immature brain development, eg, increases apoptosis, is unknown. Anesthesia increases apoptosis in immature animals. We investigated whether neuroprotective hypothermia and anesthesia disrupts normal brain development. Thirty-eight pigs <24 h old were randomized between five groups and were killed after 72 h: eighteen received a global hypoxic-ischemic insult under anesthesia, eight subsequently cooled by SHC with WBC to T(rectal) 34.5 degrees C for 24 h, followed by 48 h normothermia (NT) at T(rectal) 39.0 degrees C, while 10 remained normothermic. Sixteen underwent anesthetized sham hypoxic-ischemic, six then following normothermia and 10 following hypothermia protocols. There were four normothermic controls. The hypothermia groups demonstrated significant brain hypothermia. In the hypoxic-ischemic groups this conferred approximately 60% neuroprotection reducing histological injury scores in all brain areas. Immunohistochemical/histochemical analyses of neuronal, glial, endothelial, axonal, transcriptional apoptotic markers in areas devoid of histological lesions revealed no hypothermia/normothermia group and differences whether exposed to hypoxic-ischemic or not. Neither 36-h anesthesia nor 24-h hypothermia produced adverse effects at 4-day survival on a panel of brain maturation/neural death markers in newborn pigs. Longer survival studies are necessary to verify the safety of hypothermia in the developing brain.
Gressens
Pierre
P
INSERM, U676, Paris, France.
Dingley
John
J
Plaisant
Frank
F
Porter
Helen
H
Schwendimann
Leslie
L
Verney
Catherine
C
Tooley
James
J
Thoresen
Marianne
M
D018685:Anesthetics, Inhalation / Q000009:adverse effects*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001831:Body Temperature / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000254:growth & development* / Q000503:physiopathology; D019610:Cytoprotection / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D005452:Fluoresceins; D007036:Hypothermia, Induced / Q000009:adverse effects*; D020925:Hypoxia-Ischemia, Brain / Q000628:therapy*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D009410:Nerve Degeneration / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009930:Organic Chemicals; D034421:Sus scrofa
D018685:Anesthetics, Inhalation; D015415:Biomarkers; D005452:Fluoresceins; D009419:Nerve Tissue Proteins; D009930:Organic Chemicals; C435731:fluoro jade