Table 1.

Summary of selected neuroprotective effects of sigma ligands on disease model systems. METH, methamphetamine. MCAO, middle cerebral artery occlusion. PPBP, 4-phenyl-1-(4-phenylbutyl) piperidine.

Disease	Model	Sigma ligand	Subtype specificity	Major outcome	Reference
Amyotrophic lateral sclerosis	In vivo SOD1G93A mouse model	PRE-084	Sigma-1	Chronic treatment improves survival, and the function and preservation of spinal motor neurons Modulates NMDA receptor function and reduces microglial reactivity	(Mancuso et al., 2012)
Alzheimer's disease	In vitro Aβ25-35-induced toxicity in primary microglia culture	Afobazole	Nonselective	Decreases microglial activation and cell death Reduces expression of Bax and caspase-3 Increases expression of Bcl-2 Blocks increases in intracellular calcium and RNS production	(Behensky et al., 2013a, b)
	In vivo Aβ25-35-induced toxicity mouse model	PRE-084, Donepezil	Sigma-1	Single treatment before behavioral tests shows anti-amnesic effects in spontaneous alternation performance in the Y-maze and step-through passive avoidance procedure Single pretreatment or chronic post-treatment blocks lipid peroxidation in the hippocampus and learning deficits in the step-through passive avoidance procedure	(Meunier et al., 2006)
Huntington's disease	In vitro PC6-3 cell model transfected with mutant huntingtin proteins	PRE-084	Sigma-1	Increases cellular antioxidants and reduces ROS/RNS production Counteracts the down regulation of NF-κB pathway and decrease in calpastatin level	(Hyrskyluoto et al., 2013)
METH neurotoxicity	In vitro Differentiated NG108-15 cell model	SN79	Nonselective	Attenuates ROS/RNS production and activation of caspases Attenuates cell death at normal (37°C) and elevated (40°C) cell culture temperature	(Kaushal et al., 2014)
	In vivo Repeated METH dosing mouse model	SN79	Nonselective	Pretreatment reduces striatal terminal damage and hyperthermia Pretreatment blocks striatal reactive astrogliosis through mitigation of OSMR/gp130 signaling and STAT3 phosphorylation Post-treatment restores striatal dopamine levels by 25%	(Kaushal et al., 2013; Robson et al., 2014)
Parkinson's disease	In vivo 6-hydroxydopamine mouse lesion model	PRE-084	Sigma-1	Chronic treatment improves motor function and density of dopaminergic fibers Reduces microglial activation and increases neurotropic factors and the activation of ERK1/2 and Akt	(Francardo et al., 2014)
Retinal degeneration	In vitro Glutamate-induced cell death in retinal ganglion cells (RGCs)	(+)-SKF10047	Sigma-1	Mitigates intracellular calcium overload and cell death Decreases Bax expression and caspase-3 activation	(Tchedre and Yorio, 2008)
	H2O2-induced toxicity in human lens epithelial cells (FHL124) and human whole lenses	(+)-Pentazocine	Sigma-1	Reduces cell death, cleavage of pro-caspase 12, and induction of BiP and eLF2α in FHL124 cells Reduces cell death, LDH release and opacification in whole lenses	(Wang et al., 2012)
	In vivo Ins2Akita/+ mouse model of spontaneous arising diabetic retinopathy	(+)-Pentazocine	Sigma-1	Chronic treatment at onset of diabetes preserves retinal architecture and maintains uniform organization of radial Müller fibers Reduces cell death and ROS/RNS generation	(Smith et al., 2008)
Stroke	In vitro Ischemic model of primary rat cortical neurons	DTG	Nonselective	Blocks intracellular Ca2+ overload induced by sodium azide and glucose deprivation	(Katnik et al., 2006)
		Carbetapentane, PRE-084, (+)-Pentazocine	Sigma-1
	In vivo Rat stoke model; Permanent MCAO	DTG	Nonselective	Treatment 24h post-MCAO decreases infarct size, neurodegeneration and inflammation	(Ajmo et al., 2006)
	Mouse stroke model; Transient MCAO	(+)-Pentazocine	Sigma-1	Treatment before reperfusion reduces infarct size throug hinhibition of inducible NOS	(Vagnerova et al., 2006)
	Piglet model of neonatal hypoxic-ischemia	PPBP	Nonselective	Treatment post resuscitation reduces striatal neuronal damage and ROS/RNS stress Modulates neuronal NOS/postsynaptic density-95 coupling	(Yang et al., 2010)