Clinical NeuroscienceResearch PaperPoly (ADP-ribose) polymerase-1 initiated neuronal cell death pathway—do androgens matter?
Section snippets
Animals
The present study was conducted in accordance with the National Institutes of Health guidelines for the care and use of animals in research and under protocols approved by the Oregon Health and Science University Animal Care and Use Committee. We used PARP-1 gene deficient (KO) male mice raised in our laboratory (homozygous breeding with intermittent confirmation of genotype, as described previously (Eliasson et al., 1997); animals bred to confluence on background strain [129S1/SvImJ]).
Infarct volumes of intact and castrated WT and PARP-1 KO male mice
Gonadally intact and castrated male 129S1/SvImJ mice (WT) and PARP-1 KO (KO) mice were subjected to 90 min MCAO and infarct volume of cortex, striatum, and total (hemisphere) was analyzed. Castrated WT mice had significantly smaller total infarct volumes compared to intact WT male mice, consistent with our recently published results (Cheng et al., 2007, Uchida et al., 2009), 16.9%±2.1% (n=10) in CAST vs. 37.3%±6.9% (n=10) in intact. Similar findings were observed in cortical and striatal
Discussion
This study provided three important findings. First, removal of testicular androgens prevents the protection from ischemic damage in male brain following pharmacological inhibition of PARP and increases damage in PARP-1 KO mice, indicative of reversal of neuroprotection following gene deletion. Second, DHT replacement rescues this protection in WT and PARP-1 KO mice in an androgen receptor-mediated mechanism. Lastly, we found that ischemia causes increase in expression of PARP-1 mRNA and that
Conclusion
Removal of endogenous androgens reversed the protection observed with pharmacological inhibition or genetic deletion of PARP-1 following experimental stroke in male mice, suggesting a fundamental interaction between androgens and PARP-1. Our data further implicates that androgen-AR signaling is an essential component of the PARP-1-mediated cell death pathway following ischemia in male mice. Lastly, castration reversed the effects of ischemia on PARP-1 transcription; and androgen replacement
Acknowledgments
The authors thank Ms. Kathy Gage, Grant and Publications Writer for the Department of Anesthesiology and Perioperative Medicine, OHSU, for her outstanding editorial work in the preparation of this manuscript. The authors would also like to acknowledge the excellent service and care provided by the Department of Anesthesiology and Perioperative Medicine Mouse Colony Core, which oversaw management of the PARP-1 KO mouse breeding colony. Work supported by NIH grants PO1NS49210 and the Bugher
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2019, Neurochemistry InternationalCitation Excerpt :Similarly, in adult rodents, genetic deletion or pharmacological inhibition of PARP-1 resulted in neuroprotection in males but exacerbated ischemic brain damage in females (Liu et al., 2011; McCullough et al., 2005). Thus, the male-specific cell death mechanism mediated by PARP-1/AIF pathway may be dependent on androgen availability and androgen receptor signaling (Vagnerova et al., 2010). In contrast, in females, caspase-dependent apoptotic cell death may be the major pathway activated after ischemic injury.
Contributions of sex to cerebrovascular function and pathology
2019, Brain ResearchCitation Excerpt :In both intact and GDX female mice, caspase inhibition is neuroprotective after MCAO, but has no effect in males, suggesting that XX chromosome status, rather than E2, is responsible for the increased caspase-mediated cell death in females (Liu et al., 2009a). Conversely, intact male PARP-1 knockout mice also have smaller infarcts after MCAO, but protection is lost with GDX and restored with androgen replacement, suggesting androgens may mediate some of the PARP-1 selective cell death in males (Vagnerova et al., 2010). Taken together, these findings suggest that not only sex hormones, but also sex complement, can play a significant role in stroke outcomes.
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2016, Neurobiology of DiseaseSirtuin-2 mediates male specific neuronal injury following experimental cardiac arrest through activation of TRPM2 ion channels
2016, Experimental NeurologyCitation Excerpt :It is now recognized that the mechanisms of neuronal injury can differ between males and females and this is an important consideration in preclinical studies of neuroprotection. Cell death in males after in vivo or in vitro ischemia is predominantly mediated by excessive oxidative stress and subsequent over-activation of poly(ADP)ribose polymerase (PARP), while female cell death appears to recruit caspase-dependent apoptosis (McCullough et al., 2005; Lang and McCullough, 2008; Liu et al., 2009; Yuan et al., 2009; Vagnerova et al., 2010; Liu et al., 2011). Relevant to the male-specific PARP-mediated cell death pathway, we have recently demonstrated that the calcium-permeable ion channel transient receptor potential channels, M2 (TRPM2) contributes to male-specific injury following cerebral ischemia in a PARP-dependent manner (Shimizu et al., 2013).
17-beta estradiol inhibits oxidative stress-induced accumulation of AIF into nucleolus and PARP1-dependent cell death via estrogen receptor alpha
2015, Toxicology LettersCitation Excerpt :It has been well acknowledged that PARP1-mediated cell death plays a vital role in the pathophysiology of circulatory diseases and others, including stroke, Parkinson's disease, heart attack, diabetes, and ischemia reperfusion injury (Wang et al., 2003; Pacher and Szabo, 2007). Intriguingly, the toxicity of PARP1 activation has been reported as manifesting a gender differential (Mabley et al., 2005; Vagnerova et al., 2010; Sharma et al., 2011). For example, female mice produce less tumor necrosis factor alpha (TNF-α) and macrophage inflammatory protein 1 alpha (MIP-1α) than do male mice in response to systemic inflammation induced by endotoxin and are more resistant to endotoxin-induced mortality (Mabley et al., 2005).
Androgens and stroke: Good, bad or indifferent?
2014, Experimental NeurologyCitation Excerpt :Multiple studies using the middle cerebral artery occlusion (MCAO) model of focal ischemic stroke have examined the effects of androgen removal and replacement in cerebral infarction. The majority of studies focused on the role of androgens in ischemic outcome demonstrate that castration of young males to remove endogenous androgens prior to MCAO reduced infarct size and androgen replacement increases infarct to levels similar to that observed in hormonally intact males (Cheng et al., 2007, 2009; Uchida et al., 2009; Vagnerova et al., 2010; Yang et al., 2002). These studies led to the conclusion that androgens enhance injury in male animals (Table 1).