Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo

Kaushal, Nidhi; Seminerio, Michael J.; Robson, Matthew J.; McCurdy, Christopher R.; Matsumoto, Rae R.

doi:10.1016/j.euroneuro.2012.08.005

Cited by 23 publications

(33 citation statements)

References 33 publications

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“…2. K i values were determined to be $10 mM at sigma-1 and 14.6 6 6.9 nM at sigma-2, demonstrating a $700-fold selectivity of the ligand for sigma-2 over sigma-1, compared with a ∼4-fold selectivity for SN79 (K i 5 7 nM and 27 nM at sigma-2 and sigma-1, respectively) (Kaushal et al, 2013). The increase in selectivity compared with the Affinity of CM572 at sigma-1 and sigma-2 receptors.…”

Section: Resultsmentioning

confidence: 99%

“…Despite these advances in classifying sigma-2 agonists, little has been reported on the direct characterization of antagonists in these assays, that is, direct demonstration that the activity of putative agonists can be attenuated by other sigma-2 ligands that do not exert an effect. The moderately sigma-2-selective ligand SN79 [6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one] has been characterized as an antagonist of sigma-1/sigma-2 receptors (Kaushal et al, 2011(Kaushal et al, , 2013. SN79 protects against neurotoxicity induced by high doses of methamphetamine, which binds to sigma receptors, whereas the sigma receptor agonist 1,3-di-o-tolylguanidine (DTG) enhanced the neurotoxic effect.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of CM572, a Selective Irreversible Partial Agonist of the Sigma-2 Receptor with Antitumor Activity

Nicholson

Comeau

Mésangeau

et al. 2015

J Pharmacol Exp Ther

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The sigma-2 receptors are promising therapeutic targets because of their significant upregulation in tumor cells compared with normal tissue. Here, we characterize CM572 [3-(4-(4-(4-14.6 6 6.9 nM), a novel isothiocyanate derivative of the putative sigma-2 antagonist, SN79 [6-acetyl-3-(4-(4-(4-CM572 bound irreversibly to sigma-2 receptors by virtue of the isothiocyanate moiety but not to sigma-1. Studies in human SK-N-SH neuroblastoma cells revealed that CM572 induced an immediate dose-dependent increase in cytosolic calcium concentration. A 24-hour treatment of SK-N-SH cells with CM572 induced dose-dependent cell death, with an EC 50 5 7.6 6 1.7 mM. This effect was sustained over 24 hours even after a 60-minute pretreatment with CM572, followed by extensive washing to remove ligand, indicating an irreversible effect consistent with the irreversible binding data. Western blot analysis revealed that CM572 also induced cleavage activation of proapoptotic BH3-interacting domain death agonist. These data suggest irreversible agonist-like activity. Low concentrations of CM572 that were minimally effective were able to attenuate significantly the calcium signal and cell death induced by the sigma-2 agonist CB-64D [(1)-1R,5R-(E)-8-benzylidene-5-(3-hydroxyphenyl)-2-methylmorphan-7-one]. CM572 was also cytotoxic against PANC-1 pancreatic and MCF-7 breast cancer cell lines. The cytotoxic activity of CM572 was selective for cancer cells over normal cells, being much less potent against primary human melanocytes and human mammary epithelial cells. Taken together, these data show that CM572 is a selective, irreversible sigma-2 receptor partial agonist. This novel irreversible ligand may further our understanding of the endogenous role of this receptor, in addition to having potential use in targeted cancer diagnosis and therapy.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of CM572, a Selective Irreversible Partial Agonist of the Sigma-2 Receptor with Antitumor Activity

Nicholson

Comeau

Mésangeau

et al. 2015

J Pharmacol Exp Ther

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“…as a pretreatment 15 min prior to the second compound in each treatment group (Saline or METH, i.p.). Each animal underwent four pretreatments/treatments at 2 h apart as previously described (Kaushal et al 2013). …”

Section: Methodsmentioning

confidence: 99%

“…There are currently two known subtypes of sigma receptors (Hellewell and Bowen 1990). METH interacts with both subtypes of sigma receptors, denoted sigma-1 and sigma-2 receptors, at physiologically relevant concentrations and sigma receptor antagonists have been shown to mitigate the neurotoxic effects of METH on dopaminergic and serotonergic systems within the CNS (Kaushal et al 2013; Matsumoto et al 2008; Nguyen et al 2005). Sigma receptors are expressed in astrocytes and sigma receptor modulation has been shown to modulate the activity of astrocytes both in vitro and in vivo (Ajmo et al 2006; Klouz et al 2003); however whether sigma receptor modulation alters METH-induced astrocyte activation has yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation

Robson

Turner

Naser

et al. 2014

Experimental Neurology

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Methamphetamine (METH) exposure results in dopaminergic neurotoxicity in striatal regions of the brain, an effect that has been linked to an increased risk of Parkinson's disease. Various aspects of neuroinflammation, including astrogliosis, are believed to be contributory factors in METH neurotoxicity. METH interacts with sigma receptors at physiologically relevant concentrations and treatment with sigma receptor antagonists has been shown to mitigate METH-induced neurotoxicity in rodent models. Whether these compounds alter the responses of glial cells within the central nervous system to METH however has yet to be determined. Therefore, the purpose of the current study was to determine whether the sigma receptor antagonist, SN79, mitigates METH-induced striatal reactive astrogliosis. Male, Swiss Webster mice treated with a neurotoxic regimen of METH exhibited time-dependent increases in striatal gfap mRNA and concomitant increases in GFAP protein, indicative of astrogliosis. This is the first report that similar to other neurotoxicants that induce astrogliosis through the activation of JAK2/STAT3 signaling by stimulating gp-130-linked cytokine signaling resulting from neuroinflammation, METH treatment also increases astrocytic oncostatin m receptor (OSMR) expression and the phosphorylation of STAT3 (Tyr-705) in vivo. Pretreatment with SN79 blocked METH-induced increases in OSMR, STAT3 phosphorylation and astrocyte activation within the striatum. Additionally, METH treatment resulted in striatal cellular degeneration as measured by Fluoro-Jade B, an effect that was mitigated by SN79. The current study provides evidence that sigma receptor antagonists attenuate METH-induced astrocyte activation through a pathway believed to be shared by various neurotoxicants.

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“…In addition, there are also sigma-2 ligands that produce a calcium signal, but do not have the ability to kill cells. The sigma-2 receptor ligand, SN79 [6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl) butyl)benzo [d]oxazol-2(3H)-one] (Kaushal et al, 2011(Kaushal et al, , 2012 produces a small calcium signal in SK-N-SH neuroblastoma cells, but is unable to induce significant levels of cytotoxicity even at high doses (Garcia 2012). Based on such data we have proposed that the sigma-2 receptor may signal to pathways that bifurcate to those that result in apoptotic cell death and those that result in as yet uncharacterized nonapoptotic effects (Garcia and Bowen, 2010;Garcia 2012).…”

Section: Introductionmentioning

confidence: 99%

Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma

Nicholson

Mésangeau

McCurdy

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Sigma-2 receptors are attractive antineoplastic targets due to their ability to induce apoptosis and their upregulation in rapidly proliferating cancer cells compared with healthy tissue. However, this role is inconsistent with overexpression in cancer, which is typically associated with upregulation of prosurvival factors. Here, we report a novel metabolic regulatory function for sigma-2 receptors. CM764 [6-acetyl-3-(4-(4-(2-amino-4-fluorophenyl)piperazin-1-yl)butyl)benzo[d ]oxazol-2 (3H)-one] binds with K i values of 86.6 6 2.8 and 3.5 6 0.9 nM at the sigma-1 and sigma-2 receptors, respectively. CM764 increased reduction of MTT [3-[4,5 dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide] in human SK-N-SH neuroblastoma compared with untreated cells, an effect not due to proliferation. This effect was attenuated by five different sigma antagonists, including CM572 [3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-6-isothiocyanatobenzo[d]oxazol-2(3H)-one], which has no significant affinity for sigma-1 receptors. This effect was also observed in MG-63 osteosarcoma and HEK293T cells, indicating that this function is not exclusive to neuroblastoma or to cancer cells. CM764 produced an immediate, robust, and transient increase in cytosolic calcium, consistent with sigma-2 receptor activation. Additionally, we observed an increase in the total NAD 1 /NADH level and the ATP level in CM764-treated SK-N-SH cells compared with untreated cells. After only 4 hours of treatment, basal levels of reactive oxygen species were reduced by 90% in cells treated with CM764 over untreated cells, and HIF1a and VEGF levels were increased after 3-24 hours of treatment. These data indicate that sigma-2 receptors may play a role in induction of glycolysis, representing a possible prosurvival function for the sigma-2 receptor that is consistent with its upregulation in cancer cells compared with healthy tissue.

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Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo

Cited by 23 publications

References 33 publications

Characterization of CM572, a Selective Irreversible Partial Agonist of the Sigma-2 Receptor with Antitumor Activity

Characterization of CM572, a Selective Irreversible Partial Agonist of the Sigma-2 Receptor with Antitumor Activity

SN79, a sigma receptor antagonist, attenuates methamphetamine-induced astrogliosis through a blockade of OSMR/gp130 signaling and STAT3 phosphorylation

Sigma-2 Receptors Play a Role in Cellular Metabolism: Stimulation of Glycolytic Hallmarks by CM764 in Human SK-N-SH Neuroblastoma

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