Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair

Garcia-Segura, Luis Miguel; Wozniak, A.; Azcoitia, Íñigo; Toledo-Rodriguez, Maria; Hutchison, R. E.; Hutchison, J.B.

doi:10.1016/s0306-4522(98)00340-6

Cited by 340 publications

(243 citation statements)

References 79 publications

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“…Accordingly, brain aromatase may be important to ischemic pathophysiology. Consistent with this hypothesis, aromatase activity is induced in astrocytes after brain injury (Garcia-Segura, et al, 1999;Azcoitia, et al, 2003).…”

Section: Introductionsupporting

confidence: 68%

A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture

Liu

Oyarzabal

Yang

et al. 2008

Journal of Neuroscience Methods

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Female astrocytes sustain less cell death from oxygen-glucose deprivation (OGD) than male astrocytes. Arimidex, an aromatase inhibitor, abolishes these sex differences. To verify sexdependent differences in P450 aromatase function in astrocyte cell death following OGD, we developed a novel method that uses sex-specific and genotype-specific single pup primary astrocyte cultures from wild-type (WT) and aromatase-knockout (ArKO) mice. After determining sex by external and internal examination as well as PCR and genotype by PCR amplification of tail cDNA, we established cultures from 1−3 day-old male and female, WT and ArKO mice pups and grew them to confluence in estrogen-free media. Cell death was measured by lactate dehydrogenase (LDH) assay. Our study shows that, while WT female astrocytes are more resistant to OGD than WT male cells, sex differences disappear in ArKO cells. Cell death is significantly increased in ArKO compared to WT in female astrocytes but not male cells. Therefore, P450 aromatase appears to be essential in endogenous neuroprotection in females, and this finding may have clinical implications. This innovative technique may also be applied to other in vitro studies of sex-related functional differences.

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Section: Introductionsupporting

confidence: 68%

A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture

Liu

Oyarzabal

Yang

et al. 2008

Journal of Neuroscience Methods

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show abstract

“…Accordingly, brain aromatase and local estradiol production may be important to ischemic pathophysiology. Consistent with this hypothesis, aromatase activity and expression are induced in brain after injury in astrocytes (Garcia-Segura et al, 1999;Azcoitia et al, 2003). More recently, Carswell et al (2005) showed that aromatase expression is also induced in astrocytes after experimental stroke.…”

Section: Introductionmentioning

confidence: 55%

Role of P450 Aromatase in Sex-Specific Astrocytic Cell Death

Liu

Hurn

Roselli

et al. 2006

J Cereb Blood Flow Metab

134

116

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Female animals are protected from ischemic brain damage relative to age-matched males, in part through protection provided by endogenous estradiol. In brain, estradiol is produced from testosterone by cytochrome P450 aromatase (cyp 19), a steroid synthetic enzyme present in astrocytes. We tested the hypothesis that astrocytes derived from neonatal female rat brain are less susceptible than male cells to oxygen-glucose deprivation (OGD), and that this endogenous protection is associated with enhanced aromatase activity. Primary cultured cortical astrocytes were prepared from male and female rat pups separately and grown to confluence in estrogen-free media. Cell death in response to OGD, alone or in combination with hydrogen peroxide, lipopolysaccharides, interleukin-1b, tissue necrosis factor-a, or nitric oxide (NO) donor diethylenetriamine/nitric oxide adduct (DETA/NO) was quantified as the ratio of propidium iodide to calcein AM-positive cells. Aromatase activity and cyp19 mRNA and protein levels were measured in cultures from each sex. Female astrocytes are more resistant to OGD and oxidant cell death induced by H 2 O 2 , but sustain greater cell death when inflammatory mediators are combined with OGD compared with OGD alone. Media transfer from female to male cells conferred protection against OGD-induced cell death. Aromatase activity and expression is greater in female than in male astrocytes. The aromatase inhibitor, Arimidex (100 nmol/L), abolishes sex differences in OGD-induced cell death, whereas treatment with 17b-estradiol (10 nmol/L) protects cells of either sex. We conclude that astrocytes isolated from neonatal cortex exhibit marked sex differences in sensitivity to OGD, in part because of enhanced aromatization and estradiol formation in female cells.

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“…As glial response is associated with hypermetabolism (Roh et al, 1998), the absence of frontal hypometabolism in female MA users in the current study may be associated with enhanced glial repair response to MA in females rather than males. After MA exposure, female mice have been reported to express augmented mRNA of glial fibrillary acidic protein, which is associated with glial repair response to brain injury (Dluzen et al, 2003;Garcia-Segura et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Frontal Glucose Hypometabolism in Abstinent Methamphetamine Users

Kim

Lyoo

Hwang

et al. 2005

Neuropsychopharmacol

111

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Changes in relative regional cerebral glucose metabolism (rCMRglc) and their potential gender differences in abstinent methamphetamine (MA) users were explored. Relative rCMRglc, as measured by 18 F-fluorodeoxyglucose positron emission tomography, and frontal executive functions, as assessed by Wisconsin card sorting test (WCST), were compared between 35 abstinent MA users and 21 healthy comparison subjects. In addition, male and female MA users and their gender-matched comparison subjects were compared to investigate potential gender differences. MA users had lower rCMRglc levels in the right superior frontal white matter and more perseveration and nonperseveration errors in the WCST, relative to healthy comparison subjects. Relative rCMRglc in the frontal white matter correlated with number of errors in the WCST in MA users. In the subanalysis for gender differences, lower rCMRglc in the frontal white matter and more errors in the WCST were found only in male MA users, not in female MA users, relative to their gender-matched comparison subjects. The current findings suggest that MA use causes persistent hypometabolism in the frontal white matter and impairment in frontal executive function. Our findings also suggest that the neurotoxic effect of MA on frontal lobes of the brain might be more prominent in men than in women.

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Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair

Cited by 340 publications

References 79 publications

A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture

A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture

Role of P450 Aromatase in Sex-Specific Astrocytic Cell Death

Frontal Glucose Hypometabolism in Abstinent Methamphetamine Users

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