Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

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120

Stroke is a leading cause of permanent disability and death. It is well accepted that the principal mammalian estrogen (E2), 17-b estradiol, provides robust neuroprotection in a variety of brain injury models in animals of both sexes. E2 enhances neurogenesis after stroke in the subventricular zone; however, it is unknown if these cells survive long-term or enhance functional recovery. In this study, we examined stroke-induced neurogenesis in male, gonadally intact female, and ovariectomized female mice 2 and 6 weeks after stroke. Treatment with 17-b estradiol increased 5-bromo-2 0 -deoxyuridine-labeled cells at both time points in both the dentate gyrus and subventricular zone; the majority were colabeled with doublecortin at 2 weeks and with NeuN at 6 weeks. Stroke-induced neurogenesis was reduced in estrogen receptor knockout mice, as well as in mice lacking the gene for aromatase, which converts testosterone into E2. Improved behavioral deficits were seen in E2-treated mice, suggesting that E2-induced increases in poststroke neurogenesis contribute to poststroke recovery.

Section: Focal Cerebral Ischemia Modelmentioning

confidence: 95%

Section: Ovariectomy and 17-b Estradiol Replacementmentioning

confidence: 99%

Section: Behavioral Scoringmentioning

confidence: 99%

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Estrogen Enhances Neurogenesis and Behavioral Recovery after Stroke

Siegel

Yuan

et al. 2010

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120

“…In contrast, in females, cell death involves caspase-dependent apoptosis. [19][20][21] The male-specific overactivation of PARP-1 in ischemic cell death is particularly relevant because PARP-1-generated adenosine-5 0 -diphosphoribose (ADPr) directly activates TRPM2 channels after exposure to exogenous oxidants. 22,23 Transient receptor potential M2 channels are the only known ion channels to be directly activated by intracellular ADPr, therefore we hypothesize that TRPM2 is a downstream mediator of PARP-1-induced cell death.…”

Section: Introductionmentioning

confidence: 99%

Androgen and PARP-1 Regulation of TRPM2 Channels after Ischemic Injury

Shimizu

Macey

Quillinan

et al. 2013

The calcium-permeable transient receptor potential M2 (TRPM2) ion channel was recently demonstrated to have a sexually dimorphic contribution to ischemic brain injury, with inhibition or knockdown of the channel protecting male brain preferentially. We tested the hypothesis that androgen signaling is required for this male-specific cell-death pathway. Additionally, we tested the hypothesis that differential activation of the enzyme poly (ADP-ribose) polymerase-1 (PARP-1) is responsible for male-specific TRPM2 channel activation and neuronal injury. We observed that administration of the TRPM2 inhibitor clotrimazole (CTZ) 2 hours after onset of ischemia reduced infarct volume in male mice and that protection from ischemic damage by CTZ was abolished by removal of testicular androgens (castration; CAST) and rescued by androgen replacement. Male PARP-1 knockout mice had reduced ischemic damage compared with WT mice and inhibition of TRPM2 with CTZ failed to reduce infarct size. Lastly, we observed that ischemia increased PARP activity in the peri-infarct region of male mice to a greater extent than female mice and the difference was abolished in CAST male mice. Data presented in the current study indicate that TRPM2-mediated neuronal death in the male brain requires intact androgen signaling and PARP-1 activity.

“…While animal studies have shown these observations across different animal models and genetic strains and implied that endogenous sex steroids are a major influence in outcome after ischemic stroke (Alkayed et al, 1998(Alkayed et al, , 2000Hurn and Macrae, 2000;McCullough and Hurn, 2003), emerging data suggest that excitotoxic pathways might have a differential effect in males versus females. For example, neuronally derived NO has been shown to be deleterious in the male, but not in the female, rodent model of focal ischemic stroke (Sampei et al, 2000;McCullough et al, 2005). We have previously shown that the selective KOR agonist provides ischemic neuroprotection in male, but not in female, rats, and that the lack of protection by BRL 52537 is not due to female sex steroids (Chen et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect of Selective Kappa Opioid Receptor Agonist is Gender Specific and Linked to Reduced Neuronal Nitric Oxide

Zeynalov

Nemoto

Hurn

et al. 2005

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We have previously shown that treatment with selective kappa-opioid receptor agonist BRL 52537 hydrochloride [(7)-1-(3,4-dichlorophenyl) acetyl-2-(1-pyrrolidinyl) methylpiperidine] (1) has a long therapeutic window for providing ischemic neuroprotection and (2) attenuates ischemia-evoked nitric oxide (NO) production in vivo in rats. Neuronally derived NO has been shown to be deleterious in the male, but not in the female, rodent model of focal ischemic stroke. We sought to determine if the agent fails to protect ischemic brain when neuronal NO synthase (nNOS) is genetically deleted in male, but not female, mice. Halothane-anesthetized adult male and female nNOS null mutants (nNOS À/À ) and the genetically matched wildtype (WT) strain were subjected to transient (2 h) middle cerebral artery occlusion by the intraluminal filament technique. Vehicle or BRL 52537 treatment with continuous intravenous infusion was instituted at the onset of reperfusion and continued for 22 h. In WT male mice, infarct volumes measured at 72 h of reperfusion were robustly decreased with BRL 52537 treatment. In contrast, BRL 52537 did not decrease infarct volume in male nNOS À/À mice. BRL 52537 had no effect in the WT or nNOS À/À female mice. These data support that BRL 52537's mechanism of neuroprotection in vivo is through attenuation of nNOS activity and ischemia-evoked NO production. Neuroprotective effects of BRL 52537 are lost in the male when nNOS is not present; therefore, BRL 52537 likely acts upstream from NO generation and its subsequent neurotoxicity.