Neuroprotective effects of high affinity sigma 1 receptor selective compounds

Abstract

We previously reported that the antipsychotic drug haloperidol, a multifunctional D2-like dopamine and sigma receptor subtype antagonist, has neuroprotective properties. In this study we further examined the association between neuroprotection and receptor antagonism by evaluating a panel of novel compounds with varying affinity at sigma and D2-like dopamine receptors. These compounds were evaluated using an in vitro cytotoxicity assay that utilizes a hippocampal-derived cell line, HT-22, in the presence or absence of varying concentrations (5 to 20 mM) of glutamate. While haloperidol was found to be a potent neuroprotective agent in this in vitro cell assay, the prototypic sigma 1 receptor agonist (+)-pentazocine was found not to be neuroprotective. Subsequently, the potency for the neuroprotection of HT-22 cells was evaluated for a) three SV series indoles which have nMolar affinity at D2-like receptors but varying affinity at sigma 1 receptor and b) two benzyl phenylacetamides sigma 1 receptor selective compounds which bind with low affinity at D2-like receptors but have nMolar affinity for the sigma 1 receptor. We observed that cytoprotection correlated with the affinity of the compounds for sigma 1 receptors. Based upon results from the HT-22 cell-based in vitro assay, two phenylacetamides, LS-127 and LS-137, were further evaluated in vivo using a transient middle cerebral artery occlusion (t-MCAO) model of stroke. At a dose of 100 µg/kg, both LS-127 and LS-137 attenuated infarct volume by approximately 50%. These studies provide further evidence that sigma 1 receptor selective compounds can provide neuroprotection in cytotoxic situations. These results also demonstrate that sigma 1 receptor selective benzyl phenylacetamides are candidate pharmacotherapeutic agents that could be used to minimize neuronal death after a stroke or head trauma.

The effects of sigma (σ1) receptor‐selective ligands on muscarinic receptor antagonist‐induced cognitive deficits in mice

“…σ1 receptor activation also modulates Ca 2+ signalling at the ER, regulates IP3 receptor activity and modulates neurotransmitter release (Su and Hayashi, 2003;Hayashi and Su, 2005). The σ1 receptor has also been postulated to regulate ER stress, cellular redox, cellular survival and synaptogenesis (Hayashi and Su, 2007;Fujimoto et al, 2012).In addition to our studies demonstrating LS-1-137 neuroprotective properties in a rat transient middle cerebral artery occlusion stroke model (Luedtke et al, 2012), there have been a number of studies suggesting that σ1 receptor activation can lead to neuroprotection. Antonini et al (2009; demonstrated that occupation of the rat σ1 receptor by PPCC and (-)-MR22 can prevent cognitive impairment caused by the combined administration of the muscarinic receptor antagonist atropine and immunotoxin 192 IgG-saporin, which leads to a loss of cholinergic neurons in the basal forebrain.…”

“…The σ1-selective test drug, LS-1-137, was synthesized by the NIMH Chemical Synthesis and Drug Supply Program as described previously Luedtke et al, 2012). Scopolamine hydrobromide was purchased from Sigma-Aldrich (St. Louis, MO, USA).…”

“…The phenylacetamide LS-1-137 binds with high affinity at σ1 receptors (Ki value = 3.2 nM), 80-fold σ1 versus σ2 receptorbinding selectivity and low affinity at the D2-like (D2, D3 and D4) dopamine receptor subtypes (Ki values >500 nM; Luedtke et al, 2012).…”

“…LS-1-137 was found to protect HT-22 neuronal cells from glutamate-induced cell death and LS-1-137 was found in vivo to significantly reduce the ischaemic lesion volume in rats using a transient middle cerebral artery occlusion model of stroke (Luedtke et al, 2012). In this communication, we continue to characterize LS-1-137 by examining its (i) intrinsic efficacy in vitro, (ii) ability to moderate scopolamine-dependent cognitive deficits in C57BL/6J mice and (iii) potency to release brain-derived neurotrophic factor (BDNF) from rat astrocytes.…”

“…This modulation of NMDA receptor function might occur directly or via an interaction with σ1 receptors (Nishikawa et al, 2000;Kume et al, 2002;Martina et al, 2007). To examine whether an indirect or a direct modulation of NMDA receptors might contribute to our observed in vivo effects of LS-1-137 on cognitive function presented here or the neuroprotective effects we reported previously (Luedtke et al, 2012), we assessed the effect of LS-1-137 on NMDA responses recorded from HEK 293 cells transiently expressing rat recombinant GluN1NR2A receptors. GluN1NR2A receptors were selected for these studies because they are predominantly expressed at synaptic sites in mature neurons and are involved in long-term potentiation (Tovar and Westbrook, 2002;Massey et al, 2004) and ischaemic brain damage (Liu et al, 2007).…”