17beta-estradiol and enriched environment accelerate cognitive recovery after focal brain ischemia.
Cognitive impairments, including spatial memory and learning deficiencies, are common after ischemic stroke. Estrogen substitution improves cognitive functions in post-menopausal women and ovariectomized rodents, partially through induction of neuroplasticity in the hippocampal formation. Post-ischemic housing of male rats in an enriched environment (EE) improves functional outcome, without changing infarct volume. We hypothesized that 17beta-estradiol combined with an EE would accelerate cognitive recovery after focal brain ischemia in ovariectomized rats and that recovery would be related to altered expression of nerve growth factor-induced gene (NGFI)-A in the hippocampus. 17beta-estradiol or placebo pellets were implanted 6 h after transient middle cerebral artery occlusion. Two days later, rats were placed in an EE or a deprived environment (DE) for 6 weeks. At 5 weeks after middle cerebral artery occlusion, 17beta-estradiol-treated rats housed in an EE showed improvements in cognitive function (i.e. shorter latency and path in the Morris water maze task) compared with placebo-treated animals housed in an EE. Furthermore, beneficial effects on latency and path were observed when comparing EE-housed vs. DE-housed 17beta-estradiol-treated rats. When comparing 17beta-estradiol-treated EE-housed rats vs. placebo-treated DE-housed rats, pronounced effects on latency and path were observed. Infarct volumes did not differ between groups. 17beta-estradiol-treated EE-housed rats had significantly higher NGFI-A mRNA expression bilaterally in the cornu ammonis 1 region and in the ipsilateral dentate gyrus of the hippocampus, compared with placebo-treated EE-housed rats. In conclusion, 17beta-estradiol treatment combined with an EE improved recovery of cognitive function after experimental brain ischemia, putatively through the upregulation of NGFI-A in hippocampal subregions.
Söderström
Ingegerd
I
Department of Public Health and Clinical Medicine, Medicine, Umeå University, Umeå, Sweden. ingegerd.soderstrom@medicin.umu.se
Strand
Magnus
M
Ingridsson
Anna-Cajsa
AC
Nasic
Salmir
S
Olsson
Tommy
T
D000704:Analysis of Variance; D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy / Q000209:etiology; D002545:Brain Ischemia / Q000150:complications; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000451:nursing* / Q000473:pathology; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D004777:Environment; D004958:Estradiol / Q000097:blood / Q000627:therapeutic use*; D004967:Estrogens / Q000097:blood / Q000627:therapeutic use*; D005260:Female; D007839:Functional Laterality / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D009483:Neuropsychological Tests; D010052:Ovariectomy / Q000379:methods; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D012677:Sensation / Q000187:drug effects; D013997:Time Factors; D014738:Vibrissae / Q000187:drug effects / Q000294:innervation
D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D004967:Estrogens; D004958:Estradiol