Neurosteroid dehydroepiandrosterone sulphate inhibits persistent sodium currents in rat medial prefrontal cortex via activation of sigma-1 receptors

Cheng, Zhengxiang; Lan, Dan-Mei; Wu, Pei‐Ying; Zhu, Yanhua; Dong, Yi; Ma, Lan; Zheng, Ping

doi:10.1016/j.expneurol.2007.10.004

Cited by 61 publications

(49 citation statements)

References 36 publications

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“…1), it shares the similar pharmacophore with some of sigma-1 receptor ligands (N,N-diakyl or N-alkyl-N-arakyl pharmacophore) (Prezzavento et al, 2007). Moreover, the activation of sigma-1 receptor inhibits the voltage-gated Na 1 channel, Ca 21 channel, and K 1 channel (Aydar et al, 2002;Zhang and Cuevas, 2002;Cheng et al, 2008). Over-expression of sigma-1 receptor enhances the spontaneous release of glutamate (Meyer et al, 2002;Dong et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

SKF83959 Is a Potent Allosteric Modulator of Sigma-1 Receptor

et al. 2013

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-2,3,4,5-tetrahydro-1H-3-benzazepine), an atypical dopamine receptor-1 (D 1 receptor) agonist, has shown many D 1 receptor-independent effects, such as neuroprotection, blockade of Na 1 channel, and promotion of spontaneous glutamate release, which resemble the effects of the sigma-1 receptor activation. In the present work, we explored the potential modulation of SKF83959 on the sigma-1 receptor. The results indicated that SKF83959 dramatically promoted the binding of 3 H(1)-pentazocine (a selective sigma-1 receptor agonist) to the sigma-1 receptor in brain and liver tissues but produced no effect on 3 H-progesterone binding (a sigma-1 receptor antagonist). The saturation assay and the dissociation kinetics assay confirmed the allosteric effect. We further demonstrated that the SKF83959 analogs, such as SCH22390 [(R)-(1)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] and SKF38393 [(+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrobromide], also showed the similar allosteric effect on the sigma-1 receptor in the liver tissue but not in the brain tissue. Moreover, all three tested chemicals elicited no significant effect on 3 H-1,3-di(2-tolyl)-guanidine ( 3 H-DTG) binding to the sigma-2 receptor. The present data uncovered a new role of SKF83959 and its analogs on the sigma-1 receptor, which, in turn, may reveal the underlying mechanism for the D 1 receptor-independent effect of the drug.

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Section: Introductionmentioning

confidence: 99%

SKF83959 Is a Potent Allosteric Modulator of Sigma-1 Receptor

et al. 2013

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“…This may have clinical implications, especially for subgroups of depressed patients with low circulating steroid levels, such as the elderly. [203,204] …”

Section: Sigma Receptorsmentioning

confidence: 98%

Neuropeptide and Sigma Receptors as Novel Therapeutic Targets for the Pharmacotherapy of Depression

2009

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Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacological observations led to the development of the monoamine theory as a biological basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine) and serotonin systems, is the leading cause of the disorder. Current conventional pharmacological antidepressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects and high frequencies of non-responding patients. Neuroendocrinological data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the aetiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacological and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression.

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“…Although no specific receptors in the plasma membrane, nucleus or cytoplasm for DHEA have been clearly found, this steroid could act through several mechanisms to exert its functions [16]. In neurons, the prosurvival effect of DHEA(S) appears to be NMDA- [17]; GABAA- [11,18] and sigma1-dependent [10,19]. It has also been described a DHEA antiapoptotic effect mediated by G-protein-coupled-specific membrane binding sites in neurons [20,21].…”

Section: Introductionmentioning

confidence: 95%

Dehydroepiandrosterone effects on Akt signaling modulation in central nervous system of young and aged healthy rats

Janner

Jacob

Jahn

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

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Dehydroepiandrosterone (DHEA) is a steroid synthesized in adrenal cortex as well as in the nervous system. DHEA effects on central nervous system (CNS) have been associated with several brain functions such as marked neurotrophic and neuroprotective activity. DHEA plasma concentration decreases steadily with aging and studies have reported an inverse correlation between levels of DHEA and neurological diseases age-associated. Nonetheless, its mechanisms of action are not yet fully understood. Akt signaling pathway is one protein kinase which has been related to be DHEA modulated. The goal of this study was to investigate whether short-term (6 or 24h) or chronic (5 weeks) DHEA treatment modulates Akt in CNS of adult (3 months) and aged (18 and 24 months) healthy rats. Hypothalamus and hippocampus homogenates were prepared to quantify total-Akt and phosphorylated Akt at Ser(473) (pAkt). The results here presented have shown that acute (50mg/kg) and chronic (10mg/kg) DHEA injections modulate total and pAkt levels. This effect was dose and time-dependent as well as age and tissue-dependent. In addition, the age variable also intervenes on total and pAkt levels expression independently of DHEA treatment.

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Neurosteroid dehydroepiandrosterone sulphate inhibits persistent sodium currents in rat medial prefrontal cortex via activation of sigma-1 receptors

Cited by 61 publications

References 36 publications

SKF83959 Is a Potent Allosteric Modulator of Sigma-1 Receptor

SKF83959 Is a Potent Allosteric Modulator of Sigma-1 Receptor

Neuropeptide and Sigma Receptors as Novel Therapeutic Targets for the Pharmacotherapy of Depression

Dehydroepiandrosterone effects on Akt signaling modulation in central nervous system of young and aged healthy rats

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