Primary Hypoxic Tolerance and Chemical Preconditioning During Estrus Cycle in Mice

Abstract

Background and Purpose —Exogenous application of estrogens or progesterone ameliorates hypoxic/ischemic cell damage. This study investigates whether values of primary and induced hypoxic tolerance vary endogenously during the estrus cycle in female mice. Methods —Population spike amplitude (PSA) and NADH were measured during hypoxic hypoxia and recovery in hippocampal slices from untreated control animals (C slices) and slices prepared from animals pretreated in vivo with a single intraperitoneal injection of 3-nitropropionate (3NP) (3NP slices) or acetylsalicylate (ASA) (ASA slices). Results —Posthypoxic recovery of PSA was dose dependent in 3NP slices from males, with maximal recovery on pretreatment attained with 20 mg/kg 3NP (82±32% [mean±SD]; C slices, 38±29%; P <0.01). PSA recovered to 17±12% in C slices during proestrus, 43±23% during estrus, and 63±44% during diestrus. In 3NP slices, recovery of PSA increased to 57±36% ( P <0.05) during proestrus. Hypoxic tolerance was not increased in other stages of the estrus cycle. Hypoxic NADH increase during proestrus declined from 212±76% in C slices to 133±11% in 3NP slices ( P <0.05). Recovery of PSA in ASA slices was 75±36% ( P <0.01 versus control) in males and 48±34% during proestrus ( P <0.05 versus ASA slices from males). Conclusions —Primary and induced hypoxic tolerance are endogenously modulated during the estrus cycle. Differences in hypoxic oxidative energy metabolism mediate part of the differential tolerance. Experimental and clinical therapeutic strategies against cerebral ischemia/hypoxia need to consider sex-related dependence.