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.

Selective role of Na+/H+ exchanger in Cx3cr1+ microglial activation, white matter demyelination, and post‐stroke function recovery

“…In addition, the 30-day post-Tam injection period is needed for clearance of Tam-mediated neuroprotection effects. Tam has neuroprotective effects against neurodegenerative diseases via possible mechanisms such as stimulating MAPK/ERK signaling pathways (Wakade et al, 2008; Zou et al, 2015), preventing mitochondrial reactive oxygen species generation (Khan, Wakade, de Sevilla, & Brann, 2015; Wakade et al, 2008), and generating antioxidant enzymes (Zhang, Milatovic, Aschner, Feustel, & Kimelberg, 2007). Despite complete clearance of Tam and its metabolites in the brain by 8 days post-injection (Valny et al, 2016), we detected prolonged neuroprotective effects of Tam (75 mg/kg for consecutive 5 days) in C57/B6J, Cx3cr1-Cre ER or Nhe1 f/f , as well as Cx3cr1-Cre ER ; Nhe1 f/f mice when tMCAO was induced at 1, 12, and 20 days after Tam injection, compared with the vehicle oil control mice (Supporting Information Figure S5).…”

The neuroprotective actions of oestradiol and oestrogen receptors

“…The discovery of the role of ERs as coordinators of neuroprotective signalling mechanisms has prompted the investigation of the potential neuroprotective activity of SERMs in various experimental models of brain pathology, including cognitive decline 166 , affective disorders 167,168 , traumatic brain and spinal cord injury [169][170][171] , subarachnoid haemorrhage 172 , stroke [173][174][175] , neuroinflammation 176 multiple sclerosis 177,178 , Alzheimer's disease 179,180 and Parkinson's disease 181 . These studies, together with some clinical findings 182 , support the possible use of SERMs as new drugs for the treatment of acute and chronic neurodegenerative diseases, affective disorders and cognitive decline.…”

Regulation of astroglia by gonadal steroid hormones under physiological and pathological conditions

“…SERMs have been shown to exert neuroprotective actions in animal models for a variety of pathological conditions, such as: excitotoxicity (Ciriza et al, 2004), oxidative stress (Biewenga et al, 2005), ischemia (Castello-Ruiz et al, 2014;Khan et al, 2015;Wakade et al, 2008;Zhang et al, 2007Zhang et al, , 2005, Parkinson disease (Bourque et al, 2014;Callier et al, 2001;Dluzen et al, 2001;Mickley and Dluzen, 2004;Morissette et al, 2008), Alzheimer´s disease (Herrera et al, 2011a(Herrera et al, , 2011bO'Neill et al, 2004) Tamoxifen, raloxifene, ospemifene and bazedoxifene reduce the expression of proinflammatory molecules by primary astrocyte cultures exposed to LPS (Cerciat et al, 2010) or infected with Theiler's virus (Rubio et al, 2011;Rubio et al, 2014). In addition, raloxifene has been shown to decrease astrogliosis and chemokine (C-C motif) ligand 20 (CCL20) expression in reactive astrocytes in a model of experimental autoimmune encephalomyelitis and to decrease the number of astrocytes in the hippocampus in aged female mice (Lei et al, 2003).…”