HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 37, 38563-38570, September 10, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/37/38563    most recent M405461200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Du, L. Articles by Clark, R. S. B. Search for Related Content PubMed PubMed Citation Articles by Du, L. Articles by Clark, R. S. B. Social Bookmarking                      What's this?

Innate Gender-based Proclivity in Response to Cytotoxicity and Programmed Cell Death Pathway^*

Lina Du, Hülya Bayir, Yichen Lai, Xiaopeng Zhang, Patrick M. Kochanek¶, Simon C. Watkins||, Steven H. Graham**, and Robert S. B. Clark¶

From the Departments of Critical Care Medicine, Pediatrics, ^||Cell Biology and Physiology, and ^**Neurology, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260 and ^¶Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania15213

Many central nervous system (CNS) diseases display sexual dimorphism. Exposure to circulating sex steroids is felt to be a chief contributor to this phenomenon; however, CNS diseases of childhood and the elderly also demonstrate gender predominance and/or a sexually dimorphic response to therapies. Here we show that XY and XX neurons cultured separately are differentially susceptible to various cytotoxic agents and treatments. XY neurons were more sensitive to nitrosative stress and excitotoxicity versus XX neurons. In contrast, XX neurons were more sensitive to etoposide- and staurosporine-induced apoptosis versus XY neurons. The responses to specific therapies were also sexually dimorphic. Moreover, gender proclivity in programmed cell death pathway was observed. After cytotoxic challenge, programmed cell death proceeded predominately via an apoptosis-inducing factor-dependent pathway in XY neurons versus a cytochrome c-dependent pathway in XX neurons. This gender-dependent susceptibility is related to the incapacity of XY neurons to maintain intracellular levels of reduced glutathione. In vivo studies further demonstrated an incapacity for male, but not female, 17-day-old rats to maintain reduced glutathione levels within cerebral cortex acutely after an 8-min asphyxial cardiac arrest. This gender difference in sensitivity to cytotoxic agents may be generalized to nonneuronal cells, as splenocytes from male and female 16–18-day-old rats show similar gender-dependent responses to nitrosative stress and staurosporine-induced apoptosis. These data support gender stratification in the evaluation of mechanisms and treatment of CNS disease, particularly those where glutathione may play a role in detoxification, such as Parkinson's disease, traumatic brain injury, and conditions producing cerebral ischemia, and may apply to non-CNS diseases as well.

Received for publication, May 17, 2004 , and in revised form, June 30, 2004.

^* This work was supported by NINDS, National Institutes of Health Grants RO1 NS38620 and P50 NS30318, NICHD, National Institutes of Health Grant T32 HD40686, and by the Children's Hospital of Pittsburgh. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Safar Center for Resuscitation Research, 3434 Fifth Ave., Pittsburgh, PA 15260. Tel.: 412-383-1900; Fax: 412-624-0943; E-mail: clarkrs{at}ccm.upmc.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				K. Vagnerova, I. P. Koerner, and P. D. Hurn Gender and the Injured Brain Anesth. Analg., July 1, 2008; 107(1): 201 - 214. [Abstract] [Full Text] [PDF]

				S. Renolleau, S. Fau, and C. Charriaut-Marlangue Gender-Related Differences in Apoptotic Pathways After Neonatal Cerebral Ischemia Neuroscientist, February 1, 2008; 14(1): 46 - 52. [Abstract] [PDF]

				Z. Cao, L. Liu, W. Packwood, M. Merkel, P. D. Hurn, and D. M. Van Winkle Sex differences in the mechanism of Met5-enkephalin-induced cardioprotection: role of PI3K/Akt Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H302 - H310. [Abstract] [Full Text] [PDF]

				B. Murphy, M. Dunleavy, S. Shinoda, C. Schindler, R. Meller, C. Bellver-Estelles, S. Hatazaki, P. Dicker, A. Yamamoto, I. Koegel, et al. Bcl-w Protects Hippocampus during Experimental Status Epilepticus Am. J. Pathol., October 1, 2007; 171(4): 1258 - 1268. [Abstract] [Full Text] [PDF]

				B. M. Deasy, A. Lu, J. C. Tebbets, J. M. Feduska, R. C. Schugar, J. B. Pollett, B. Sun, K. L. Urish, B. M. Gharaibeh, B. Cao, et al. A role for cell sex in stem cell-mediated skeletal muscle regeneration: female cells have higher muscle regeneration efficiency J. Cell Biol., April 9, 2007; 177(1): 73 - 86. [Abstract] [Full Text] [PDF]

				L. R. Ment, B. S. Peterson, J. A. Meltzer, B. Vohr, W. Allan, K. H. Katz, C. Lacadie, K. C. Schneider, C. C. Duncan, R. W. Makuch, et al. A Functional Magnetic Resonance Imaging Study of the Long-term Influences of Early Indomethacin Exposure on Language Processing in the Brains of Prematurely Born Children Pediatrics, September 1, 2006; 118(3): 961 - 970. [Abstract] [Full Text] [PDF]

				C. D. Bushnell, P. Hurn, C. Colton, V. M. Miller, G. del Zoppo, M. S.V. Elkind, B. Stern, D. Herrington, G. Ford-Lynch, P. Gorelick, et al. Advancing the Study of Stroke in Women: Summary and Recommendations for Future Research From an NINDS-Sponsored Multidisciplinary Working Group Stroke, September 1, 2006; 37(9): 2387 - 2399. [Abstract] [Full Text] [PDF]

				J. G. Mabley, E. M. Horvath, K. G. K. Murthy, Z. Zsengeller, A. Vaslin, R. Benko, M. Kollai, and C. Szabo Gender Differences in the Endotoxin-Induced Inflammatory and Vascular Responses: Potential Role of Poly(ADP-ribose) Polymerase Activation J. Pharmacol. Exp. Ther., November 1, 2005; 315(2): 812 - 820. [Abstract] [Full Text] [PDF]

				L. L. Tosi, B. D. Boyan, and A. L. Boskey Does Sex Matter in Musculoskeletal Health? The Influence of Sex and Gender on Musculoskeletal Health J. Bone Joint Surg. Am., July 1, 2005; 87(7): 1631 - 1647. [Full Text] [PDF]

				C.-H. Chen, T. J.K. Toung, P. D. Hurn, R. C. Koehler, and A. Bhardwaj Ischemic Neuroprotection With Selective {kappa}-Opioid Receptor Agonist Is Gender Specific Stroke, July 1, 2005; 36(7): 1557 - 1561. [Abstract] [Full Text] [PDF]

				R. J. Davenport Mars and Venus Sci. Aging Knowl. Environ., June 8, 2005; 2005(23): ns1 - ns1. [Abstract] [Full Text] [PDF]

				J. M. Van Raamsdonk, J. Pearson, D. A. Rogers, N. Bissada, A. W. Vogl, M. R. Hayden, and B. R. Leavitt Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease Hum. Mol. Genet., May 15, 2005; 14(10): 1379 - 1392. [Abstract] [Full Text] [PDF]

				D. Eugene, A. Djemli, and G. Van Vliet Sexual Dimorphism of Thyroid Function in Newborns with Congenital Hypothyroidism J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2696 - 2700. [Abstract] [Full Text] [PDF]

				P. D. Hurn, S. J. Vannucci, and H. Hagberg Adult or Perinatal Brain Injury: Does Sex Matter? Stroke, February 1, 2005; 36(2): 193 - 195. [Full Text] [PDF]