Deficiency in indoleamine-2, 3-dioxygenase induces upregulation of guanylate binding protein 1 and inducible nitric oxide synthase expression in the brain during cerebral infection with Toxoplasma gondii in genetically resistant BALB/c mice but not in genetically susceptible C57BL/6 mice

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.

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Isoflurane Preconditioning Improves Long-term Neurologic Outcome after Hypoxic–Ischemic Brain Injury in Neonatal Rats

Anesthesiology ◽

10.1097/01.anes.0000291447.21046.4d ◽

2007 ◽

Vol 107 (6) ◽

pp. 963-970 ◽

Cited By ~ 70

Author(s):

Ping Zhao ◽

Longyun Peng ◽

Liaoliao Li ◽

Xuebing Xu ◽

Zhiyi Zuo

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Brain Ischemia ◽

Neurologic Outcome ◽

Hypoxia Ischemia ◽

Oxide Synthase ◽

The Brain ◽

Inducible Nitric Oxide

Background Preconditioning the brain with relatively safe drugs seems to be a viable option to reduce ischemic brain injury. The authors and others have shown that the volatile anesthetic isoflurane can precondition the brain against ischemia. Here, the authors determine whether isoflurane preconditioning improves long-term neurologic outcome after brain ischemia. Methods Six-day-old rats were exposed to 1.5% isoflurane for 30 min at 24 h before the brain hypoxia-ischemia that was induced by left common carotid arterial ligation and then exposure to 8% oxygen for 2 h. The neuropathology, motor coordination, and learning and memory functions were assayed 1 month after the brain ischemia. Western analysis was performed to quantify the expression of the heat shock protein 70, Bcl-2, and survivin 24 h after isoflurane exposure. Results The mortality was 45% after brain hypoxia-ischemia. Isoflurane preconditioning did not affect this mortality. However, isoflurane preconditioning attenuated ischemia-induced loss of neurons and brain tissues, such as cerebral cortex and hippocampus in the survivors. Isoflurane also improved the motor coordination of rats at 1 month after ischemia. The learning and memory functions as measured by performance of Y-maze and social recognition tasks in the survivors were not affected by the brain hypoxia-ischemia or isoflurane preconditioning. The expression of Bcl-2, a well-known antiapoptotic protein, in the hippocampus is increased after isoflurane exposure. This increase was reduced by the inhibitors of inducible nitric oxide synthase. Inducible nitric oxide synthase inhibition also abolished isoflurane preconditioning-induced neuroprotection. Conclusions Isoflurane preconditioning improved the long-term neurologic outcome after brain ischemia. Inducible nitric oxide synthase may be involved in this neuroprotection.

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