Hypoxic preconditioning attenuated in kainic acid-induced neurotoxicity in rat hippocampus.
The neuroprotective effect of hypoxic preconditioning on kainate (KA)-induced neurotoxicity, including apoptosis and necrosis, was investigated in rat hippocampus. Female Wistar-Kyoto rats were subjected to 380 mm Hg in an altitude chamber for 15 h/day for 28 days. Intrahippocampal infusion of KA was performed in chloral hydrate anesthetized rats, which acutely elevated 2,3-dihydroxybenzoic acid levels in normoxic rats. Seven days after the infusion, KA increased lipid peroxidation in the infused hippocampus and resulted in hippocampal CA3 neuronal loss. A 4-week hypoxic preconditioning attenuated KA-induced elevation in hydroxyl radical formation and lipid peroxidation as well as KA-induced neuronal loss. The effects of hypoxic preconditioning on KA-induced apoptosis and necrosis were investigated further. Two hours after KA infusion, cytosolic cytochrome c content was increased in the infused hippocampus. Twenty-four hours after KA infusion, pyknotic nuclei, cellular shrinkage, and cytoplasmic disintegration, but not TUNEL-positive staining, were observed in the CA3 region of hippocampus. Forty-eight hours after KA infusion, both DNA smear and DNA fragmentation were demonstrated in the infused hippocampus. Furthermore, TUNEL-positive cells, indicative of apoptosis, in the infused hippocampus were detected 72 h after KA infusion. Hypoxic pretreatment significantly reduced necrotic-like events in the KA-infused hippocampus. Moreover, hypoxic preconditioning attenuated apoptosis induced by KA infusion, including elevation in cytosolic cytochrome c content, TUNEL-positive cells, and DNA fragmentation. Our data suggest that hypoxic preconditioning may exert its neuroprotection of KA-induced oxidative injuries via attenuating both apoptosis and necrosis in rat hippocampus.
Chang
A Y
AY
Institute of Pharmaceutical Sciences, National Yang-Ming University, Taiwan.
Wang
C H
CH
Chiu
T H
TH
Chi
J W
JW
Chen
C F
CF
Ho
L T
LT
Lin
A M Y
AM
D000818:Animals; D015139:Blotting, Southern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count / Q000379:methods; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D045304:Cytochromes c / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D004563:Electrochemistry / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D062385:Hydroxybenzoates / Q000032:analysis; D020287:In Situ Nick-End Labeling / Q000379:methods; D019194:Ischemic Preconditioning / Q000379:methods*; D007608:Kainic Acid / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D017551:Microdialysis / Q000379:methods; D009474:Neurons / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D013194:Staining and Labeling / Q000379:methods; D013997:Time Factors
D018690:Excitatory Amino Acid Agonists; D062385:Hydroxybenzoates; C009135:2,3-dihydroxybenzoic acid; D045304:Cytochromes c; D010100:Oxygen; D007608:Kainic Acid