WWW.JNEUROSCI.ORG
-
The Journal of Neuroscience Synaptic Systems Antibody Company
QUICK SEARCH:   [advanced]


     
-


HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit an eLetter
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (247)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dubal, D. B.
Right arrow Articles by Wise, P. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dubal, D. B.
Right arrow Articles by Wise, P. M.

 Previous Article  |  Next Article 

The Journal of Neuroscience, August 1, 1999, 19(15):6385-6393

Estradiol Modulates bcl-2 in Cerebral Ischemia: A Potential Role for Estrogen Receptors

Dena B. Dubal1, Paul J. Shughrue2, Melinda E. Wilson1, Istvan Merchenthaler2, and Phyllis M. Wise1

1 Department of Physiology, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, and 2 The Women's Health Research Institute, Wyeth-Ayerst Research, Radnor, Pennsylvania 19087

We have shown that physiological levels of estradiol exert profound protective effects on the cerebral cortex in ischemia induced by permanent middle cerebral artery occlusion. The major goal of this study was to begin to elucidate potential mechanisms of estradiol action in injury. Bcl-2 is a proto-oncogene that promotes cell survival in a variety of tissues including the brain. Because estradiol is known to promote cell survival via Bcl-2 in non-neural tissues, we tested the hypothesis that estradiol decreases cell death by influencing bcl-2 expression in ischemic brain injury. Furthermore, because estradiol may protect the brain through estrogen receptor-mediated mechanisms, we examined expression of both receptor subtypes ERalpha and ERbeta in the normal and injured brain. We analyzed gene expression by RT-PCR in microdissected regions of the cerebral cortex obtained from injured and sham female rats treated with estradiol or oil. We found that estradiol prevented the injury-induced downregulation of bcl-2 expression. This effect was specific to bcl-2, as expression of other members of the bcl-2 family (bax, bcl-xL, bcl-xS, and bad) was unaffected by estradiol treatment. We also found that estrogen receptors were differentially modulated in injury, with ERbeta expression paralleling bcl-2 expression. Finally, we provide the first evidence of functional ERbeta protein that is capable of binding ligand within the region of the cortex where estradiol-mediated neuroprotection was observed in cerebral ischemia. These findings indicate that estradiol modulates the expression of bcl-2 in ischemic injury. Furthermore, our data suggest that estrogen receptors may be involved in hormone-mediated neuroprotection.

Key words: estradiol; estrogen; neuroprotection; cerebral ischemia; stroke; menopause; bcl-2; bcl-2 family; estrogen receptors; ERbeta ; ERalpha ; receptor binding; RT-PCR; in situ hybridization

Copyright © 1999 Society for Neuroscience  0270-6474/99/19156385-09$05.00/0


This article has been cited by other articles:


Home page
 J. Neurosci.Home page
C. K. Thompson and E. A. Brenowitz
Caspase Inhibitor Infusion Protects an Avian Song Control Circuit from Seasonal-Like Neurodegeneration
J. Neurosci., July 9, 2008; 28(28): 7130 - 7136.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
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]

Home page
 Proc. Natl. Acad. Sci. USAHome page
C. K. Thompson, G. E. Bentley, and E. A. Brenowitz
Rapid seasonal-like regression of the adult avian song control system
PNAS, September 25, 2007; 104(39): 15520 - 15525.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. Rev.Home page
N. Heldring, A. Pike, S. Andersson, J. Matthews, G. Cheng, J. Hartman, M. Tujague, A. Strom, E. Treuter, M. Warner, et al.
Estrogen Receptors: How Do They Signal and What Are Their Targets
Physiol Rev, July 1, 2007; 87(3): 905 - 931.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
S. Suzuki, C. M. Brown, C. D. Dela Cruz, E. Yang, D. A. Bridwell, and P. M. Wise
Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective and antiinflammatory actions
PNAS, April 3, 2007; 104(14): 6013 - 6018.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
T. Jover-Mengual, R. S. Zukin, and A. M. Etgen
MAPK Signaling Is Critical to Estradiol Protection of CA1 Neurons in Global Ischemia
Endocrinology, March 1, 2007; 148(3): 1131 - 1143.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
M. Yao, T.-V. V. Nguyen, and C. J. Pike
Estrogen Regulates Bcl-w and Bim Expression: Role in Protection against {beta}-Amyloid Peptide-Induced Neuronal Death
J. Neurosci., February 7, 2007; 27(6): 1422 - 1433.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
J. L. Turgeon, M. C. Carr, P. M. Maki, M. E. Mendelsohn, and P. M. Wise
Complex Actions of Sex Steroids in Adipose Tissue, the Cardiovascular System, and Brain: Insights from Basic Science and Clinical Studies
Endocr. Rev., October 1, 2006; 27(6): 575 - 605.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
P. Mannella and R. D. Brinton
Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action.
J. Neurosci., September 13, 2006; 26(37): 9439 - 9447.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
D. B. Dubal, S. W. Rau, P. J. Shughrue, H. Zhu, J. Yu, A. B. Cashion, S. Suzuki, L. M. Gerhold, M. B. Bottner, S. B. Dubal, et al.
Differential Modulation of Estrogen Receptors (ERs) in Ischemic Brain Injury: A Role for ER{alpha} in Estradiol-Mediated Protection against Delayed Cell Death
Endocrinology, June 1, 2006; 147(6): 3076 - 3084.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
G. D. Hilton, L. L. Bambrick, S. M. Thompson, and M. M. McCarthy
Estradiol Modulation of Kainic Acid-Induced Calcium Elevation in Neonatal Hippocampal Neurons
Endocrinology, March 1, 2006; 147(3): 1246 - 1255.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
G. Juhasz-Vedres, E. Rozsa, G. Rakos, M. B. Dobszay, Z. Kis, J. Wolfling, J. Toldi, A. Parducz, and T. Farkas
Dehydroepiandrosterone Sulfate Is Neuroprotective when Administered Either before or after Injury in a Focal Cortical Cold Lesion Model
Endocrinology, February 1, 2006; 147(2): 683 - 686.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
K. P. Miller, R. K. Gupta, C. R. Greenfeld, J. K. Babus, and J. A. Flaws
Methoxychlor Directly Affects Ovarian Antral Follicle Growth and Atresia through Bcl-2- and Bax-Mediated Pathways
Toxicol. Sci., November 1, 2005; 88(1): 213 - 221.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
Y. Merot, F. Ferriere, E. Debroas, G. Flouriot, D. Duval, and C. Saligaut
Estrogen receptor alpha mediates neuronal differentiation and neuroprotection in PC12 cells: critical role of the A/B domain of the receptor
J. Mol. Endocrinol., October 1, 2005; 35(2): 257 - 267.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
N. R. Miller, T. Jover, H. W. Cohen, R. S. Zukin, and A. M. Etgen
Estrogen Can Act via Estrogen Receptor {alpha} and {beta} to Protect Hippocampal Neurons against Global Ischemia-Induced Cell Death
Endocrinology, July 1, 2005; 146(7): 3070 - 3079.
[Abstract] [Full Text] [PDF]

Home page
 Endocr. Rev.Home page
P. M. Wise, D. B. Dubal, S. W. Rau, C. M. Brown, and S. Suzuki
Are Estrogens Protective or Risk Factors in Brain Injury and Neurodegeneration? Reevaluation after the Women's Health Initiative
Endocr. Rev., May 1, 2005; 26(3): 308 - 312.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
C. B. Huppenbauer, L. Tanzer, L. L. DonCarlos, and K. J. Jones
Gonadal Steroid Attenuation of Developing Hamster Facial Motoneuron Loss by Axotomy: Equal Efficacy of Testosterone, Dihydrotestosterone, and 17-{beta} Estradiol
J. Neurosci., April 20, 2005; 25(16): 4004 - 4013.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
K. Kurata, M. Takebayashi, S. Morinobu, and S. Yamawaki
{beta}-Estradiol, Dehydroepiandrosterone, and Dehydroepiandrosterone Sulfate Protect against N-Methyl-D-aspartate-Induced Neurotoxicity in Rat Hippocampal Neurons by Different Mechanisms
J. Pharmacol. Exp. Ther., October 1, 2004; 311(1): 237 - 245.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
H.V.O. Carswell, I.M. Macrae, L. Gallagher, E. Harrop, and K.J. Horsburgh
Neuroprotection by a selective estrogen receptor {beta} agonist in a mouse model of global ischemia
Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1501 - H1504.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
O. Kretz, L. Fester, U. Wehrenberg, L. Zhou, S. Brauckmann, S. Zhao, J. Prange-Kiel, T. Naumann, H. Jarry, M. Frotscher, et al.
Hippocampal Synapses Depend on Hippocampal Estrogen Synthesis
J. Neurosci., June 30, 2004; 24(26): 5913 - 5921.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
S. W. Rau, D. B. Dubal, M. Bottner, L. M. Gerhold, and P. M. Wise
Estradiol Attenuates Programmed Cell Death after Stroke-Like Injury
J. Neurosci., December 10, 2003; 23(36): 11420 - 11426.
[Abstract] [Full Text] [PDF]

Home page
 Behav Cogn Neurosci RevHome page
P. M. Greenwood and R. Parasuraman
Normal Genetic Variation, Cognition, and Aging
Behav Cogn Neurosci Rev, December 1, 2003; 2(4): 278 - 306.
[Abstract] [PDF]

Home page
 Mol. Biol. CellHome page
S. Caporali, M. Imai, L. Altucci, M. Cancemi, S. Caristi, L. Cicatiello, F. Matarese, R. Penta, D. K. Sarkar, F. Bresciani, et al.
Distinct Signaling Pathways Mediate Stimulation of Cell Cycle Progression and Prevention of Apoptotic Cell Death by Estrogen in Rat Pituitary Tumor PR1 Cells
Mol. Biol. Cell, December 1, 2003; 14(12): 5051 - 5059.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
S. W. Rau, D. B. Dubal, M. Bottner, and P. M. Wise
Estradiol Differentially Regulates c-Fos after Focal Cerebral Ischemia
J. Neurosci., November 19, 2003; 23(33): 10487 - 10494.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
E. J. Molloy, A. J. O'Neill, J. J. Grantham, M. Sheridan-Pereira, J. M. Fitzpatrick, D. W. Webb, and R. W. G. Watson
Sex-specific alterations in neutrophil apoptosis: the role of estradiol and progesterone
Blood, October 1, 2003; 102(7): 2653 - 2659.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
J. K. Wong, H. H. Le, A. Zsarnovszky, and S. M. Belcher
Estrogens and ICI182,780 (Faslodex) Modulate Mitosis and Cell Death in Immature Cerebellar Neurons via Rapid Activation of p44/p42 Mitogen-Activated Protein Kinase
J. Neurosci., June 15, 2003; 23(12): 4984 - 4995.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
S. L. Zup, H. Carrier, E. M. Waters, A. Tabor, L. Bengston, G. J. Rosen, R. B. Simerly, and N. G. Forger
Overexpression of Bcl-2 Reduces Sex Differences in Neuron Number in the Brain and Spinal Cord
J. Neurosci., March 15, 2003; 23(6): 2357 - 2362.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. Nilsen and R. D. Brinton
Mechanism of estrogen-mediated neuroprotection: Regulation of mitochondrial calcium and Bcl-2 expression
PNAS, March 4, 2003; 100(5): 2842 - 2847.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
P. D. Hurn and L. M. Brass
Estrogen and Stroke: A Balanced Analysis
Stroke, February 1, 2003; 34(2): 338 - 341.
[Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
J. A. Mong, N. Devidze, D. E. Frail, L. T. O'Connor, M. Samuel, E. Choleris, S. Ogawa, and D. W. Pfaff
Estradiol differentially regulates lipocalin-type prostaglandin D synthase transcript levels in the rodent brain: Evidence from high-density oligonucleotide arrays and in situ hybridization
PNAS, January 7, 2003; 100(1): 318 - 323.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
K. M. Dhandapani and D. W. Brann
Protective Effects of Estrogen and Selective Estrogen Receptor Modulators in the Brain
Biol Reprod, November 1, 2002; 67(5): 1379 - 1385.
[Abstract] [Full Text] [PDF]

Home page
 Exp. Biol. Med.Home page
L. Zhao, Q. Chen, and R. D. Brinton
Neuroprotective and Neurotrophic Efficacy of Phytoestrogens in Cultured Hippocampal Neurons
Experimental Biology and Medicine, July 1, 2002; 227(7): 509 - 519.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
J. A. Mong, C. Krebs, and D. W. Pfaff
Perspective: Micoarrays and Differential Display PCR--Tools for Studying Transcript Levels of Genes in Neuroendocrine Systems
Endocrinology, June 1, 2002; 143(6): 2002 - 2006.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
T. Jover, H. Tanaka, A. Calderone, K. Oguro, M. V. L. Bennett, A. M. Etgen, and R. S. Zukin
Estrogen Protects against Global Ischemia-Induced Neuronal Death and Prevents Activation of Apoptotic Signaling Cascades in the Hippocampal CA1
J. Neurosci., March 15, 2002; 22(6): 2115 - 2124.
[Abstract] [Full Text] [PDF]

Home page
 Recent Prog Horm ResHome page
P. M. Wise, M. J. Smith, D. B. Dubal, M. E. Wilson, S. W. Rau, A. B. Cashion, M. Bottner, and K. L. Rosewell
Neuroendocrine Modulation and Repercussions of Female Reproductive Aging
Recent Prog. Horm. Res., January 1, 2002; 57(1): 235 - 256.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
N. J. Alkayed, S. Goto, N. Sugo, H.-D. Joh, J. Klaus, B. J. Crain, O. Bernard, R. J. Traystman, and P. D. Hurn
Estrogen and Bcl-2: Gene Induction and Effect of Transgene in Experimental Stroke
J. Neurosci., October 1, 2001; 21(19): 7543 - 7550.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
A. C. DeVries, H.-D. Joh, O. Bernard, K. Hattori, P. D. Hurn, R. J. Traystman, and N. J. Alkayed
Social stress exacerbates stroke outcome by suppressing Bcl-2 expression
PNAS, September 5, 2001; (2001) 201215298.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
C. Harms, M. Lautenschlager, A. Bergk, J. Katchanov, D. Freyer, K. Kapinya, U. Herwig, D. Megow, U. Dirnagl, J. R. Weber, et al.
Differential Mechanisms of Neuroprotection by 17 {beta}-Estradiol in Apoptotic versus Necrotic Neurodegeneration
J. Neurosci., April 15, 2001; 21(8): 2600 - 2609.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
P. M. Wise, D. B. Dubal, M. E. Wilson, S. W. Rau, and M. Bottner
Minireview: Neuroprotective Effects of Estrogen--New Insights into Mechanisms of Action
Endocrinology, March 1, 2001; 142(3): 969 - 973.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
L. D. McCullough, N. J. Alkayed, R. J. Traystman, M. J. Williams, and P. D. Hurn
Postischemic Estrogen Reduces Hypoperfusion and Secondary Ischemia After Experimental Stroke
Stroke, March 1, 2001; 32(3): 796 - 802.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
L. Wang, S. Andersson, M. Warner, and J.-A. Gustafsson
Morphological abnormalities in the brains of estrogen receptor beta knockout mice
PNAS, February 15, 2001; (2001) 41617498.
[Abstract] [Full Text]

Home page
 Biol. Reprod.Home page
E. D. Lephart, S. B. Call, R. W. Rhees, N. A. Jacobson, K. Scott Weber, J. Bledsoe, and C. Teuscher
Neuroendocrine Regulation of Sexually Dimorphic Brain Structure and Associated Sexual Behavior in Male Rats Is Genetically Controlled
Biol Reprod, February 1, 2001; 64(2): 571 - 578.
[Abstract] [Full Text]

Home page
 Proc. Natl. Acad. Sci. USAHome page
D. B. Dubal, H. Zhu, J. Yu, S. W. Rau, P. J. Shughrue, I. Merchenthaler, M. S. Kindy, and P. M. Wise
Estrogen receptor alpha , not beta , is a critical link in estradiol-mediated protection against brain injury
PNAS, February 1, 2001; (2001) 41483198.
[Abstract] [Full Text]

Home page
 EndocrinologyHome page
D. B. Dubal and P. M. Wise
Neuroprotective Effects of Estradiol in Middle-Aged Female Rats
Endocrinology, January 1, 2001; 142(1): 43 - 48.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
M. I. Rossberg, S. J. Murphy, R. J. Traystman, P. D. Hurn, and H. A. Kontos
LY353381.HCl, a Selective Estrogen Receptor Modulator, and Experimental Stroke Editorial Comment
Stroke, December 1, 2000; 31(12): 3041 - 3046.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
T. K. Toung, P. D. Hurn, R. J. Traystman, F. E. Sieber, and F. M. Faraci
Estrogen Decreases Infarct Size After Temporary Focal Ischemia in a Genetic Model of Type 1 Diabetes Mellitus Editorial Comment
Stroke, November 1, 2000; 31(11): 2701 - 2706.
[Abstract] [Full Text] [PDF]

Home page
 Biol. Reprod.Home page
P. M. Wise and D. B. Dubal
Estradiol Protects Against Ischemic Brain Injury in Middle-Aged Rats
Biol Reprod, October 1, 2000; 63(4): 982 - 985.
[Abstract] [Full Text]

Home page
 StrokeHome page
W.-R. Schabitz, C. Sommer, W. Zoder, M. Kiessling, M. Schwaninger, S. Schwab, and S. P. Finklestein
Intravenous Brain-Derived Neurotrophic Factor Reduces Infarct Size and Counterregulates Bax and Bcl-2 Expression After Temporary Focal Cerebral Ischemia Editorial Comment
Stroke, September 1, 2000; 31(9): 2212 - 2217.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
H. SAWADA, M. IBI, T. KIHARA, M. URUSHITANI, K. HONDA, M. NAKANISHI, A. AKAIKE, and S. SHIMOHAMA
Mechanisms of antiapoptotic effects of estrogens in nigral dopaminergic neurons
FASEB J, June 1, 2000; 14(9): 1202 - 1214.
[Abstract] [Full Text]

Home page
 StrokeHome page
K. Sampei, S. Goto, N. J. Alkayed, B. J. Crain, K. S. Korach, R. J. Traystman, G. E. Demas, R. J. Nelson, P. D. Hurn, and S. Piper Duckles
Stroke in Estrogen Receptor-{alpha}-Deficient Mice • Editorial Comment
Stroke, March 1, 2000; 31(3): 738 - 744.
[Abstract] [Full Text] [PDF]

Home page
 JAMAHome page
R. A. Mulnard, C. W. Cotman, C. Kawas, C. H. van Dyck, M. Sano, R. Doody, E. Koss, E. Pfeiffer, S. Jin, A. Gamst, et al.
Estrogen Replacement Therapy for Treatment of Mild to Moderate Alzheimer Disease: A Randomized Controlled Trial
JAMA, February 23, 2000; 283(8): 1007 - 1015.
[Abstract] [Full Text] [PDF]

Home page
 StrokeHome page
N. J. Alkayed, S. J. Murphy, R. J. Traystman, P. D. Hurn, and V. M. Miller
Neuroprotective Effects of Female Gonadal Steroids in Reproductively Senescent Female Rats Editorial Comment
Stroke, January 1, 2000; 31(1): 161 - 168.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
D. B. Dubal, H. Zhu, J. Yu, S. W. Rau, P. J. Shughrue, I. Merchenthaler, M. S. Kindy, and P. M. Wise
Estrogen receptor alpha , not beta , is a critical link in estradiol-mediated protection against brain injury
PNAS, February 13, 2001; 98(4): 1952 - 1957.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
A. C. DeVries, H.-D. Joh, O. Bernard, K. Hattori, P. D. Hurn, R. J. Traystman, and N. J. Alkayed
Social stress exacerbates stroke outcome by suppressing Bcl-2 expression
PNAS, September 25, 2001; 98(20): 11824 - 11828.
[Abstract] [Full Text] [PDF]


-

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help
-
Copyright 2008 by Society for Neuroscience ONLINE ISSN: 1529-2401
-