Alpha1-adrenergic receptor antagonist tamsulosin ameliorates aging-induced memory impairment by enhancing neurogenesis and suppressing apoptosis in the hippocampus of old-aged rats

Sung-Eun Kim,Jin-Hee Han,Il-Gyu Ko,Chang-Ju Kim,Khae Hawn Kim

doi:10.1080/19768354.2017.1404492

Abstract

ABSTRACTAge-related memory decline is closely associated with decreased neurogenesis and increased apoptosis in the hippocampus. Noradrenaline exerts its effect by selectively binding to and activating adrenergic receptors (ARs). Tamsulosin, α1-AR antagonist, is reported to have access to the brain and interact with α1-AR. In this study, the effects of tamsulosin on short-term and spatial learning memory in terms of neurogenesis and apoptosis were investigated using rats. Step-down avoidance test for short-term memory and radial 8-arm maze test for spatial learning memory were conducted. Neurogenesis was detected by 5-bromo-2’-deoxyuridine (BrdU) immunohistochemistry and apoptosis was evaluated by caspase-3 immunohistochemisty and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNE) staining. Western blot for protein kinase C (PKC), cAMP-responsive element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), tyrosine kinase B (TrkB), phosphatidylinositol 3-kinase (PI 3-kinase), Akt, Bcl-2, and Bax was conducted. In the aged rats, short-term and spatial learning memory was declined. Hippocampal nerogenesis was suppressed and hippocampal apoptosis was enhanced in the aged rats. In addition, phosphorylation of PKCα, CREB, PI-3 kinase, and Akt was decreased in the hippocampus of old-aged rats. Tamsulosin activated PKC/CREB and PI-3 kinase/Akt pathways. With these pathways, BDNF-TrkB signaling enhanced hippocampal neurogenesis and suppressed apoptosis in the old-aged rats. As the results, tamsulosin improved performance of short-term and spatial learning memory in the aged rats.

Highlights

Age-related memory decline is closely associated with decreased neurogenesis and increased apoptosis in the hippocampus (Driscoll and Sutherland 2005; Kim et al 2010)
Brain-derived neurotrophic factor (BDNF) plays a crucial role in the learning process, and deficit or loss of BDNF in the hippocampus of aged rats contributes to learning and memory impairment (Yang et al 2014)
We evaluated whether α1-adrenergic receptors (ARs) antagonist tamsulosin was effective in improving learning and memory impairment by aging

Summary

Introduction

Age-related memory decline is closely associated with decreased neurogenesis and increased apoptosis in the hippocampus (Driscoll and Sutherland 2005; Kim et al 2010). BDNF plays a crucial role in the learning process, and deficit or loss of BDNF in the hippocampus of aged rats contributes to learning and memory impairment (Yang et al 2014). Aging-related hippocampal susceptibility to apoptosis was demonstrated by increased pro-apoptotic Bax expression, enhanced caspase-3 activity, and reduced anti-apoptotic Bcl-2 expression (Kaufmann et al 2001; Jin et al 2008). Noradrenaline modulates hippocampal synaptic plasticity and deterioration of noradrenaline system may cause learning and memory impairment during aging (Knauber and Müller 2000). Noradrenaline exerts its influence by selectively binding to and activating adrenergic receptors (ARs); alpha (α1), alpha (α2) and beta (β) subtypes

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Conclusion