Innate gender-based proclivity in response to cytotoxicity and programmed cell death pathway

被引:277
作者
Du, LN
Bayir, H
Lai, YC
Zhang, XP
Kochanek, PM
Watkins, SC
Graham, SH
Clark, RSB
机构
[1] Univ Pittsburgh, Sch Med, Safar Ctr Resuscitat Res, Dept Crit Care Med, Pittsburgh, PA 15260 USA
[2] Univ Pittsburgh, Sch Med, Safar Ctr Resuscitat Res, Dept Pediat, Pittsburgh, PA 15260 USA
[3] Univ Pittsburgh, Sch Med, Safar Ctr Resuscitat Res, Dept Cell Biol & Physiol, Pittsburgh, PA 15260 USA
[4] Univ Pittsburgh, Sch Med, Safar Ctr Resuscitat Res, Dept Neurol, Pittsburgh, PA 15260 USA
[5] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA
关键词
D O I
10.1074/jbc.M405461200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 non-neuronal 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.
引用
收藏
页码:38563 / 38570
页数:8
相关论文
共 42 条
[11]   Intra-mitochondrial poly(ADP-ribosylation) contributes to NAD+ depletion and cell death induced by oxidative stress [J].
Du, LN ;
Zhang, XP ;
Han, YY ;
Burke, NA ;
Kochanek, PM ;
Watkins, SC ;
Graham, SH ;
Carcillo, JA ;
Szabó, C ;
Clark, RSB .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (20) :18426-18433
[12]  
Fink Ericka L, 2004, Pediatr Crit Care Med, V5, P139, DOI 10.1097/01.PCC.0000112376.29903.8F
[13]   QUANTITATIVE-ANALYSIS OF FACTORS INFLUENCING NEURONAL NECROSIS INDUCED BY MK-801 IN THE RAT POSTERIOR CINGULATE RETROSPLENIAL CORTEX [J].
FIX, AS ;
WOZNIAK, DF ;
TRUEX, LL ;
MCEWEN, M ;
MILLER, JP ;
OLNEY, JW .
BRAIN RESEARCH, 1995, 696 (1-2) :194-204
[14]   Gender differences in the relation between comorbidity and mortality of patients with Alzheimer's disease [J].
Gambassi, G ;
Lapane, KL ;
Landi, F ;
Sgadari, A ;
Mor, V ;
Bernabei, R .
NEUROLOGY, 1999, 53 (03) :508-516
[15]   Gender differences in disability and health-related quality of life in patients with Parkinson's disease treated with stereotactic surgery [J].
Hariz, GM ;
Lindberg, M ;
Hariz, MI ;
Bergenheim, AT .
ACTA NEUROLOGICA SCANDINAVICA, 2003, 108 (01) :28-37
[16]   Differential mechanisms of neuroprotection by 17 β-estradiol in apoptotic versus necrotic neurodengeneration [J].
Harms, C ;
Lautenschlager, M ;
Bergk, A ;
Katchanov, J ;
Freyer, D ;
Kapinya, K ;
Herwig, U ;
Megow, D ;
Dirnagl, U ;
Weber, JR ;
Hörtnagl, H .
JOURNAL OF NEUROSCIENCE, 2001, 21 (08) :2600-2609
[17]   Estrogen as a neuroprotectant in stroke [J].
Hurn, PD ;
Macrae, IM .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2000, 20 (04) :631-652
[18]  
Hurvitz E A, 1999, Pediatr Rehabil, V3, P43
[19]   Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? [J].
Ikonomidou, C ;
Turski, L .
LANCET NEUROLOGY, 2002, 1 (06) :383-386
[20]   Outcome of acute lymphoblastic leukemia in children with AL90 regimen: Impact of response to treatment and sex difference on prognostic factors [J].
Ishii, E ;
Eguchi, H ;
Matsuzaki, A ;
Koga, H ;
Yanai, F ;
Kuroda, H ;
Kawakami, K ;
Ayukawa, H ;
Akiyoshi, K ;
Kamizono, J ;
Tamai, Y ;
Kinukawa, N ;
Okamura, J .
MEDICAL AND PEDIATRIC ONCOLOGY, 2001, 37 (01) :10-19