Inhibition of sigma-1 receptor reduces N-methyl-d-aspartate induced neuronal injury in methamphetamine-exposed and -naive hippocampi

Abstract

Acute and prolonged methamphetamine (METH) exposure has been reported to moderate the function of N-methyl-D-aspartate type glutamate receptors (NMDAr) in the hippocampus. These effects have been found to be associated with enhanced NMDAr-dependent release of Ca 2+ from IP 3 -sensitive intracellular stores. The present studies were designed to extend these findings and examine the role of the endoplasmic membrane (ER) bound orphan receptor, the sigma 1 receptor, in NMDA-induced neuronal injury and METH withdrawal-potentiated NMDA-induced neuronal injury. Organotypic hippocampal slice cultures were exposed to METH (0 or 100 µM) for 6 days and withdrawn for 7 days, then exposed to NMDA (0 or 5 µM) for 24 hrs. Additional cultures were also exposed to this regimen and were co-incubated with BD1047 (100 µM), a specific inhibitor of ER-bound sigma 1 receptors, for the 24 hr NMDA exposure. Cytotoxicity was assessed by analysis of propidium iodide uptake. These studies demonstrated that protracted METH exposure and withdrawal significantly potentiated the neuronal injury produced by NMDA exposure. Further, co-exposure to BD1047 with NMDA markedly attenuated neuronal injury in METH-naïve and METH-withdrawn organotypic cultures. As a whole, these data demonstrate that prolonged METH exposure, even at non-toxic concentrations, significantly alters glutamate receptor signaling. Inhibition of sigma 1 receptor-dependent Ca 2+ release from the ER entirely prevented NMDA-induced toxicity in METH-naïve cultures and markedly reduced METHpotentiated toxicity. These findings demonstrate the importance of Ca 2+ -induced intracellular Ca 2+ release in excitotoxic insult and suggest that blockade of glutamatergic overactivity may represent a therapeutic target in the treatment of METH withdrawal.

SN79, a sigma receptor ligand, blocks methamphetamine-induced microglial activation and cytokine upregulation

“…Sigma receptors themselves and ligands targeting sigma receptors, including SN79, are known to modulate molecular signaling related to cellular toxicity, including those hypothesized to be involved in METH neurotoxicity (Hayashi and Su, 2007; Kaushal et al, 2012a; Kaushal et al, 2011a; Kaushal et al, 2012b; Mori et al, 2012; Smith et al, 2010). Therefore, it is plausible that the combination of alterations in cellular signaling related to METH-induced neurotoxicity and the mitigation of METH-induced increases in core body temperature contribute to the ability of SN79 to convey protective effects against METH in vivo.…”

Neuroimmune Basis of Methamphetamine Toxicity

“…Calcium release has been implicated in the mechanism of action of glutamate and methamphetamine neurotoxicity: NMDA + methamphetamine-induced neurotoxicity could be reduced by exposure of hippocampal slices in culture to the endoplasmic reticulum-bound sigma-1 receptor antagonist BD1047 which is coupled to calcium-mediated signal cascades (Smith, Butler, & Prendergast, 2010). Thus, evidence suggests both direct and indirect roles for glutamate receptors in methamphetamine-induced neurotoxic events.…”

Protective role of neuropeptide Y Y2 receptors in cell death and microglial response following methamphetamine injury

“…, 2009; Yamamoto et al. , 2010) and release of high levels of glutamate resulting in excitotoxicity (Smith et al. , 2010).…”