PRE-084 hydrochloride is a highly selective sigma-1 receptor (S1R) agonist with an IC50 value of 44nM[1]. PRE-084 hydrochloride has demonstrated broad neuroprotective and anti-inflammatory effects across multiple models of neurodegeneration and neuroinflammation such as Parkinson’s disease and amyotrophic lateral sclerosis[3][4][5].
In vitro, PRE-084 hydrochloride (10µM) treatment on dorsal root ganglia (DRG) neurons isolated from CFA-treated rats for 30min led to a decrease in the fast sodium current, which was associated with a diminished action potential (AP) peak and maximum depolarizing rate (MDR), as well as an increased rheobase[2]. PRE-084 hydrochloride (0.1–20µM) and β-amyloid fragment 25–35 (25µM) were co-applied to rat cortical neuronal cultures for 24h. PRE-084 hydrochloride reduced neuronal toxicity in a bell shaped-manner with maximally neuroprotective effect at 10µM and blocked the β-amyloid-induced rise in the pro-apoptotic protein Bax[3]. PRE-084 hydrochloride (2.5μg/mL) applied on BV-2 cells when cells challenged with S. pneumoniae at 20 MOI for 6h exerted anti-inflammatory effect by reducing the expression of phosphorylated STAT1 (p-STAT1) and NLRP3[4].
In vivo, PRE-084 hydrochloride (0.25µg/g) was administered intraperitoneally into the wobbler (wr) mouse model of spontaneous motor-neuron degeneration three times per week from the 4th to the 12th week of age. PRE-084 hydrochloride treatment increased the number of surviving motor neurons, raised cervical spinal-cord BDNF levels, while attenuating reactive astrogliosis and shifting microglia/macrophages toward a CD68⁺ and CD206⁺ tissue-repair phenotype in wr mice[5]. PRE-084 hydrochloride (3mg/kg) administrated intraperitoneally into streptozotocin induced diabetic rats once a day for a week enhanced vasoconstrictor and platelet aggregator and reduced vasodilator and anti-aggregator cyclooxygenase product formation[6]. PRE-084 hydrochloride (1mg/kg) were administered into myocardial ischemia/reperfusion model rats 1h before operation. PRE-084 hydrochloride preserved cardiac function and reduced myocardial apoptosis through the activation of Akt and eNOS[7].
References:
[1] Su T P, Wu X Z, Cone E J, et al. Sigma compounds derived from phencyclidine: identification of PRE-084, a new, selective sigma ligand. J Pharmacol Exp Ther. 1991 Nov;259(2):543-50.
[2] Song Y L, Xu Z F, Zhang L P, et al. Sigma-1 Receptor Modulates CFA-Induced Inflammatory Pain via Sodium Channels in Small DRG Neurons. Biomolecules. 2025 Jan 6;15(1):73.
[3] Marrazzo A, Caraci F, Salinaro E T, et al. Neuroprotective effects of sigma-1 receptor agonists against beta-amyloid-induced toxicity. Neuroreport. 2005 Aug 1;16(11):1223-6.
[4] Gao Z F, Xie S, Wang L Y, et al. Hypidone hydrochloride (YL-0919) protects mice from meningitis via Sigma1R-STAT1-NLRP3-GSDMD pathway. Int Immunopharmaco. 2024 Feb 15:128:111524.
[5] Peviani M, Salvaneschi E, Bontempi L, et al. Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation. Neurobiol Dis. 2014 Feb:62:218-32.
[6] Váczi S, Barna L, Laczi K, et al. Effects of sub-chronic, in vivo administration of sigma-1 receptor ligands on platelet and aortic arachidonate cascade in streptozotocin-induced diabetic rats. PLoS One. 2022 Nov 17;17(11):e0265854.
[7] Gao Q J, Yang B, Chen J, et al. Sigma-1 Receptor Stimulation with PRE-084 Ameliorates Myocardial Ischemia-Reperfusion Injury in Rats. Chin Med J (Engl). 2018 Mar 5;131(5):539-543.