Hyperbaric oxygenation and 20-HETE inhibition reduce stroke volume in female diabetic Sprague–Dawley rats

Abstract

We evaluated the effects of acute and repetitive hyperbaric oxygenation (HBO₂), 20-HETE inhibition by N-hydroxy-N'-(4-butyl-2methylphenyl)-formamidine (HET0016) and their combinations on experimental stroke outcomes. Streptozotocin-induced type-1 diabetic Sprague-Dawley female rats (N = 42, N = 7/group), were subjected to 30' transient middle cerebral artery occlusion (t-MCAO) / reperfusion and divided in following groups; (a) Control group, without treatment; and groups exposed to: (b) HBO₂; (c) multiple HBO₂ (HBO₂ immediately and second exposure 12 h after t-MCAO); (d) HET0016 pretreatment (1 mg kg⁻¹/3 days prior to t-MCAO) combined with HBO₂ after t-MCAO; (e) HET0016 treatment (1 h before, during and for 6 hours after t-MCAO); and (f) HET0016 treatment followed by HBO₂ after t-MCAO. mRNA expression of CYP2J3, CYP2C11, CYP4A1, eNOS and EPHX2 was determined by real-time qPCR. Cortical infarct size and total infarct size were equally significantly reduced in HBO₂ and HET0016 treated rats. Combined treatment with HET0016 and HBO₂ provided no significant additive effect compared to HET0016 treatment only. mRNA of Cyp2J3 was significantly increased in all study groups, and mRNA of Cyp2C11 was significantly increased in multiple HBO₂ and HET0016 treatment followed by HBO₂ groups, compared to Control. eNOS expression was significantly increased after HBO₂ treatments and expression of EPHX2 was increased in all groups compared to Control group. In diabetic female SD rats HBO₂ and HET0016 are highly effective stroke treatments, suggesting involvement of CYP450 metabolites and NO pathway in this therapeutic effect.

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