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Oxidative Stress and Mineralocorticoid Receptor Signaling in the Brain: Possible Therapeutic Targets for Dementia

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Oxidative Stress and Mineralocorticoid Receptor Signaling in the Brain: Possible Therapeutic Targets for Dementia Central Annals of Clinical and Experimental Hypertension Review Article *Corresponding author Tatsuo Shimosawa, 113-8655 7-3-1, Hongo, Bunkyo-Ku, Oxidative Stress and Tokyo, Japan, Tel: 81-33815-5411; Email: Submitted: 10 October 2014 Accepted: 19 November 2014 Mineralocorticoid Receptor Published: 28 November 2014 Copyright Signaling in the Brain: Possible © 2014 Shimosawa et al. Therapeutic Targets for OPEN ACCESS Keywords • Mineralocorticoid receptor Dementia • Oxidative stress • Brain damage Fumiko Kawakami-Mori1 and Tatsuo Shimosawa2* • Hypertension 1Division of Clinical Epigenetics ,University of Tokyo, Japan 2Department of Clinical Laboratory, University of Tokyo Faculty of Medicine, Japan Abstract Glucocorticoid and mineralocorticoid receptor signals are important for memory formation, salt cravings, sympathetic tone and hypothalamic–pituitary–adrenal (HPA) axis control in the brain. Exacerbations of glucocorticoid and mineralocorticoid receptor signaling cause atherosclerosis, cognitive dysfunction, and depression. Mineralocorticoid activity is modulated by oxidative stress, and chronic stress desensitize further non- genomic mineralocorticoid receptor action. In patients with chronic diseases such as diabetes and hypertension, oxidative stress in the brain is increased, which alters the balance of the HPA axis, resulting in an elevated risk of dementia. Therefore, oxidative stress and mineralocorticoid receptor blockade are possible therapeutic targets for cognitive dysfunction. INTRODUCTION is critical to prevent disease progression. In spite of these There is compelling evidence that diabetes mellitus, antihypertensive agent is most effective. hypertension, ischemic brain injury, and psychiatric disease findings, to date there are no adequate data to indicate which In the brain, neurotransmitters are secreted from the and dementia[1-3].The development of effective treatments for presynapse and bind mainly to postsynaptic receptors to open improvingcause oxidative cognitive stress function in the brainis of greatleading public to cognitive health concerndeficits ionic channels and modulate the activity of postsynaptic cells. because of the high prevalence of hypertension and diabetes Glutamate is an excitatory neurotransmitter that induces in the growing elderly population. The association between hypertension and cognitive decline has been of particular interest 4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate cation entry by activation of the α-amino-3-hydroxy-5-methyl- and there have been several clinical trials of antihypertensive (NMDA) receptors on glial cells. Glutamate plays an important drugs in the elderly, such as SCOPE, PROGRESS, HYVET, Sys-Eur role in learning and in establishing memory. Meanwhile, excessive secretion of glutamate induces cell vulnerability and/ antihypertensive drugs on preservation of cognitive function. or cell death by over-excitation [7].Glutamate release is regulated However,[4,5];among these these, studies only the were Sys-Eur limited trial by showed the relatively any benefit short of by many neuro modulators that are affected by chronic diseases observation periods and initiation of treatment late in the disease such as cerebral ischemia, diabetes, and hypertension. process, which precluded the ability to observe any meaningful Here, we review the role of the neuro modulator glucocorticoid impact on cognitive decline. In support, a recently published20- (GC) and oxidative stress in the development and progression of year large-scale retrospective clinical trial showed that midlife dementia. hypertension was strongly associated with cognitive decline in Steroid receptor distribution and effect in the brain later life, and early intervention with antihypertensive drugs could ameliorate this process [6].High blood pressure causes There are many ligands and receptors on neurons, in addition cognitive decline after a long time, therefore early intervention to neurotransmitter receptors, that modulate transmitter release Cite this article: Kawakami-Mori F, Shimosawa T (2014) Oxidative Stress and Mineralocorticoid Receptor Signaling in the Brain: Possible Therapeutic Targets for Dementia. Ann Clin Exp Hypertension 2(2): 1015. Shimosawa et al. (2014) Email: Central and/or ionic channel activation. Among these, GC is a known neuromodulator that has an important role in cognitive memory, concurrently; an imbalance is associated with cognitive fear memory, and salt cravings [8, 9]. GCs bind two steroid impairmentis for memory and acquisitiondysregulation [11].Both of the hypothalamic–pituitary–receptors are activated receptors, glucocorticoid receptors (GRs) and mineralocorticoid adrenal (HPA) axis [12-14]. Imbalances can be induced by selective agonists such as dexamethasone, or chronic diseases that increase oxidative stress in the brain. Oxidative stress receptors (MRs). In the brain, GRs are expressed ubiquitously, hippocampus, para ventricular nucleus, and brainstem. The modulates mainly the MR signal. whereas MRs is localized to specific areas, such as the MRs act not only through classical transcriptional pathways, than GRs, and under normal conditions, CS preferentially binds but also via short-term, non-genomic action through G-protein- tobinding MRs. affinityMRs bind of corticosterone not only aldosterone (CS) for MRsbut alsois 10-fold cortisol higher and coupled receptors (GPCRs). When circulating CS levels are increased by stress, CS binds membranous MRs, which are of conditions, the concentration of cortisol and CS is at least three ordersCS with of almost magnitude the same higher affinity. than Underaldosterone; normal therefore, physiological the dependent L-type Ca2+ channels and increase glutamate release active ligands of MRs are mainly cortisol and CS in regions of the fromlower theaffinity presynapse, than intracellular while simultaneously MRs. These activateinactivating voltage- the postsynaptic K+ channel (IA current) within minutes in a non- brain where 11β-hydroxysteroid dehydrogenase2(11βHSD2) genomic manner [15-18]. regionsis not expressed. area such as11βHSD2 the tractus metabolizes solitarius, CS subcommisural to its inactive organ, form Relationship between oxidative stress and MR action andcortisone ventromedial and in the hypothalamus brain, 11βHSD2 [10]. is Hence, expressed in most only of in the specific brain, In peripheral tissue, MR controls sodium transport and the main MR agonist is CS. For memory formation, GR and MR balance is important; independent of serum ligand concentration, and is potentiated by induces inflammation, fibrosis, and hypertrophy. This action is for instance, GR is mainly for memory consolidation and MR oxidative stress, which has been a paradoxical problem regarding Figure 1 A) perforate pathway. B) The representative data of field excitatory postsynaptic potentials fEPSPs in the CA1 region of the hippocampus induced by stimulation of the C) Applying 100nM corticosterone (CS) and/or 1μM NADPH rapidly increased fEPSPs via non-genomic action. All data were obtained in the presence Theseof 500 datanM actinomycin are from (25). D to confirm non-genomic action. Simultaneous application of 100nM CS and 1μM NADPH increased fEPSP remarkably. Non-genomic action by CS is ameliorated by an NADPH oxidase inhibitor (100μM apocynin) or Rac1 inhibitor (50μM NSC23766). Ann Clin Exp Hypertension 2(2): 1015 (2014) 2/6 Shimosawa et al. (2014) Email: Central MRs for a long time [19, 20]. One factor that exacerbates MR hippocampal neurons. Furthermore, simultaneous stimulation (Figure 1) and ERK pathway activation remarkably. Meanwhile, toaction CS orunder deoxycorticosterone, conditions of oxidative which stress is NADPH-dependent is 11βHSD1/2[19, and 21, theof MR non-genomic and NADPH action oxidase of MRincreases activates potentiation Rac1 GTP, of and field induces EPSPs 22], and another is Rac1 (23, 24). 11βHSD1 converts cortisone MR translocation (Figure2). These results indicate that both CS elevation and oxidative stress induce MR activation, and oxidative then11βHSD2 metabolize CS to cortisone, which is also NADPH- tissue.dependent. Oxidative stress activates 11βHSD1 and inactivates a feedback loop. 11βHSD2, resulting in increased concentrations of CS in the stress is subsequently further increased by MR activation [24] in In contrast, Rac1 GTPase, a member of the Rho family GTPases, The physiological roles of non-genomic action of MRs include activates MR nuclear translocation, MR-dependent transcription, memory retrieval [26-29], negative feedback with the HPA axis and MR-dependent signals such as serum and glucocorticoid- via hippocampal activation, suppression of adrenocorticotropic regulated kinase 1(SgK1) [23,24]. Rac1 is dispensable for the hormone(ACTH) and CS [30],and possibly ,effects on transition to non-genomic action of MR in the brain. The Rac1 inhibitor, genomic action [31]. It is plausible that oxidative stress modulates NSC23766, and the NADPH oxidase inhibitor apocynin block the the physiological functions of the non-genomic action of MR leading to pathologica postsynaptic potential (EPSP), and ERK1/2 phosphorylation in and multiple organ dysfunction. non-genomic action of CS, rapid potentiation of field excitatory l consequences of cognitive dysfunction Figure 2 A) Ten min after addition of corticosterone (CS) and/or NADPH, Rac1 GTPase was activated in the CA1 region of the hippocampus. CS and NADPH had an additive effect. B) C) Rac1 is a key factor in the feedback loop between mineralocorticoid receptors
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