Sigma-1 receptor stimulation by dehydroepiandrosterone ameliorates cognitive impairment through activation of CaM kinase II, protein kinase C and extracellular signal-regulated kinase in olfactory bulbectomized mice

Moriguchi, Shigeki; Yamamoto, Yoshiyuki; Ikuno, Tatsuya; Fukunaga, Kohji

doi:10.1111/j.1471-4159.2011.07256.x

Cited by 56 publications

(46 citation statements)

References 83 publications

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“…In this study, DHEA treatment caused a significant up-regulation of the p-CREB protein level in cultured rat primary Leydig cells. This result was consistent with Moriguchi et al [27], who reported that DHEA significantly restored the reduced ERK phosphorylation concomitant with increased CREB phosphorylation in hippocampal ca1. Saxena et al [52] reported that DHEA regulates the MAPK pathway in humans via a novel MAPK phosphatase, which not only controls the activity of MAPKs, but also mediates crosstalk between the cAMP system and the MAPK cascade.…”

Section: Discussionsupporting

confidence: 92%

“…Additional studies suggested that DHEA affects the phosphorylation/activation of ERKs by enhancing phosphorylation of the steroidogenic factor-1 (SF-1) and regulating the protein expression of steroidogenic enzymes. Moriguchi et al [27] reported that DHEA restored reduced ERK phosphorylation concomitant with increased CREB phosphorylation in the hippocampal ca1 region of olfactory bulbectomized mouse. Nevertheless, the molecular mechanisms underlying these DHEA effects in Leydig cells remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Dehydroepiandrosterone-Regulated Testosterone Biosynthesis via Activation of the ERK1/2 Signaling Pathway in Primary Rat Leydig Cells

Liu

Kang

Ding

et al. 2015

Cell Physiol Biochem

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Background: Dehydroepiandrosterone decreases with age and this reduction has been shown to be associated with physical health in human. Some studies have suggested that the effects of DHEA are exerted after it is biotransformed into more biologically-active hormones in peripheral target cells. This study investigated the effects of DHEA on the testosterone biosynthesis and possible signaling pathway mechanism underlying these DHEA effects were also explored in primary rat Leydig cells. Methods: Primary Leydig cells were treated with DHEA and then detected testosterone content by RIA and steroidogenic enzymes, ERK1/2 signal pathway factors protein expression level by Western blot. Results: Incubation of primary Leydig cells with DHEA significantly increased testosterone content and 3β-HSD and 17β-HSD protein expression levels, while aromatase protein expression levels were decreased. Compared with the control group, p-ERK1/2 and p-CREB protein levels were significantly increased in DHEA-treated groups. Testosterone content was significantly decreased in the DHEA-treated group pre-incubated with U0126 (p-ERK1/2 inhibitor). Additionally, the rise in p-ERK1/2, 3β-HSD and 17β-HSD protein levels induced by DHEA was reversed when cells were pre-incubated with U0126. Interestingly, no significant difference was found in aromatase protein expression level in cells pretreated with U0126. Conclusion: These findings demonstrate that (a) exogenous DHEA might preferentially convert to testosterone rather than estradiol due to the up-regulation of 3β-HSD and 17β-HSD protein levels and the down-regulation of aromatase protein level in primary Leydig cells, and (b) the action of DHEA is at least partly associated with the elevation of p-ERK1/2 and p-CREB protein levels.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Dehydroepiandrosterone-Regulated Testosterone Biosynthesis via Activation of the ERK1/2 Signaling Pathway in Primary Rat Leydig Cells

Liu

Kang

Ding

et al. 2015

Cell Physiol Biochem

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“…Memory-Related Behavioral Tasks (1) Y-maze task: The Ymaze task is described elsewhere [7]. Spontaneous alternation behavior in a Y-maze is assessed as an indicator of spatial reference memory.…”

Section: Methodsmentioning

confidence: 99%

“…Knockout mice lacking Sig-1R exhibit depressive-like behaviors [6]. We also recently reported that impaired cognitive-related and depressive-like behaviors in olfactory bulbectomized mice are improved by chronic oral administration of dehydroepiandrosterone (DHEA), an endogenous Sig-1R ligand [7,8].…”

Section: Introductionmentioning

confidence: 99%

Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice

et al. 2014

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Sigma-1 receptor (Sig-1R) is a molecular chaperone regulating calcium efflux from the neuronal endoplasmic reticulum to the mitochondria. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) null mice exhibit depressive-like behaviors and impaired neurogenesis as assessed by bromodeoxyuridine (BrdU) incorporation into newborn cells of the hippocampal dentate gyrus (DG). Here, we demonstrate that chronic stimulation of Sig-1R by treatment with the agonist SA4503 or the SSRI fluvoxamine for 14 days improves depressive-like behaviors in CaMKIV null mice. By contrast, treatment with paroxetine, which lacks affinity for Sig-1R, did not alter these behaviors. Reduced numbers of BrdU-positive cells and decreased brain-derived neurotrophic factor (BDNF) mRNA expression and protein kinase B (Akt; Ser-473) phosphorylation seen in the DG of CaMKIV null mice were significantly rescued by chronic Sig-1R stimulation. Interestingly, reduced ATP production observed in the DG of CaMKIV null mice was improved by chronic Sig-1R stimulation. Such stimulation also improved hippocampal long-term potentiation (LTP) induction and maintenance, which are impaired in the DG of CaMKIV null mice. LTP rescue was closely associated with both increases in calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and GluA1 (Ser-831) phosphorylation. Taken together, Sig-1R stimulation by SA4503 or fluvoxamine treatment increased hippocampal neurogenesis, which is closely associated with amelioration of depressive-like behaviors in CaMKIV null mice.

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“…ST101 promotes nicotine-induced acetylcholine (ACh) release in the hippocampus via enhancement of Cav3.1 T-type calcium channel activity [18,19]. Recently, we developed a novel spiroimidazopyridine derivative called SAK3 (ethyl-8'-m e t h y l -2 ' , 4 -d i o x o -2 -[ p i p e r i d i n -1 -y l ] -2 ' Hspiro[cyclopentane-1, 3′-imidazo[1, 2-α]pyridin]-2-ene-3,carboxylate) that is a more effective T-type calcium channel enhancer than ST101 [20].…”

Section: Introductionmentioning

confidence: 99%

Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling

Noreen¹,

Yabuki²,

Shinoda³

et al. 2018

Pharmacology

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Hypothyroidism is a common disorder that is associated with psychological disturbances such as dementia, depression, and psychomotor disorders. We recently found that chronic treatment with the T-type calcium channel enhancer SAK3 prevents the cholinergic neurodegeneration induced by a single intraperitoneal (i.p.) injection of methimazole (MMI; 75 mg/kg), thereby improving cognition. Here, we evaluated the acute effect of SAK3 on cognitive impairments and its mechanism of action following the induction of hypothyroidism. Hypothyroidism was induced by 2 injections of MMI (75 mg/kg, i.p.) administered once per week. Four weeks after the final MMI treatment, MMI-treated mice showed reduced serum thyroxine (T4) levels and cognitive impairments without depression-like behaviors. Although acute SAK3 (1.0 mg/kg, p.o.) administration failed to ameliorate the decreased T4 levels and histochemical destruction of the glomerular structure, acute SAK3 (1.0 mg/kg, p.o.) administration significantly reduced cognitive impairments in MMI-treated mice. Importantly, the α7 nicotinic acetylcholine receptor (nAChR)-selective inhibitor methyllycaconitine (MLA; 12 mg/kg, i.p.) and T-type calcium channel-specific blocker NNC 55–0396 (25 mg/kg, i.p.) antagonized the acute effect of SAK3 on memory deficits in MMI-treated mice. We also confirmed that acute SAK3 administration does not rescue reduced olfactory marker protein or choline acetyltransferase immunoreactivity levels in the olfactory bulb or medial septum. Taken together, these results suggest that SAK3 has the ability to improve the cognitive decline caused by hypothyroidism directly through activation of nAChR signaling and T-type calcium channels.

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Sigma-1 receptor stimulation by dehydroepiandrosterone ameliorates cognitive impairment through activation of CaM kinase II, protein kinase C and extracellular signal-regulated kinase in olfactory bulbectomized mice

Abstract: Sigma-1 receptor (sigma-1R) was cloned in human and several animal species (Hanner et al.

Cited by 56 publications

References 83 publications

Dehydroepiandrosterone-Regulated Testosterone Biosynthesis via Activation of the ERK1/2 Signaling Pathway in Primary Rat Leydig Cells

Dehydroepiandrosterone-Regulated Testosterone Biosynthesis via Activation of the ERK1/2 Signaling Pathway in Primary Rat Leydig Cells

Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice

Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling

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