title: Genetic vulnerability of cortical neurons isolated from stroke-prone spontaneously hypertensive rats in hypoxia and oxygen reperfusion.
abstract: Severe hypertension and cerebrovascular diseases develop in stroke-prone spontaneously hypertensive rats (SHRSP). Cortical neurons from SHRSP are more vulnerable than those from Wistar Kyoto rats (WKY) to the effects of nitric oxide (NO)- and N-methyl-D-aspartate (NMDA)-mediated neurotoxic agents. Growth factors, idebenone, and nilvadipine (a Ca2+ channel blocker) can reduce neuronal damage caused by hypoxia or neurotoxic agents. This study was designed to determine 1) whether cortical neurons from SHRSP are more vulnerable than those from WKY and 2) whether neuronal damage is minimized by the so-called neuroprotective agents in cells exposed to hypoxia and oxygen reperfusion. We demonstrated that 6 to 24 h of hypoxia did not increase cell death in either WKY or SHRSP, whereas 36 h of hypoxia significantly increased cell death in SHRSP (p < 0.01). Furthermore, 6 to 36 h of hypoxia and 1.5 to 5 h of reperfusion heavily damaged cells from both strains of rats, and most cells became apoptotic or necrotic. We also verified that the ability to protect neurons in hypoxia and oxygen reperfusion was as follows: idebenone > insulin-like growth factor-1 (IGF-1) > nilvadipine. These data indicate that oxygen radical generation occurs and the free radicals heavily damage neurons in hypoxia and oxygen reperfusion. SHRSP neurons are weaker than WKY neurons in these conditions. Furthermore, we surmise that idebenone, an antioxidant, decreases free radicals, and IGF-I attenuates p53-mediated apoptosis and thereby prevents cell death. We conclude that antioxidants are more potent than IGF-1 in protecting cortical neurons from damage caused by hypoxia and oxygen reperfusion, although both are very useful in minimizing damage to cortical neurons.
authors.affiliation: Department of Internal Medicine, Sanraku Hospital, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Tagami
authors.forename: K
authors.initials: K
authors.lastname: Yamagata
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: H
authors.initials: H
authors.lastname: Fujino
authors.forename: Y
authors.initials: Y
authors.lastname: Nara
authors.forename: K
authors.initials: K
authors.lastname: Nakagawa
authors.forename: A
authors.initials: A
authors.lastname: Kubota
authors.forename: F
authors.initials: F
authors.lastname: Numano
authors.forename: Y
authors.initials: Y
authors.lastname: Yamori
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D016923:Cell Death; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020022:Genetic Predisposition to Disease / Q000473:pathology*; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications* / Q000517:prevention & control; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D002546:Ischemic Attack, Transient / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010100:Oxygen / Q000008:administration & dosage; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications* / Q000517:prevention & control
chemical_list: D000975:Antioxidants; D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D007334:Insulin-Like Growth Factor I; D007770:L-Lactate Dehydrogenase; D010100:Oxygen