Elsevier

Neuroscience

Volume 166, Issue 2, 17 March 2010, Pages 476-481
Neuroscience

Clinical Neuroscience
Research Paper
Poly (ADP-ribose) polymerase-1 initiated neuronal cell death pathway—do androgens matter?

https://doi.org/10.1016/j.neuroscience.2009.12.041Get rights and content

Abstract

Activation of poly (ADP-ribose) polymerases (PARP) contributes to ischemic damage by causing neuronal nicotinamide adenine dinucleotide (NAD+) depletion, release of apoptosis-inducing factor and consequent caspase-independent cell death. PARP-mediated cell death is sexually dimorphic, participating in ischemic damage in the male brain, but not the female brain. We tested the hypothesis that androgen signaling is required for this male-specific neuronal cell death pathway. We observed smaller damage following focal cerebral ischemia (MCAO) in male PARP-1 knockout mice compared to wild type (WT) as well as decreased damage in male mice treated with the PARP inhibitor PJ34. Protection from ischemic damage provided by PJ-34 in WT mice is lost after removal of testicular androgens (CAST) and rescued by androgen replacement. CAST PARP-1 KO mice exhibit increased damage compared to intact male KO mice, an effect reversed by androgen replacement in an androgen receptor-dependent manner. Lastly, we observed that ischemia causes an increase in PARP-1 expression that is diminished in the absence of testicular androgens. Our data indicate that PARP-mediated neuronal cell death in the male brain requires intact androgen-androgen receptor signaling.

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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