Isoflurane preconditioning induces neuroprotection that is inducible nitric oxide synthase-dependent in neonatal rats.
BACKGROUND
Perinatal stroke is a common human disease. Neonatal brains are immature and engaged in active synaptogenesis. Preconditioning adult rats with the volatile anesthetic isoflurane induces neuroprotection. Whether isoflurane preconditioning induces neuroprotection in neonates is not known.


METHODS
Seven-day-old Sprague-Dawley rats had left common carotid arterial ligation followed by hypoxia with 8% oxygen for 1, 2, or 2.5 h at 37 degrees C. Isoflurane preconditioning with 1 or 1.5% isoflurane for 30 min was performed at 24 h before the brain hypoxia/ischemia. The inducible nitric oxide synthase inhibitor aminoguanidine (200 mg/kg, intraperitoneally) was administered 30 min before the isoflurane pretreatment. The weight ratio of left to right cerebral hemispheres at 7 days after the brain hypoxia/ischemia was calculated. The mortality during the period from cerebral hypoxia/ischemia to 7 days afterwards was monitored. In another experiment, 6-day-old rats were exposed to 1.5% isoflurane for 30 min. The cerebral hemispheres were removed at various time points for Western analysis of inducible nitric oxide synthase.


RESULTS
The mortality was about 40% in neonates with brain hypoxia/ischemia for 2 h or 2.5 h and was not altered by isoflurane preconditioning. The weight ratio of left/right cerebral hemispheres in the survivors was 0.99 +/- 0.02, 0.65 +/- 0.19, and 0.86 +/- 0.15 (n = 7-18) for the rats in control, brain hypoxia/ischemia for 2.5 h, and isoflurane preconditioning plus brain hypoxia/ischemia for 2.5 h groups, respectively (P < 0.05 for the comparisons between control versus brain hypoxia/ischemia and brain hypoxia/ischemia versus isoflurane preconditioning plus brain hypoxia/ischemia). This isoflurane preconditioning-induced neuroprotection was abolished by aminoguanidine (the weight ratio was 0.61 +/- 0.18, n = 12). Isoflurane induced a time-dependent increase in the inducible nitric oxide synthase proteins.


CONCLUSIONS
Isoflurane preconditioning induces neuroprotection in neonatal rats. This neuroprotection is inducible nitric oxide synthase-dependent.
Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia 22908-0710, USA.
Ping
P
Zhao
Zhiyi
Z
Zuo
D018685:Anesthetics, Inhalation / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D001784:Blood Gas Analysis; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D017536:Carotid Artery, Common / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007839:Functional Laterality / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology; D007530:Isoflurane / Q000494:pharmacology* / Q000633:toxicity; D008026:Ligation; D018696:Neuroprotective Agents; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley
D018685:Anesthetics, Inhalation; D004791:Enzyme Inhibitors; D006146:Guanidines; D018696:Neuroprotective Agents; D007530:Isoflurane; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine