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.
PRE-084 hydrochloride是一种高选择性sigma-1受体（S1R）激动剂，IC50值为44nM[1]。PRE-084 hydrochloride在多种神经退行性疾病和神经炎症模型中展现出广泛的神经保护和抗炎作用，如帕金森病和肌萎缩侧索硬化症[3][4][5]。
在体外实验中，PRE-084 hydrochloride（10µM）处理CFA诱导的大鼠背根神经节（DRG）神经元30min，可降低快钠电流，进而减少动作电位（AP）峰值和最大去极化速率（MDR），并提高基强度[2]。将PRE-084 hydrochloride（0.1–20µM）与β-淀粉样蛋白片段25–35（25µM）共处理大鼠皮层神经元培养物24h，PRE-084 hydrochloride以钟形剂量依赖方式降低神经元毒性，在10µM时神经保护作用最强，并阻断β-淀粉样蛋白诱导的促凋亡蛋白Bax升高[3]。当BV-2细胞以20 MOI的S.pneumoniae刺激6h时，PRE-084 hydrochloride（2.5μg/mL）通过降低磷酸化STAT1（p-STAT1）和NLRP3的表达发挥抗炎作用[4]。
在体内实验中，PRE-084 hydrochloride（0.25µg/g）于第4至第12周龄期间每周三次腹腔注射给予自发性运动神经元退化的wobbler（wr）小鼠模型。PRE-084 hydrochloride治疗增加了存活运动神经元数量，提高颈髓BDNF水平，同时减轻反应性星形胶质细胞增生，并使小胶质细胞/巨噬细胞向CD68⁺和CD206⁺组织修复表型转变[5]。PRE-084 hydrochloride（3mg/kg）每日一次腹腔注射给予链脲佐菌素诱导的糖尿病大鼠，持续一周，可增强血管收缩剂和血小板聚集剂，并减少血管舒张剂和抗聚集剂环氧化酶产物的形成[6]。PRE-084 hydrochloride（1mg/kg）于手术前1h腹腔注射给予心肌缺血/再灌注模型大鼠，PRE-084 hydrochloride通过激活Akt和eNOS保留心脏功能并减少心肌细胞凋亡[7]。