ABSTRACT
Biologic sex and sex steroids are important factors in clinical and experimental stroke
and traumatic brain injury (TBI). Laboratory data strongly show that progesterone
treatment after TBI reduces edema, improves outcomes, and restores blood-brain barrier
function. Clinical studies to date agree with these data, and there are ongoing human
trials for progesterone treatment after TBI. Estrogen has accumulated an impressive
reputation as a neuroprotectant when evaluated at physiologically relevant doses in
laboratory studies of stroke, but translation to patients remains to be shown. The
role of androgens in male stroke or TBI is understudied and important to pursue given
the epidemiology of stroke and trauma in men. To date, male sex steroids remain largely
evaluated at the bench rather than the bedside. This review evaluates key evidence
and highlights the importance of the platform on which brain injury occurs (i.e.,
genetic sex and hormonal modulators).
KEYWORDS
Stroke - brain ischemia - estradiol - neurosteroids - progesterone - allopregnanolone
- androgens
REFERENCES
- 1
Giroud M, Milan C, Beuriat P et al..
Incidence and survival rates during a two-year period of intracerebral and subarachnoid
haemorrhages, cortical infarcts, lacunes and transient ischaemic attacks. the stroke
registry of dijon: 1985–1989.
Int J Epidemiol.
1991;
20
892-899
- 2
Sacco R L, Boden-Albala B, Gan R et al..
Stroke incidence among white, black, and hispanic residents of an urban community:
the Northern Manhattan Stroke Study.
Am J Epidemiol.
1998;
147
259-268
- 3
Yamori Y, Horie R, Handa H, Sato M, Fukase M.
Pathogenetic similarity of strokes in stroke-prone spontaneously hypertensive rats
and humans.
Stroke.
1976;
7
46-53
- 4
Hall E D, Pazara K E, Braughler J M.
Effects of tirilazad mesylate on postischemic brain lipid peroxidation and recovery
of extracellular calcium in gerbils.
Stroke.
1991;
22
361-366
- 5
Alkayed N J, Harukuni I, Kimes A S, London E D, Traystman R J, Hurn P D.
Gender-linked brain injury in experimental stroke.
Stroke.
1998;
29
159-166
- 6
Carswell H V, Anderson N H, Clark J S et al..
Genetic and gender influences on sensitivity to focal cerebral ischemia in the stroke-prone
spontaneously hypertensive rat.
Hypertension.
1999;
33
681-685
- 7
Alkayed N J, Murphy S J, Traystman R J, Hurn P D, Miller V M.
Neuroprotective effects of female gonadal steroids in reproductively senescent female
rats.
Stroke.
2000;
31
161-168
- 8
Li X, Blizzard K K, Zeng Z, DeVries A C, Hurn P D, McCullough L D.
Chronic behavioral testing after focal ischemia in the mouse: functional recovery
and the effects of gender.
Exp Neurol.
2004;
187
94-104
- 9
Bramlett H M, Dietrich W D.
Neuropathological protection after traumatic brain injury in intact female rats versus
males or ovariectomized females.
J Neurotrauma.
2001;
18
891-900
- 10
Toung T K, Hurn P D, Traystman R J, Sieber F E.
Estrogen decreases infarct size after temporary focal ischemia in a genetic model
of type 1 diabetes mellitus.
Stroke.
2000;
31
2701-2706
- 11
Vannucci S J, Willing L B, Goto S et al..
Experimental stroke in the female diabetic, db/db, mouse.
J Cereb Blood Flow Metab.
2001;
21
52-60
- 12
Lieb K, Andrae J, Reisert I, Pilgrim C.
Neurotoxicity of dopamine and protective effects of the NMDA receptor antagonist AP-5
differ between male and female dopaminergic neurons.
Exp Neurol.
1995;
134
222-229
- 13
Zhang L, Li P P, Feng X, Barker J L, Smith S V, Rubinow D R.
Sex-related differences in neuronal cell survival and signaling in rats.
Neurosci Lett.
2003;
337
65-68
- 14
Du L, Bayir H, Lai Y et al..
Innate gender-based proclivity in response to cytotoxicity and programmed cell death
pathway.
J Biol Chem.
2004;
279
38563-38570
- 15
Liu M, Hurn P D, Roselli C E, Alkayed N J.
Role of P450 aromatase in sex-specific astrocytic cell death.
J Cereb Blood Flow Metab.
2007;
27
135-141
- 16
Li H, Pin S, Zeng Z, Wang M M, Andreasson K A, McCullough L D.
Sex differences in cell death.
Ann Neurol.
2005;
58
317-321
- 17
Baulieu E E, Robel P, Schumacher M.
Neurosteroids: beginning of the story.
Int Rev Neurobiol.
2001;
46
1-32
- 18
Schumacher M, Baulieu E E.
Neurosteroids: synthesis and functions in the central and peripheral nervous systems.
Ciba Found Symp.
1995;
191
90-106
- 19
Jung-Testas I, Schumacher M, Robel P, Baulieu E E.
The neurosteroid progesterone increases the expression of myelin proteins (MBP and
CNPase) in rat oligodendrocytes in primary culture.
Cell Mol Neurobiol.
1996;
16
439-443
- 20
Schumacher M, Robel P, Baulieu E E.
Development and regeneration of the nervous system: a role for neurosteroids.
Dev Neurosci.
1996;
18
6-21
- 21
Baulieu E E.
Neurosteroids: of the nervous system, by the nervous system, for the nervous system.
Recent Prog Horm Res.
1997;
52
1-32
- 22
De Nicola A F, Gonzalez S L, Labombarda F et al..
Progesterone treatment of spinal cord injury: effects on receptors, neurotrophins,
and myelination.
J Mol Neurosci.
2006;
28
3-15
- 23
Labombarda F, Gonzalez S, Gonzalez Deniselle M C et al..
Progesterone increases the expression of myelin basic protein and the number of cells
showing NG2 immunostaining in the lesioned spinal cord.
J Neurotrauma.
2006;
23
181-192
- 24
Garcia-Estrada J, Del Rio J A, Luquin S, Soriano E, Garcia-Segura L M.
Gonadal hormones down-regulate reactive gliosis and astrocyte proliferation after
a penetrating brain injury.
Brain Res.
1993;
628
271-278
- 25
Garcia-Estrada J, Luquin S, Fernandez A M, Garcia-Segura L M.
Dehydroepiandrosterone, pregnenolone and sex steroids down-regulate reactive astroglia
in the male rat brain after a penetrating brain injury.
Int J Dev Neurosci.
1999;
17
145-151
- 26
O'Connor C A, Cernak I, Johnson F, Vink R.
Effects of progesterone on neurologic and morphologic outcome following diffuse traumatic
brain injury in rats.
Exp Neurol.
2007;
205
145-153
- 27
Stein D G.
Progesterone exerts neuroprotective effects after brain injury.
Brain Res Rev.
2008;
57
386-397
- 28
Schumacher M, Guennoun R, Stein D G, De Nicola A F.
Progesterone: therapeutic opportunities for neuroprotection and myelin repair.
Pharmacol Ther.
2007;
116
77-106
- 29
Jiang N, Chopp M, Stein D, Feit H.
Progesterone is neuroprotective after transient middle cerebral artery occlusion in
male rats.
Brain Res.
1996;
735
101-107
- 30
Roof R L, Duvdevani R, Heyburn J W, Stein D G.
Progesterone rapidly decreases brain edema: treatment delayed up to 24 hours is still
effective.
Exp Neurol.
1996;
138
246-251
- 31
Rossouw J E, Anderson G L, Prentice R L et al..
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal
results from the Women's Health Initiative randomized controlled trial.
JAMA.
2002;
288
321-333
- 32
Simon J A, Hsia J, Cauley J A et al..
Postmenopausal hormone therapy and risk of stroke: The Heart and Estrogen-Progestin
Replacement Study (HERS).
Circulation.
2001;
103
638-642
- 33
Hulley S, Grady D, Bush T et al..
Randomized trial of estrogen plus progestin for secondary prevention of coronary heart
disease in postmenopausal women. Heart and Estrogen/Progestin Replacement Study (HERS)
research group.
JAMA.
1998;
280
605-613
- 34
Nilsen J, Brinton R D.
Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear
mitogen-activated protein kinase signaling.
Proc Natl Acad Sci U S A.
2003;
100
10506-10511
- 35
Nilsen J, Morales A, Brinton R D.
Medroxyprogesterone acetate exacerbates glutamate excitotoxicity.
Gynecol Endocrinol.
2006;
22
355-361
- 36
Nilsen J, Brinton R D.
Impact of progestins on estradiol potentiation of the glutamate calcium response.
Neuroreport.
2002;
13
825-830
- 37
Littleton-Kearney M T, Klaus J A, Hurn P D.
Effects of combined oral conjugated estrogens and medroxyprogesterone acetate on brain
infarction size after experimental stroke in rat.
J Cereb Blood Flow Metab.
2005;
25
421-426
- 38
Toung T J, Chen T Y, Littleton-Kearney M T, Hurn P D, Murphy S J.
Effects of combined estrogen and progesterone on brain infarction in reproductively
senescent female rats.
J Cereb Blood Flow Metab.
2004;
24
1160-1166
- 39
Corpechot C, Robel P, Axelson M, Sjovall J, Baulieu E E.
Characterization and measurement of dehydroepiandrosterone sulfate in rat brain.
Proc Natl Acad Sci U S A.
1981;
78
4704-4707
- 40
Corpechot C, Synguelakis M, Talha S et al..
Pregnenolone and its sulfate ester in the rat brain.
Brain Res.
1983;
270
119-125
- 41
Mellon S H, Vaudry H.
Biosynthesis of neurosteroids and regulation of their synthesis.
Int Rev Neurobiol.
2001;
46
33-78
- 42
Baulieu E E, Robel P.
Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) as neuroactive
neurosteroids.
Proc Natl Acad Sci U S A.
1998;
95
4089-4091
- 43
Stoffel-Wagner B.
Neurosteroid biosynthesis in the human brain and its clinical implications.
Ann N Y Acad Sci.
2003;
1007
64-78
- 44
Watzka M, Bidlingmaier F, Schramm J, Klingmuller D, Stoffel-Wagner B.
Sex- and age-specific differences in human brain CYP11A1 mRNA expression.
J Neuroendocrinol.
1999;
11
901-905
- 45
Lavaque E, Mayen A, Azcoitia I, Tena-Sempere M, Garcia-Segura L M.
Sex differences, developmental changes, response to injury and cAMP regulation of
the mRNA levels of steroidogenic acute regulatory protein, cytochrome p450scc, and
aromatase in the olivocerebellar system.
J Neurobiol.
2006;
66
308-318
- 46
Kimonides V G, Khatibi N H, Svendsen C N, Sofroniew M V, Herbert J.
Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) protect hippocampal neurons
against excitatory amino acid-induced neurotoxicity.
Proc Natl Acad Sci U S A.
1998;
95
1852-1857
- 47
Mao X, Barger S W.
Neuroprotection by dehydroepiandrosterone-sulfate: role of an NFkappaB-like factor.
Neuroreport.
1998;
9
759-763
- 48
Cardounel A, Regelson W, Kalimi M.
Dehydroepiandrosterone protects hippocampal neurons against neurotoxin-induced cell
death: mechanism of action.
Proc Soc Exp Biol Med.
1999;
222
145-149
- 49
Kaasik A, Kalda A, Jaako K, Zharkovsky A.
Dehydroepiandrosterone sulphate prevents oxygen-glucose deprivation-induced injury
in cerebellar granule cell culture.
Neuroscience.
2001;
102
427-432
- 50
Li Z, Zhou R, Cui S et al..
Dehydroepiandrosterone sulfate prevents ischemia-induced impairment of long-term potentiation
in rat hippocampal CA1 by up-regulating tyrosine phosphorylation of NMDA receptor.
Neuropharmacology.
2006;
51
958-966
- 51
Weaver Jr C E, Marek P, Park-Chung M, Tam S W, Farb D H.
Neuroprotective activity of a new class of steroidal inhibitors of the N-methyl-D-aspartate
receptor.
Proc Natl Acad Sci U S A.
1997;
94
10450-10454
- 52
Gursoy E, Cardounel A, Kalimi M.
Pregnenolone protects mouse hippocampal (HT-22) cells against glutamate and amyloid
beta protein toxicity.
Neurochem Res.
2001;
26
15-21
- 53
Gibson C L, Murphy S P.
Progesterone enhances functional recovery after middle cerebral artery occlusion in
male mice.
J Cereb Blood Flow Metab.
2004;
24
805-813
- 54
Gibson C L, Constantin D, Prior M J, Bath P M, Murphy S P.
Progesterone suppresses the inflammatory response and nitric oxide synthase-2 expression
following cerebral ischemia.
Exp Neurol.
2005;
193
522-530
- 55
Alkayed N J, Murphy S J, Traystman R J, Hurn P D, Miller V M.
Neuroprotective effects of female gonadal steroids in reproductively senescent female
rats.
Stroke.
2000;
31
161-168
- 56
Murphy S J, Littleton-Kearney M T, Hurn P D.
Progesterone administration during reperfusion, but not preischemia alone, reduces
injury in ovariectomized rats.
J Cereb Blood Flow Metab.
2002;
22
1181-1188
- 57
Sayeed I, Guo Q, Hoffman S W, Stein D G.
Allopregnanolone, a progesterone metabolite, is more effective than progesterone in
reducing cortical infarct volume after transient middle cerebral artery occlusion.
Ann Emerg Med.
2006;
47
381-389
- 58
Chen Z, Yuhanna I S, Galcheva-Gargova Z, Karas R H, Mendelsohn M E, Shaul P W.
Estrogen receptor alpha mediates the nongenomic activation of endothelial nitric oxide
synthase by estrogen.
J Clin Invest.
1999;
103
401-406
- 59
Kumon Y, Kim S C, Tompkins P, Stevens A, Sakaki S, Loftus C M.
Neuroprotective effect of postischemic administration of progesterone in spontaneously
hypertensive rats with focal cerebral ischemia.
J Neurosurg.
2000;
92
848-852
- 60
Morali G, Letechipia-Vallejo G, Lopez-Loeza E, Montes P, Hernandez-Morales L, Cervantes M.
Post-ischemic administration of progesterone in rats exerts neuroprotective effects
on the hippocampus.
Neurosci Lett.
2005;
382
286-290
- 61
Cervantes M, Gonzalez-Vidal M D, Ruelas R, Escobar A, Morali G.
Neuroprotective effects of progesterone on damage elicited by acute global cerebral
ischemia in neurons of the caudate nucleus.
Arch Med Res.
2002;
33
6-14
- 62
Murphy S J, Traystman R J, Hurn P D, Duckles S P.
Progesterone exacerbates striatal stroke injury in progesterone-deficient female animals.
Stroke.
2000;
31
1173-1178
- 63
Roof R L, Duvdevani R, Stein D G.
Gender influences outcome of brain injury: progesterone plays a protective role.
Brain Res.
1993;
607
333-336
- 64
Roof R L, Duvdevani R, Braswell L, Stein D G.
Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused
by cortical contusion injury in male rats.
Exp Neurol.
1994;
129
64-69
- 65
Robertson C L, Puskar A, Hoffman G E, Murphy A Z, Saraswati M, Fiskum G.
Physiologic progesterone reduces mitochondrial dysfunction and hippocampal cell loss
after traumatic brain injury in female rats.
Exp Neurol.
2006;
197
235-243
- 66
Wright D W, Bauer M E, Hoffman S W, Stein D G.
Serum progesterone levels correlate with decreased cerebral edema after traumatic
brain injury in male rats.
J Neurotrauma.
2001;
18
901-909
- 67
Goss C W, Hoffman S W, Stein D G.
Behavioral effects and anatomic correlates after brain injury: a progesterone dose-response
study.
Pharmacol Biochem Behav.
2003;
76
231-242
- 68
Shear D A, Galani R, Hoffman S W, Stein D G.
Progesterone protects against necrotic damage and behavioral abnormalities caused
by traumatic brain injury.
Exp Neurol.
2002;
178
59-67
- 69
Pan D S, Liu W G, Yang X F, Cao F.
Inhibitory effect of progesterone on inflammatory factors after experimental traumatic
brain injury.
Biomed Environ Sci.
2007;
20
432-438
- 70
Chen G, Shi J, Jin W et al..
Progesterone administration modulates TLRs/NF-kappaB signaling pathway in rat brain
after cortical contusion.
Ann Clin Lab Sci.
2008;
38
65-74
- 71
Wright D W, Kellermann A L, Hertzberg V S et al..
ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury.
Ann Emerg Med.
2007;
49
391-402
- 72
Xiao G, Wei J, Yan W, Wang W, Lu Z.
Improved outcomes from the administration of progesterone for patients with acute
severe traumatic brain injury: a randomized controlled trial.
Crit Care.
2008;
12
1-10
- 73
Betz A L, Coester H C.
Effect of steroids on edema and sodium uptake of the brain during focal ischemia in
rats.
Stroke.
1990;
21
1199-1204
- 74
Guo Q, Sayeed I, Baronne L M, Hoffman S W, Guennoun R, Stein D G.
Progesterone administration modulates AQP4 expression and edema after traumatic brain
injury in male rats.
Exp Neurol.
2006;
198
469-478
- 75
Yao X L, Liu J, Lee E, Ling G S, McCabe J T.
Progesterone differentially regulates pro- and anti-apoptotic gene expression in cerebral
cortex following traumatic brain injury in rats.
J Neurotrauma.
2005;
22
656-668
- 76
Djebaili M, Guo Q, Pettus E H, Hoffman S W, Stein D G.
The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and
functional deficits after traumatic brain injury in rats.
J Neurotrauma.
2005;
22
106-118
- 77
Cai W, Zhu Y, Furuya K, Li Z, Sokabe M, Chen L.
Two different molecular mechanisms underlying progesterone neuroprotection against
ischemic brain damage.
Neuropharmacology.
2008;
55
127-138
- 78
Roof R L, Hoffman S W, Stein D G.
Progesterone protects against lipid peroxidation following traumatic brain injury
in rats.
Mol Chem Neuropathol.
1997;
31
1-11
- 79
Miller L, Hunt J S.
Regulation of TNF-alpha production in activated mouse macrophages by progesterone.
J Immunol.
1998;
160
5098-5104
- 80
Drew P D, Chavis J A.
Female sex steroids: effects upon microglial cell activation.
J Neuroimmunol.
2000;
111
77-85
- 81
He J, Hoffman S W, Stein D G.
Allopregnanolone, a progesterone metabolite, enhances behavioral recovery and decreases
neuronal loss after traumatic brain injury.
Restor Neurol Neurosci.
2004;
22
19-31
- 82
Pettus E H, Wright D W, Stein D G, Hoffman S W.
Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain
injury.
Brain Res.
2005;
1049
112-119
- 83
Chan J R, Phillips II L J, Glaser M.
Glucocorticoids and progestins signal the initiation and enhance the rate of myelin
formation.
Proc Natl Acad Sci U S A.
1998;
95
10459-10464
- 84
Koenig H L, Schumacher M, Ferzaz B et al..
Progesterone synthesis and myelin formation by Schwann cells.
Science.
1995;
268
1500-1503
- 85
Ghoumari A M, Ibanez C, El-Etr M et al..
Progesterone and its metabolites increase myelin basic protein expression in organotypic
slice cultures of rat cerebellum.
J Neurochem.
2003;
86
848-859
- 86
Ghoumari A M, Baulieu E E, Schumacher M.
Progesterone increases oligodendroglial cell proliferation in rat cerebellar slice
cultures.
Neuroscience.
2005;
135
47-58
- 87
Ibanez C, Shields S A, El-Etr M, Baulieu E E, Schumacher M, Franklin R J.
Systemic progesterone administration results in a partial reversal of the age-associated
decline in CNS remyelination following toxin-induced demyelination in male rats.
Neuropathol Appl Neurobiol.
2004;
30
80-89
- 88
Ardeshiri A, Kelley M H, Korner I P, Hurn P D, Herson P S.
Mechanism of progesterone neuroprotection of rat cerebellar Purkinje cells following
oxygen-glucose deprivation.
Eur J Neurosci.
2006;
24
2567-2574
- 89
Brinton R D, Wang J M.
Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer's
disease: allopregnanolone as a proof of concept neurogenic agent.
Curr Alzheimer Res.
2006;
3
185-190
- 90
Mellon S H, Gong W, Schonemann M D.
Endogenous and synthetic neurosteroids in treatment of Niemann-Pick type C disease.
Brain Res Rev.
2008;
57
410-420
- 91
Ciriza I, Azcoitia I, Garcia-Segura L M.
Reduced progesterone metabolites protect rat hippocampal neurones from kainic acid
excitotoxicity in vivo.
J Neuroendocrinol.
2004;
16
58-63
- 92
Djebaili M, Hoffman S W, Stein D G.
Allopregnanolone and progesterone decrease cell death and cognitive deficits after
a contusion of the rat pre-frontal cortex.
Neuroscience.
2004;
123
349-359
- 93
Wang J M, Johnston P B, Ball B G, Brinton R D.
The neurosteroid allopregnanolone promotes proliferation of rodent and human neural
progenitor cells and regulates cell-cycle gene and protein expression.
J Neurosci.
2005;
25
4706-4718
- 94
Xilouri M, Avlonitis N, Calogeropoulou T, Papazafiri P.
Neuroprotective effects of steroid analogues on P19-N neurons.
Neurochem Int.
2007;
50
660-670
- 95
Charalampopoulos I, Tsatsanis C, Dermitzaki E et al..
Dehydroepiandrosterone and allopregnanolone protect sympathoadrenal medulla cells
against apoptosis via antiapoptotic bcl-2 proteins.
Proc Natl Acad Sci U S A.
2004;
101
8209-8214
- 96
Charalampopoulos I, Alexaki V I, Tsatsanis C et al..
Neurosteroids as endogenous inhibitors of neuronal cell apoptosis in aging.
Ann N Y Acad Sci.
2006;
1088
139-152
- 97
Belelli D, Lambert J J.
Neurosteroids: endogenous regulators of the GABA(A) receptor.
Nat Rev Neurosci.
2005;
6
565-575
- 98
Carswell H V, Dominiczak A F, Macrae I M.
Estrogen status affects sensitivity to focal cerebral ischemia in stroke-prone spontaneously
hypertensive rats.
Am J Physiol Heart Circ Physiol.
2000;
278
H290-H294
- 99
Hall E D, Pazara K E, Linseman K L.
Sex differences in postischemic neuronal necrosis in gerbils.
J Cereb Blood Flow Metab.
1991;
11
292-298
- 100
Hurn P D, Macrae I M.
Estrogen as a neuroprotectant in stroke.
J Cereb Blood Flow Metab.
2000;
20
631-652
- 101
Toung T J, Traystman R J, Hurn P D.
Estrogen-mediated neuroprotection after experimental stroke in male rats.
Stroke.
1998;
29
1666-1670
- 102
Hawk T, Zhang Y Q, Rajakumar G, Day A L, Simpkins J W.
Testosterone increases and estradiol decreases middle cerebral artery occlusion lesion
size in male rats.
Brain Res.
1998;
796
296-298
- 103
Jover T, Tanaka H, Calderone A et al..
Estrogen protects against global ischemia-induced neuronal death and prevents activation
of apoptotic signaling cascades in the hippocampal CA1.
J Neurosci.
2002;
22
2115-2124
- 104
Gulinello M, Lebesgue D, Jover-Mengual T, Zukin R S, Etgen A M.
Acute and chronic estradiol treatments reduce memory deficits induced by transient
global ischemia in female rats.
Horm Behav.
2006;
49
246-260
- 105
Carswell H V, Bingham D, Wallace K et al..
Differential effects of 17beta-estradiol upon stroke damage in stroke prone and normotensive
rats.
J Cereb Blood Flow Metab.
2004;
24
298-304
- 106
Bingham D, Macrae I M, Carswell H V.
Detrimental effects of 17beta-oestradiol after permanent middle cerebral artery occlusion.
J Cereb Blood Flow Metab.
2005;
25
414-420
- 107
Vergouwen M D, Anderson R E, Meyer F B.
Gender differences and the effects of synthetic exogenous and non-synthetic estrogens
in focal cerebral ischemia.
Brain Res.
2000;
878
88-97
- 108
Gordon K B, Macrae I M, Carswell H V.
Effects of 17beta-oestradiol on cerebral ischaemic damage and lipid peroxidation.
Brain Res.
2005;
1036
155-162
- 109
Sohrabji F, Bake S.
Age-related changes in neuroprotection: is estrogen pro-inflammatory for the reproductive
senescent brain?.
Endocrine.
2006;
29
191-197
- 110
Suzuki S, Brown C M, Dela Cruz C D, Yang E, Bridwell D A, Wise P M.
Timing of estrogen therapy after ovariectomy dictates the efficacy of its neuroprotective
and antiinflammatory actions.
Proc Natl Acad Sci U S A.
2007;
104
6013-6018
- 111
Rusa R, Alkayed N J, Crain B J et al..
17beta-Estradiol reduces stroke injury in estrogen-deficient female animals.
Stroke.
1999;
30
1665-1670
- 112
Dubal D B, Kashon M L, Pettigrew L C et al..
Estradiol protects against ischemic injury.
J Cereb Blood Flow Metab.
1998;
18
1253-1258
- 113
Liu R, Wen Y, Perez E et al..
17beta-Estradiol attenuates blood-brain barrier disruption induced by cerebral ischemia-reperfusion
injury in female rats.
Brain Res.
2005;
1060
55-61
- 114
O'Donnell M E, Lam T I, Tran L Q, Foroutan S, Anderson S E.
Estradiol reduces activity of the blood-brain barrier na-K-cl cotransporter and decreases
edema formation in permanent middle cerebral artery occlusion.
J Cereb Blood Flow Metab.
2006;
26
1234-1249
- 115
Pelligrino D A, Santizo R, Baughman V L, Wang Q.
Cerebral vasodilating capacity during forebrain ischemia: effects of chronic estrogen
depletion and repletion and the role of neuronal nitric oxide synthase.
Neuroreport.
1998;
9
3285-3291
- 116
Hurn P D, Littleton-Kearney M T, Kirsch J R, Dharmarajan A M, Traystman R J.
Postischemic cerebral blood flow recovery in the female: effect of 17 beta-estradiol.
J Cereb Blood Flow Metab.
1995;
15
666-672
- 117
Mori M, Tsukahara F, Yoshioka T, Irie K, Ohta H.
Suppression by 17beta-estradiol of monocyte adhesion to vascular endothelial cells
is mediated by estrogen receptors.
Life Sci.
2004;
75
599-609
- 118
Wen Y, Yang S, Liu R et al..
Estrogen attenuates nuclear factor-kappa B activation induced by transient cerebral
ischemia.
Brain Res.
2004;
1008
147-154
- 119
Alkayed N J, Goto S, Sugo N et al..
Estrogen and bcl-2: gene induction and effect of transgene in experimental stroke.
J Neurosci.
2001;
21
7543-7550
- 120
Xu Y, Zhang W, Klaus J et al..
Role of cocaine- and amphetamine-regulated transcript in estradiol-mediated neuroprotection.
Proc Natl Acad Sci U S A.
2006;
103
14489-14494
- 121
Keller J N, Germeyer A, Begley J G, Mattson M P.
17beta-Estradiol attenuates oxidative impairment of synaptic Na+/K+-ATPase activity,
glucose transport, and glutamate transport induced by amyloid beta-peptide and iron.
J Neurosci Res.
1997;
50
522-530
- 122
Vedder H, Anthes N, Stumm G, Wurz C, Behl C, Krieg J C.
Estrogen hormones reduce lipid peroxidation in cells and tissues of the central nervous
system.
J Neurochem.
1999;
72
2531-2538
- 123
Behl C, Manthey D.
Neuroprotective activities of estrogen: an update.
J Neurocytol.
2000;
29
351-358
- 124
Connell B J, Crosby K M, Richard M J, Mayne M B, Saleh T M.
Estrogen-mediated neuroprotection in the cortex may require NMDA receptor activation.
Neuroscience.
2007;
146
160-169
- 125
Weaver Jr C E, Park-Chung M, Gibbs T T, Farb D H.
17beta-Estradiol protects against NMDA-induced excitotoxicity by direct inhibition
of NMDA receptors.
Brain Res.
1997;
761
338-341
- 126
Suzuki S, Gerhold L M, Bottner M et al..
Estradiol enhances neurogenesis following ischemic stroke through estrogen receptors
alpha and beta.
J Comp Neurol.
2007;
500
1064-1075
- 127
Shughrue P J, Bushnell C D, Dorsa D M.
Estrogen receptor messenger ribonucleic acid in female rat brain during the estrous
cycle: a comparison with ovariectomized females and intact males.
Endocrinology.
1992;
131
381-388
- 128
Mor G, Nilsen J, Horvath T et al..
Estrogen and microglia: a regulatory system that affects the brain.
J Neurobiol.
1999;
40
484-496
- 129
Azcoitia I, Sierra A, Garcia-Segura L M.
Localization of estrogen receptor beta-immunoreactivity in astrocytes of the adult
rat brain.
Glia.
1999;
26
260-267
- 130
Sawada M, Alkayed N J, Goto S et al..
Estrogen receptor antagonist ICI182,780 exacerbates ischemic injury in female mouse.
J Cereb Blood Flow Metab.
2000;
20
112-118
- 131
Sampei K, Goto S, Alkayed N J et al..
Stroke in estrogen receptor-alpha-deficient mice.
Stroke.
2000;
31
738-744
- 132
Dubal D B, Zhu H, Yu J et al..
Estrogen receptor alpha, not beta, is a critical link in estradiol-mediated protection
against brain injury.
Proc Natl Acad Sci U S A.
2001;
98
1952-1957
- 133
Carswell H V, Macrae I M, Gallagher L, Harrop E, Horsburgh K J.
Neuroprotection by a selective oestrogen receptor {beta} agonist in a mouse model
of global ischaemia.
Am J Physiol Heart Circ Physiol.
2004;
287
H1501-1504
- 134
Jeppesen L L, Jorgensen H S, Nakayama H, Raaschou H O, Olsen T S, Winther K.
Decreased serum testosterone in men with acute ischemic stroke.
Arterioscler Thromb Vasc Biol.
1996;
16
749-754
- 135
Yang S H, Perez E, Cutright J et al..
Testosterone increases neurotoxicity of glutamate in vitro and ischemia-reperfusion
injury in an animal model.
J Appl Physiol.
2002;
92
195-201
- 136
Cheng J, Alkayed N J, Hurn P D.
Deleterious effects of dihydrotestosterone on cerebral ischemic injury.
J Cereb Blood Flow Metab.
2007;
27
1553-1562
- 137
Pan Y, Zhang H, Acharya A B, Patrick P H, Oliver D, Morley J E.
Effect of testosterone on functional recovery in a castrate male rat stroke model.
Brain Res.
2005;
1043
195-204
- 138
Jones K J.
Gonadal steroids as promoting factors in axonal regeneration.
Brain Res Bull.
1993;
30
491-498
- 139
Kujawa K A, Jacob J M, Jones K J.
Testosterone regulation of the regenerative properties of injured rat sciatic motor
neurons.
J Neurosci Res.
1993;
35
268-273
- 140
Tanzer L, Jones K J.
Gonadal steroid regulation of hamster facial nerve regeneration: effects of dihydrotestosterone
and estradiol.
Exp Neurol.
1997;
146
258-264
- 141
Chen R, Cohen L G, Hallett M.
Nervous system reorganization following injury.
Neuroscience.
2002;
111
761-773
Patricia D HurnPh.D.
Department of Anesthesiology and Perioperative Medicine
UHS-2, 3181 SW Sam Jackson Park Road., Portland OR 97239-3098
Email: hurnp@ohsu.edu