Repeated preconditioning with hyperbaric oxygen induces neuroprotection against forebrain ischemia via suppression of p38 mitogen activated protein kinase.
We previously reported in rats that preconditioning with hyperbaric oxygen (HBO; 100% O(2) 3.5-atomsphere absolute (ATA), 1 h/day for 5 days) provided neuroprotection against transient (8 min) forebrain ischemia possibly through protein synthesis relevant to neurotrophin receptor and inflammatory-immune system. A recent report suggested that HBO-induced neuroprotection is relevant to brain derived neurotrophic factor and its downstream event involving suppression of p38 mitogen activated protein kinase (p38) activation. In the present study, we first performed a dose comparison (1, 2, and 3.5 ATA) of HBO-induced neuroprotection and then investigated pharmacological modification by 10 mg/kg anisomycin (a protein synthesis inhibitor and potent activator for p38) and 200 microg/kg SB203580 (a p38 inhibitor), which were given intraperitoneally 60 and 30 min before every 3.5 ATA-HBO treatment, respectively. Most prominent protective effect on hippocampal CA1 neurons was observed with 3.5 ATA-HBO (survived neurons: 69% [62-73%] vs. untreated: 3.9% [2-8%], 1 ATA: 8.8% [0-26%], 2 ATA-HBO: 46% [22-62%] (median [range]) (7 days after ischemia). Anisomycin abolished a neuroprotective effect (survived neuron: 1.2% [0-7%]). SB203580, when given between administration of anisomycin and HBO treatment, resumed a neuroprotective effect (survived neuron: 52% [37-62%]). The level of phosphorylated p38 at 10-min reperfusion was significantly decreased in 3.5 ATA-HBO group (32% [12-53%] of sham). Single pretreatment with 100 and 200 microg/kg of SB203580 exerted a similar neuroprotective effect (39% [25-51%] and 59% [50-72%]) to 2 and 3.5 ATA-HBO preconditioning, respectively. It is concluded that suppression of p38 phosphorylation plays a key role in HBO-induced neuroprotection and that pretreatment with a p38 inhibitor (SB203580) can provide similar neuroprotection.
Yamashita
Satoshi
S
Department of Anesthesiology, Yamaguchi University Graduate School of Medicine, Ube, Japan.
Hirata
Takao
T
Mizukami
Yoichi
Y
Cui
Ying Jun
YJ
Fukuda
Shiro
S
Ishida
Kazuyoshi
K
Matsumoto
Mishiya
M
Sakabe
Takefumi
T
D000704:Analysis of Variance; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D015153:Blotting, Western; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count; D002470:Cell Survival / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005106:Exploratory Behavior / Q000502:physiology; D006931:Hyperbaric Oxygenation; D007093:Imidazoles / Q000008:administration & dosage; D019194:Ischemic Preconditioning; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D000841:Anisomycin; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580