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The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of insulin-like growth factor-1.

ABSTRACT: Hormone therapy to postmenopausal females increases the risk and severity of ischemic stroke. Our previous work using an animal model of menopause (reproductive senescence) shows that middle cerebral artery occlusion (MCAo) causes a larger cortical-striatal infarct in this older acyclic group compared with younger females. Moreover, although estrogen treatment is neuroprotective in younger females, estrogen paradoxically increases infarct volume in acyclic females. We hypothesized that the neurotoxic effects of estrogen in older females occurs because of decreased availability of IGF-1, a neuroprotectant that decreases with advancing age and is downregulated by estrogen treatment. Our data show that plasma IGF-1 levels are significantly reduced in reproductive senescent females and further reduced by estrogen at all ages. The neuroprotective effect of estrogen on MCAo-induced cortical infarct volume in mature adult female is reversed by intracerebroventricular injections of IGF-1 receptor antagonist JB-1. Similarly, estrogens neurotoxic effects on cortical infarct volume in senescent females is attenuated by concurrent IGF-1 treatment, and reversed when IGF-1 is infused 4 h after the onset of ischemia (delayed IGF-1 treatment). Delayed IGF-1/estrogen treatment also suppressed ischemia-induced ERK1 phosphorylation, reduced protein oxidation, and stimulated an early increase in prostaglandin E(2) at the infarct site. IGF-1 treatment was only protective in senescent females that received estrogen, indicating that the neuroprotective actions of this peptide require interaction with the steroid hormone receptor. These data support the hypothesis that stroke severity in older females is associated with decreased IGF-1 and further indicate that short-term postischemic IGF-1 therapy may be beneficial for stroke.

SUBMITTER: Selvamani A

PROVIDER: S-EPMC2887690 | biostudies-other | 2010 May

REPOSITORIES: biostudies-other

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The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of insulin-like growth factor-1.

Selvamani Amutha A Sohrabji Farida F

The Journal of neuroscience : the official journal of the Society for Neuroscience 20100501 20

Hormone therapy to postmenopausal females increases the risk and severity of ischemic stroke. Our previous work using an animal model of menopause (reproductive senescence) shows that middle cerebral artery occlusion (MCAo) causes a larger cortical-striatal infarct in this older acyclic group compared with younger females. Moreover, although estrogen treatment is neuroprotective in younger females, estrogen paradoxically increases infarct volume in acyclic females. We hypothesized that the neuro ...[more]

PMID: 20484627

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Project description:Background. Women account for 60% of all stroke deaths and are more often permanently disabled than men, despite their higher observed stroke incidence. Considering the clinical population affected by stroke, an obvious drawback is that many pre-clinical and clinical studies only investigate young males. To improve therapeutic translation from bench to bedside, we believe that it is advantageous to include both sexes in experimental models of stroke. The aims of this study were to identify early cerebral vascular responses to ischemic stroke in females, compare the differential gene expression patterns with those seen in males, and identify potential new therapeutic targets. Results. Transient middle cerebral artery occlusion (tMCAO) was used to induce stroke in both female and male rats, the middle cerebral arteries (MCAs) were isolated 3 hours post reperfusion and RNA was extracted. Affymetrix whole transcriptome expression profiling was performed on female (n = 12) MCAs to reveal differentially expressed genes. In total, 1076 genes had an increased expression and 879 genes a decreased expression in the occluded MCAs as compared with the control MCAs from female rats. An enrichment of genes related to apoptosis, regulation of transcription, protein autophosphorylation, inflammation, oxidative stress, and tissue repair and recovery were seen in the occluded MCA. The high expression genes chosen for qPCR verification (Adamts4, Olr1, JunB, Fosl1, Serpine1, S1pr3, Ccl2 and Socs3) were all shown to be upregulated in the same manner in both females and males after tMCAO (p < 0.05; n = 23). When comparing the differentially expressed genes in female MCAs (occluded and non-occluded) with our previous findings in males after tMCAO, a total of 297 genes overlapped (all groups had 32 genes in common). Conclusions. The cascades of processes initiated in the vasculature following reperfusion are complex. Dynamic gene expression alterations were observed in the occluded MCAs, and to a less pronounced degree in the non-occluded MCAs. Dysregulation of inflammation and blood-brain barrier breakdown are possible pharmacological targets. The sample of genes (<1% of differentially expressed genes) validated for this microarray did not reveal any sex differences.

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The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of insulin-like growth factor-1.

Publications

The neurotoxic effects of estrogen on ischemic stroke in older female rats is associated with age-dependent loss of insulin-like growth factor-1.

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