Background
Cutamesine (SA4503) is a potent and selective agonist for the sigma 1 receptor subtype in the brain. Cutamesine (SA4503) inhibited specific (+)-[3H]pentazocine binding in a competitive manner(IC50 = 17.4 +/- 1.9 nM) in guinea pig meninges[1，4].
Cutamesine (SA4503) prevents cultured cortical neurons from cell death caused by H2O2 application. The survival effect by Cutamesine (SA4503) reached a plateau at 0.1 μM[3]. Cutamesine(SA4503) reduces the activation of the MAPK/ERK pathway and down-regulated the ionotropic glutamate receptor, GluR1[2]. Cutamesine(SA4503) protects motor neuron NSC34 cells against superoxide dismutase 1 and serum free neurotoxicity. It upregulates the phosphorylation levels of Akt and extracellular signal-regulated kinase (ERK) 1/2 [2].
Cutamesine (SA4503) extended the survival time, but it did not delay the disease onset in the SOD1G93A mice. The extended survival time in the Cutamesine (SA4503) group may be associated with the suppression of the progression of motor neuron damage by the upregulation of phosphorylated Akt and ERK1/2. From these results, Cutamesine (SA4503) may have the protective effect against FALS, because SOD1G93A mice are model of FALS [2]. When examined the effects of Cutamesine (SA4503) on the cholinergic dysfunction-induced memory impairments in a passive avoidance task. Single administration of Cutamesine (SA4503) significantly reduced the scopolamine-induced memory impairment [5]. Cutamesine (SA4503) produced a significant decrease and rise in the number of spontaneously active SNC and VTA DA neurons in rats. Cutamesine (SA4503) produced a significant increase in the number of spontaneously active VTA DA neurons relative to SNC DA neurons Repeated administration of Cutamesine (SA4503) produced a greater change in the firing pattern of spontaneously active VTA[6]. Repeated treatment with Cutamesine (SA4503) (0.3 mg/kg) improved the behavior disorder similar to depressive symptoms in rats in olfactory bulb resection group. Cutamesine (SA4503) also reversed the reduction of NMDA receptor subunit (NR)1 protein expression in the prefrontal cortex, hippocampus, and amygdala of olfactory bulbectomy rats, but did not affect NR2A or NR2B[7].
参考文献:
[1]: Lever JR, Gustafson JL, et,al. Sigma1 and sigma2 receptor binding affinity and selectivity of SA4503 and fluoroethyl SA4503. Synapse. 2006 May;59(6):350-8. doi: 10.1002/syn.20253. PMID: 16463398.
[2]: Ono Y, Tana19996ka H, et,al. SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models. Neurosci Lett. 2014 Jan 24;559:174-8. doi: 10.1016/j.neulet.2013.12.005. Epub 2013 Dec 12. PMID: 24334165.
[3]: Tuerxun T, Numakawa T, et,al. SA4503, a sigma-1 receptor agonist, prevents cultured cortical neurons from oxidative stress-induced cell death via suppression of MAPK pathway activation and glutamate receptor expression. Neurosci Lett. 2010 Jan 29;469(3):303-8. doi: 10.1016/j.neulet.2009.12.013. Epub 2009 Dec 16. PMID: 20025928.
[4]: Matsuno K, Nakazawa M, et,al.Binding properties of SA4503, a novel and selective sigma 1 receptor agonist. Eur J Pharmacol. 1996 Jun 13;306(1-3):271-9. doi: 10.1016/0014-2999(96)00201-4. PMID: 8813641.
[5]: Senda T, Matsuno K, et,al. Ameliorating effect of SA4503, a novel sigma 1 receptor agonist, on memory impairments induced by cholinergic dysfunction in rats. Eur J Pharmacol. 1996 Nov 7;315(1):1-10. doi: 10.1016/s0014-2999(96)00572-9. PMID: 8960858.
[6]: Minabe Y, Matsuno K, et,al. Acute and chronic administration of the selective sigma1 receptor agonist SA4503 significantly alters the activity of midbrain dopamine neurons in rats: An in vivo electrophysiological study. Synapse. 1999 Aug;33(2):129-40. doi: 10.1002/(SICI)1098-2396(199908)33:23.0.CO;2-E. PMID: 10400891.
[7]: Wang D, Noda Y, et,al. Role of N-methyl-D-aspartate receptors in antidepressant-like effects of sigma 1 receptor agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA-4503) in olfactory bulbectomized rats. J Pharmacol Exp Ther. 2007 Sep;322(3):1305-14. doi: 10.1124/jpet.107.124685. Epub 2007 Jun 7. PMID: 17556637.
Cutamesine (SA4503) 是大脑中 sigma 1 受体亚型的有效选择性激动剂。 Cutamesine (SA4503) 在豚鼠脑膜中以竞争性方式抑制特异性 (+)-[3H]pentazocine 结合 (IC50 = 17.4 +/- 1.9 nM)[1，4]< /sup>.
Cutamesine (SA4503) 可防止培养的皮层神经元因 H2O2 应用而导致细胞死亡。 Cutamesine (SA4503) 的存活效应在 0.1 μM[3] 时达到稳定水平。 Cutamesine(SA4503) 可降低 MAPK/ERK 通路的激活并下调离子型谷氨酸受体 GluR1[2]。 Cutamesine (SA4503) 保护运动神经元 NSC34 细胞免受超氧化物歧化酶 1 和无血清神经毒性。它上调Akt和细胞外信号调节激酶（ERK）1/2的磷酸化水平[2]。
Cutamesine (SA4503) 延长了 SOD1G93A 小鼠的存活时间，但并未延迟疾病发作。 Cutamesine (SA4503) 组的延长生存时间可能与通过上调磷酸化 Akt 和 ERK1/2 抑制运动神经元损伤的进展有关。从这些结果来看，Cutamesine (SA4503) 可能对 FALS 具有保护作用，因为 SOD1G93A 小鼠是 FALS 的模型[2]。当检查 Cutamesine (SA4503) 对被动回避任务中胆碱能功能障碍引起的记忆障碍的影响时。单次服用 Cutamesine (SA4503) 可显着降低东莨菪碱诱导的记忆障碍[5]。 Cutamesine (SA4503) 使大鼠自发活跃的 SNC 和 VTA DA 神经元数量显着减少和增加。相对于 SNC DA 神经元，Cutamesine (SA4503) 显着增加了自发活跃的 VTA DA 神经元的数量重复给予 Cutamesine (SA4503) 在自发活跃的 VTA 放电模式中产生了更大的变化[6]。 Cutamesine (SA4503) (0.3 mg/kg)重复治疗改善了嗅球切除组大鼠类似抑郁症状的行为障碍。 Cutamesine (SA4503) 还可以逆转嗅球切除术大鼠前额皮质、海马和杏仁核中 NMDA 受体亚基 (NR)1 蛋白表达的减少，但不影响 NR2A 或 NR2B[7]。
Protocol
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| Kinase experiment [1]: |
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Preparation Method
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Cutamesine (SA4503) Binding affinities to sigma-1，2 receptor subtypes were assessed with 5 nM (+)-[3H]pentazocine or 5 nM [3H]DTG with 200 nM (+)-[3H]pentazocine. Incubations in the (+)-[3H]pentazocine and [3H]DTG binding studies were carried out at 37°C for 150 min or at 25°C for 90 min.
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Reaction Conditions
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10-12M-10-3M Cutamesine (SA4503) at 37°C for 150 min or at 25°C for 90 min.
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Applications
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Competition binding experiments showed that Cutamesine (SA4503) had a high affinity for (+)-[Hlpentazocine binding sites in guinea pig brain membranes . The IC50 value of this compound for the sigma-1 receptor subtype was 17.4 + 1.9 nM. Cutamesine (SA4503) had a low affinity for the sigma-2 receptor subtype, with an IC50 value of1784.1 + 314.4 nM. The inhibitory potency of Cutamesine (SA4503) for the sigma-1 receptor subtype was about 100 times higher than that for the sigma-2 receptor subtype.
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| Cell experiment [2]: |
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Cell lines
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Cultured cortical neurons( DIV4)
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Preparation Method
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Dissociated cortical neurons were cultured for 4 or 5 days before Cutamesine (SA4503) was applied. Twenty-four hours after Cutamesine (SA4503) addition, H202 was applied for 12 h. Then, the cell viability was analyzed.
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Applications
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Cutamesine (SA4503) prevents cultured cortical neurons from cell death caused by H2O2 application. The survival effect by Cutamesine (SA4503) reached a plateau at 0.1 μM.
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| Animal experiment [3]: |
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Animal models
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Transgenic G93A [B6SJL-Tg (SOD1-G93A) 1Gur/J] mice
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Preparation Method
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Cutamesine (SA4503) was dissolved in saline and subcutaneously administered at a dose of 1 mg/kg once daily to 5-week-old mice to the time of death
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Dosage form
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1 mg/kg Cutamesine (SA4503) once a day
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Applications
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Cutamesine (SA4503) prolonged the survival of SOD1 G93A mice
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参考文献:
[1]. Matsuno K, Nakazawa M, et,al. Binding properties of SA4503, a novel and selective sigma 1 receptor agonist. Eur J Pharmacol. 1996 Jun 13;306(1-3):271-9. doi: 10.1016/0014-2999(96)00201-4. PMID: 8813641.
[2]. Tuerxun T, Numakawa T, et,al. SA4503, a sigma-1 receptor agonist, prevents cultured cortical neurons from oxidative stress-induced cell death via suppression of MAPK pathway activation and glutamate receptor expression. Neurosci Lett. 2010 Jan 29;469(3):303-8. doi: 10.1016/j.neulet.2009.12.013. Epub 2009 Dec 16. PMID: 20025928.
[3]. Ono Y, Tanaka H, et,al. SA4503, a sigma-1 receptor agonist, suppresses motor neuron damage in in vitro and in vivo amyotrophic lateral sclerosis models. Neurosci Lett. 2014 Jan 24;559:174-8. doi: 10.1016/j.neulet.2013.12.005. Epub 2013 Dec 12. PMID: 24334165.
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