Hypoxic-ischemic neonatal encephalopathy and ensuing brain damage is still an important problem in modern perinatal medicine. In this paper, we would like to share some of the results of our recent studies on neuroprotective therapies in animal experiments, as well as some literature reviews. From the basic animal studies, we have now obtained some possible candidates for therapeutic measures against hypoxic-ischemic neonatal encephalopathy. For example, they are hypothermia, rehabilitation, free radical scavenger, neurotrophic factors and growth factors, steroid, calcium channel blocker, vagal stimulation, some anti apoptotic agents, pre- and post conditioning, antioxidants, cell therapy with stem cells, modulators of K(+)-ATP channels, and so on. Whether combination of these therapies may be more beneficial than any single therapy needs to be clarified. Hypoxia-ischemia is a complicated condition, in which the cause, severity, and time-course are different in each case. Likewise, each fetus has its own inherent potentials such as adaptation, preconditioning-tolerance, and intolerance. Therefore, further extensive studies are required to establish an individualized strategy for neuroprotection against perinatal hypoxic-ischemic insult. 1. Introduction Hypoxic-ischemic brain damage caused by intrapartum disastrous events is still an important problem in modern obstetrics even in developed countries. It accounts for 10% to 20% of infants with cerebral palsy [1, 2]. Since 1997, we have been performing a regional population-based study on intrauterine fetal deaths, neonatal deaths, and severely handicapped infants . From a total of 140,000 deliveries in the last 13 years, we found a perinatal mortality rate of 4 per 1,000. This is the lowest rate in the world (perinatal mortality includes stillbirths ≥22 weeks of gestation and neonatal deaths ≤7 days of life). However, even where the most advanced perinatal services are available, the incidence of brain damage is 2/1,000, similar to rates around the world . Among infants with brain damage, the most frequent cause is congenital abnormality (1/3), and hypoxic-ischemic encephalopathy constitutes 15%. Thus, it is important for us to study (1) how to predict fetal hypoxic-ischemic events early enough to prevent brain damage, (2) how to treat severely damaged neonates immediately after birth to prevent brain damage, and (3) how to individualize fetuses at high-risk of brain damage? We have been performing clinical and basic animal studies to elucidate the pathogenesis of hypoxic-ischemic brain damage of
K. Doi, H. Sameshima, Y. Kodama, S. Furukawa, M. Kaneko, and T. Ikenoue, “Perinatal death and neurological damage as a sequential chain of poor outcome,” Journal of Maternal-Fetal and Neonatal Medicine, vol. 25, no. 6, pp. 706–709, 2012.
A. Ota, T. Ikeda, T. Ikenoue, and K. Toshimori, “Sequence of neuronal responses assessed by immunohistochemistry in the newborn rat brain after hypoxia-ischemia,” American Journal of Obstetrics and Gynecology, vol. 177, no. 3, pp. 519–526, 1997.
Y. X. Xia, H. Sameshima, T. Ikeda, T. Higo, and T. Ikenoue, “Cerebral blood flow distribution and hypoxic-ischemic brain damage in newborn rats,” Journal of Obstetrics and Gynaecology Research, vol. 28, no. 6, pp. 320–326, 2002.
T. Ikeda, K. Mishima, T. Yoshikawa et al., “Selective and long-term learning impairment following neonatal hypoxic-ischemic brain insult in rats,” Behavioural Brain Research, vol. 118, no. 1, pp. 17–25, 2001.
K. Mishima, T. Ikeda, T. Yoshikawa et al., “Effects of hypothermia and hyperthermia on attentional and spatial learning deficits following neonatal hypoxia-ischemic insult in rats,” Behavioural Brain Research, vol. 151, no. 1-2, pp. 209–217, 2004.
J. Biernaskie and D. Corbett, “Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury,” Journal of Neuroscience, vol. 21, no. 14, pp. 5272–5280, 2001.
K. Mishima, T. Ikeda, N. Aoo et al., “Hypoxia-ischemic insult in neonatal rats induced slowly progressive brain damage related to memory impairment,” Neuroscience Letters, vol. 376, no. 3, pp. 194–199, 2005.
T. Ikeda, Y. X. Xia, M. Kaneko, H. Sameshima, and T. Ikenoue, “Effect of the free radical scavenger, 3-methyl-1-phenyl-2-pyrazolin-5-one (MCI-186), on hypoxia-ischemia-induced brain injury in neonatal rats,” Neuroscience Letters, vol. 329, no. 1, pp. 33–36, 2002.
J. I. Noor, T. Ikeda, K. Mishima et al., “Short-term administration of a new free radical scavenger, edaravone, is more effective than its long-term administration for the treatment of neonatal hypoxic-ischemic encephalopathy,” Stroke, vol. 36, no. 11, pp. 2468–2474, 2005.
J. I. Noor, T. Ikeda, Y. Ueda, and T. Ikenoue, “A free radical scavenger, edaravone, inhibits lipid peroxidation and the production of nitric oxide in hypoxic-ischemic brain damage of neonatal rats,” American Journal of Obstetrics and Gynecology, vol. 193, no. 5, pp. 1703–1708, 2005.
J. I. Noor, Y. Ueda, T. Ikeda, and T. Ikenoue, “Edaravone inhibits lipid peroxidation in neonatal hypoxic-ischemic rats: an in vivo microdialysis study,” Neuroscience Letters, vol. 414, no. 1, pp. 5–9, 2007.
T. Kojima, Y. Ueda, B. Adatu et al., “Gene network analysis to determine the effects of antioxidant treatment in a rat model of neonatal hypoxic-ischemic encephalopathy,” Journal of Molecular Neuroscience, vol. 42, pp. 154–161, 2010.
T. Kojima, Y. Ueda, A. Sato, H. Sameshima, and T. Ikenoue, “Comprehensive gene expression analysis of cerebral cortices from mature rats after neonatal hypoxic-ischemic brain injury,” Journal of Molecular Neuroscience, 2012.
T. Ikeda, X. Y. Xia, Y. X. Xia, T. Ikenoue, B. Han, and B. H. Choi, “Glial cell line-derived neurotrophic factor protects against ischemia/hypoxia-induced brain injury in neonatal rat,” Acta Neuropathologica, vol. 100, no. 2, pp. 161–167, 2000.
T. Ikeda, H. Koo, Y. X. Xia, T. Ikenoue, and B. H. Choi, “Bimodal upregulation of glial cell line-derived neurotrophic factor (GDNF) in the neonatal rat brain following ischemic/hypoxic injury,” International Journal of Developmental Neuroscience, vol. 20, no. 7, pp. 555–562, 2002.
T. Shingo, I. Date, H. Yoshida, and T. Ohmoto, “Neuroprotective and restorative effects of intrastriatal grafting of encapsulated GDNF-producing cells in a rat model of Parkinson's disease,” Journal of Neuroscience Research, vol. 69, no. 6, pp. 946–954, 2002.
S. Katsuragi, T. Ikeda, I. Date, T. Shingo, T. Yasuhara, and T. Ikenoue, “Grafting of glial cell line-derived neurotrophic factor secreting cells for hypoxic-ischemic encephalopathy in neonatal rats,” American Journal of Obstetrics and Gynecology, vol. 192, no. 4, pp. 1137–1145, 2005.
S. Katsuragi, T. Ikeda, I. Date et al., “Implantation of encapsulated glial cell line-derived neurotrophic factor-secreting cells prevents long-lasting learning impairment following neonatal hypoxic-ischemic brain insult in rats,” American Journal of Obstetrics and Gynecology, vol. 192, no. 4, pp. 1028–1037, 2005.
H. Ochiai, T. Ikeda, K. Mishima et al., “Local administration of glial cell line-derived neurotrophic factor improves behavioral and histological deficit of neonatal Erb's palsy in rats,” Neurosurgery, vol. 53, no. 4, pp. 973–978, 2003.
J. C. Canterino, U. Verma, P. F. Visintainer, A. Elimian, S. A. Klein, and N. Tejani, “Antenatal steroids and neonatal periventricular leukomalacia,” Obstetrics and Gynecology, vol. 97, no. 1, pp. 135–139, 2001.
T. Ikeda, K. Mishima, T. Yoshikawa et al., “Dexamethasone prevents long-lasting learning impairment following neonatal hypoxic-ischemic brain insult in rats,” Behavioural Brain Research, vol. 136, no. 1, pp. 161–170, 2002.
T. Ikeda, K. Mishima, N. Aoo et al., “Dexamethasone prevents long-lasting learning impairment following a combination of lipopolysaccharide and hypoxia-ischemia in neonatal rats,” American Journal of Obstetrics and Gynecology, vol. 192, no. 3, pp. 719–726, 2005.
L. Yang, H. Sameshima, T. Ikeda, and T. Ikenoue, “Lipopolysaccharide administration enhances hypoxic-ischemic brain damage in newborn rats,” Journal of Obstetrics and Gynaecology Research, vol. 30, no. 2, pp. 142–147, 2004.
H. Sameshima, A. Ota, and T. Ikenoue, “Pretreatment with magnesium sulfate protects against hypoxic-ischemic brain injury but postasphyxial treatment worsens brain damage in seven-day- old rats,” American Journal of Obstetrics and Gynecology, vol. 180, no. 3, pp. 725–730, 1999.
H. Sameshima and T. Ikenoue, “Long-term magnesium sulfate treatment as protection against hypoxic-ischemic brain injury in seven-day-old rats,” American Journal of Obstetrics and Gynecology, vol. 184, no. 2, pp. 185–190, 2001.
H. Sameshima and T. Ikenoue, “Effect of long-term, postasphyxial administration of magnesium sulfate on immunostaining of microtubule-associated protein-2 and activated caspase-3 in 7-day-old rat brain,” Journal of the Society for Gynecologic Investigation, vol. 9, no. 4, pp. 203–209, 2002.
S. Tanaka, H. Sameshima, T. Ikenoue, and H. Sakamoto, “Magnesium sulfate exposure increases fetal blood flow redistribution to the brain during acute non-acidemic hypoxemia in goats,” Early Human Development, vol. 82, no. 9, pp. 597–602, 2006.
C. Cheyuo, A. Jacob, R. Wu, M. Zhou, G. F. Coppa, and P. Wang, “The parasympathetic nervous system in the quest for stroke therapeutics,” Journal of Cerebral Blood Flow and Metabolism, vol. 31, no. 5, pp. 1187–1195, 2011.
S. Furukawa, H. Sameshima, L. Yang, and T. Ikenoue, “Acetylcholine receptor agonist reduces brain damage induced by hypoxia-ischemia in newborn rats,” Reproductive Sciences, vol. 18, no. 2, pp. 172–179, 2011.
W. Chen, Q. Ma, H. Suzuki, R. Hartman, J. Tang, and J. H. Zhang, “Osteopontin reduced hypoxia-ischemia neonatal brain injury by suppression of apoptosis in a rat pup model,” Stroke, vol. 42, no. 3, pp. 764–769, 2011.
Q. F. Li, Y. S. Zhu, and H. Jiang, “Isoflurane preconditioning activates HIF-1 , iNOS and Erk1/2 and protects against oxygen-glucose deprivation neuronal injury,” Brain Research, vol. 1245, pp. 26–35, 2008.
P. Zhao, L. Peng, L. Li, X. Xu, and Z. Zuo, “Isoflurane preconditioning improves long-term neurologic outcome after hypoxic-ischemic brain injury in neonatal rats,” Anesthesiology, vol. 107, no. 6, pp. 963–970, 2007.
N. Sasaoka, M. Kawaguchi, Y. Kawaraguchi et al., “Isoflurane exerts a short-term but not a long-term preconditioning effect in neonatal rats exposed to a hypoxic-ischaemic neuronal injury,” Acta Anaesthesiologica Scandinavica, vol. 53, no. 1, pp. 46–54, 2009.
N. Fathali, T. Lekic, J. H. Zhang, and J. Tang, “Long-term evaluation of granulocyte-colony stimulating factor on hypoxic-ischemic brain damage in infant rats,” Intensive Care Medicine, vol. 36, no. 9, pp. 1602–1608, 2010.
A. L. Sirén, M. Fratelli, M. Brines et al., “Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 7, pp. 4044–4049, 2001.
H. Chen, F. Spagnoli, M. Burris et al., “Nanoerythropoietin is 10-times more effective than regular erythropoietin in neuroprotection in neonatal rat model of hypoxia and ischemia,” Stroke, vol. 43, pp. 884–887, 2012.
M. Guardia Clause, P. M. Paez, A. T. Campagnoni, L. A. Pasquini, and J. M. Pasquini, “Intranasal administration of aTf protects and repairs the neonatal white matter after a cerebral hypoxic-ischemic event,” Glia, vol. 60, pp. 1540–1544, 2012.
P. M. Pimentel-Coelho, P. H. Rosado-de-Castro, L. M. da Fonseca, and R. Mendez-Otero, “Umbilical cord blood mononuclear cell transplantation for neonatal hypoxic-ischemic encephalopathy,” Pediatric Research, vol. 71, pp. 464–473, 2012.
F. Scheibe, O. Klein, J. Klose, and J. Priller, “Mesenchymal stromal cess rescue cortical neurons from apoptotic cell death in an in vitro model of cerebral ischemia,” Cellular and Molecular Neurobiology, vol. 32, no. 4, pp. 567–576, 2012.
R. Nisticò, S. Piccirilli, L. Sebastianelli, G. Nisticò, G. Bernardi, and N. B. Mercuri, “The blockade of K+-ATP channels has neuroprotective effects in an in vitro model of brain ischemia,” International Review of Neurobiology, vol. 82, pp. 383–395, 2007.