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Astrocyte-specific insulin-like growth factor-1 gene transfer in aging female rats improves stroke outcomes.

ABSTRACT: Middle aged female rats sustain larger stroke infarction and disability than younger female rats. This older group also shows age-related reduction of insulin like growth factor (IGF)-1 in serum and in astrocytes, a cell type necessary for poststroke recovery. To determine the impact of astrocytic IGF-1 for ischemic stroke, these studies tested the hypothesis that gene transfer of IGF-1 to astrocytes will improve stroke outcomes in middle aged female rats. Middle aged (10-12 month old), acyclic female rats were injected with recombinant adeno-associated virus serotype 5 (AAV5) packaged with the coding sequence of the human (h)IGF-1 gene downstream of an astrocyte-specific promoter glial fibrillary acidic protein (GFAP) (AAV5-GFP-hIGF-1) into the striatum and cortex. The AAV5-control consisted of an identical shuttle vector construct without the hIGF-1 gene (AAV5-GFAP-control). Six to eight weeks later, animals underwent transient (90 min) middle cerebral artery occlusion via intraluminal suture. While infarct volume was not altered, AAV5-GFAP-hIGF-1 treatment significantly improved blood pressure and neurological score in the early acute phase of stroke (2 days) and sensory-motor performance at both the early and late (5 days) acute phase of stroke. AAV5-GFAP-hIGF-1 treatment also reduced circulating serum levels of GFAP, a biomarker for blood brain barrier permeability. Flow cytometry analysis of immune cells in the brain at 24 hr poststroke showed that AAV5-GFAP-hIGF-1 altered the type of immune cells trafficked to the ischemic hemisphere, promoting an anti-inflammatory profile. Collectively, these studies show that targeted enhancement of IGF-1 in astrocytes of middle-aged females improves stroke-induced behavioral impairment and neuroinflammation.

SUBMITTER: Okoreeh AK

PROVIDER: S-EPMC5432389 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Astrocyte-specific insulin-like growth factor-1 gene transfer in aging female rats improves stroke outcomes.

Okoreeh Andre K AK Bake Shameena S Sohrabji Farida F

Glia 20170320 7

Middle aged female rats sustain larger stroke infarction and disability than younger female rats. This older group also shows age-related reduction of insulin like growth factor (IGF)-1 in serum and in astrocytes, a cell type necessary for poststroke recovery. To determine the impact of astrocytic IGF-1 for ischemic stroke, these studies tested the hypothesis that gene transfer of IGF-1 to astrocytes will improve stroke outcomes in middle aged female rats. Middle aged (10-12 month old), acyclic ...[more]

PMID: 28317235

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Project description:Protocatechuic acid (PCA), a strong antioxidant, has been reported for its cardiovascular-protective effects. This study aimed to investigate the effects of PCA administration on vascular endothelial function, mediated by insulin and insulin-like growth factor-1 (IGF-1), and antioxidant activities in aging hypertension. Thirty-six-week-old male aging spontaneously hypertensive rats were randomly divided into vehicle control (SHR) and PCA (SHR+PCA) groups, while age-matched Wistar⁻Kyoto rats (WKY) served as the normotensive vehicle control group. The oral PCA (200 mg/kg/day) was administered daily for a total of 12 weeks. When the rats reached the age of 48 weeks, the rat aortas were isolated for the evaluation of vascular reactivity and Western blotting. Also, nitric oxide (NO) production and antioxidant activities were examined among the three groups. The results showed that, when compared with the SHR group, the insulin-induced and IGF-1-induced vasorelaxation were significantly improved in the SHR+PCA group. There was no significant difference in the endothelium-denuded vessels among the three groups. After the pre-incubation of phosphatidylinositol 3-kinase (PI3K) or NO synthase (NOS) inhibitors, the vasorelaxation was abolished and comparable among the three groups. The protein levels of insulin receptors, IGF-1 receptors, phospho-protein kinase B (p-Akt)/Akt, and phospho-endothelial NOS (p-eNOS)/eNOS in aortic tissues were significantly enhanced in the SHR+PCA group when compared with the SHR group. Moreover, significant improvements of nitrate/nitrite concentration and antioxidant activities, including superoxide dismutase, catalase, and total antioxidants, were also found in the SHR+PCA group. In conclusion, the 12 weeks of PCA administration remarkably improved the endothelium-dependent vasorelaxation induced by insulin and IGF-1 in aging hypertension through enhancing the PI3K⁻NOS⁻NO pathway. Furthermore, the enhanced antioxidant activities partly contributed to the improved vasorelaxation.

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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Astrocyte-specific insulin-like growth factor-1 gene transfer in aging female rats improves stroke outcomes.

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Astrocyte-specific insulin-like growth factor-1 gene transfer in aging female rats improves stroke outcomes.

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