title: Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia.
abstract: Selective estrogen receptor modulators (SERMs) have been reported to enhance synaptic plasticity and improve cognitive performance in adult rats. SERMs have also been shown to induce neuroprotection against cerebral ischemia and other CNS insults. In this study, we sought to determine whether acute regulation of neurogenesis and spine remodeling could be a novel mechanism associated with neuroprotection induced by SERMs following cerebral ischemia. Toward this end, ovariectomized adult female rats were either implanted with pellets of 17β-estradiol (estrogen) or tamoxifen, or injected with raloxifene. After one week, cerebral ischemia was induced by the transient middle-cerebral artery occlusion (MCAO) method. Bromodeoxyuridine (BrdU) was injected to label dividing cells in brain. We analyzed neurogenesis and spine density at day-1 and day-5 post MCAO. In agreement with earlier findings, we observed a robust induction of neurogenesis in the ipsilateral subventricular zone (SVZ) of both the intact as well as ovariectomized female rats following MCAO. Interestingly, neurogenesis in the ipsilateral SVZ following ischemia was significantly higher in estrogen and raloxifene-treated animals compared to placebo-treated rats. In contrast, this enhancing effect on neurogenesis was not observed in tamoxifen-treated rats. Finally, both SERMs, as well as estrogen significantly reversed the spine density loss observed in the ischemic cortex at day-5 post ischemia. Taken, together these results reveal a profound structural remodeling potential of SERMs in the brain following cerebral ischemia. This article is part of a Special Issue entitled "Sex steroids and brain disorders".
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Zaiwa University, AZ-Zawia, Libya.
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Khan
authors.affiliation: Department of Physical Therapy, Georgia Regents University, Augusta, GA 30912, USA; Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Chandramohan
authors.initials: C
authors.lastname: Wakade
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Liesl
authors.initials: L
authors.lastname: de Sevilla
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: dbrann@gru.edu.
authors.forename: Darrell W
authors.initials: DW
authors.lastname: Brann
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D049229:Dendritic Spines / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology; D020547:Lateral Ventricles / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D018696:Neuroprotective Agents; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol
keywords: Cerebral cortex; Cerebral ischemia; Estrogen; Neurogenesis; Plasticity; Raloxifene; Tamoxifen