Testosterone exacerbates neuronal damage following cardiac arrest and cardiopulmonary resuscitation in mouse

Abstract

Male animals exhibit greater neuronal damage following focal cerebral ischemic injury in many experimental injury models, however the mechanism of this is unknown. This study used cardiac arrest and cardiopulmonary resuscitation (CA/CPR) in male mice exposed to physiological vs. pharmacological doses of testosterone and tested the hypothesis that testosterone increases damage following global cerebral ischemia. Analysis of histological damage 72 hrs after resuscitation revealed a complex dose-response curve for testosterone, such that low and high doses of testosterone exacerbated ischemic neuronal damage, while intermediate doses had no effect on neuronal survival. In agreement with these histological observations of neuronal damage, both low and high doses of testosterone increased sensorimotor deficit following CA/CPR compared to vehicle treated animals. Finally, the androgen receptor antagonist flutamide inhibited the increase in neuronal damage and sensorimotor impairment observed in testosterone treated mice. Our data showed that low and supra-physiological levels of testosterone increase neuronal damage following global cerebral ischemia and that blockade of androgen receptors limits this injury. Therefore, this study indicated that testosterone may have a role in determining sex-linked differences in cerebrovascular disease as well as having important health implications in clinical conditions of elevated testosterone.

GPER1/GPR30 Activation Improves Neuronal Survival Following Global Cerebral Ischemia Induced by Cardiac Arrest in Mice

“…Three days after CA/CPR, mice were deeply anesthetized with 3% isoflurane and transcardially perfused and fixed with 10% formalin as previously described [20, 22]. Brains were removed, embedded in paraffin and 6 μm coronal sections were serially cut.…”

“…All viable and nonviable neurons were counted for each microscopic field, and the percentage of nonviable neurons was calculated for the entire CA1 and striatum region (average of 3 levels/region). In order to analyze neuronal damage in the striatum, sections were stained with the neuronal-specific marker anti-NeuN antibody in addition to H&E [22]. The investigator was blinded to treatment before analyzing neuronal damage.…”

New steps forward in the neuroactive steroid field

“…Moreover, as recently demonstrated, an anabolic-androgenic molecule, as nandrolone decanoate, was able to impair the beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling [119]. Increased neurotoxicity to glutamate after T treatment has been observed in experimental ischemiareperfusion injury [120] and detrimental effects of T were also observed in global cerebral ischemia [121]. In agreement, the metabolite of T, DHT, exacerbates ischemic damage [122].…”

Androgens and stroke: Good, bad or indifferent?

“…The deleterious and protective effects of testosterone are predominantly androgen receptor dependent (Cheng et al , 2007; Uchida et al , 2009; Nakano et al , 2010). Canonical androgen signaling involves androgen binding to cytoplasmic androgen receptors, translocation to the nucleus and transcription of androgen responsive genes (for review see (Bennett et al , 2010)).…”

“…The topic of the current review is the role of androgens in shaping the male brain response to ischemic injury. Emerging experimental studies indicate that male sex steroids, or androgens (testosterone or dihydrotestosterone; DHT), can have both deleterious and protective effects on the central nervous system (CNS) following cerebrovascular insults such as stroke or cardiac arrest (Cheng et al , 2007; Uchida et al , 2009; Nakano et al , 2010; Cheng et al , 2011). Levels of circulating androgens change with normal development and aging and these changes may contribute to vulnerability of the male brain to an ischemic event.…”