新型β-内酰胺类药物MC-100093和头孢曲松对暴露于吗啡递增剂量的C57BL/6小鼠星形胶质细胞谷氨酸转运体和神经炎症因子的影响

IF 3 3区 医学 Q2 PHARMACOLOGY & PHARMACY Saudi Pharmaceutical Journal Pub Date : 2024-05-23 DOI:10.1016/j.jsps.2024.102108
Youssef Sari , Ghadeer M.S. Swiss , Fatin A. Alrashedi , Kholoud A. Baeshen , Sultan A. Alshammari , Shakir D. Alsharari , Nemat Ali , Abdullah F. Alasmari , Ali Alhoshani , Alaa A. Alameen , Wayne E. Childers , Magid Abou-Gharbia , Fawaz Alasmari
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引用次数: 0

摘要

长期暴露于阿片类药物可导致星形胶质细胞谷氨酸转运体 1(GLT-1)的下调,该转运体调节大部分谷氨酸的摄取。我们实验室的研究发现,β-内酰胺类抗生素头孢曲松可减轻氢可酮诱导的 GLT-1 下调以及中枢奖赏脑区胱氨酸/谷氨酸抗转运体(xCT)的表达。在这项研究中,我们研究了吗啡剂量递增的影响,并测试了新型合成非抗生素药物 MC-100093 和头孢曲松在减轻吗啡暴露对脑核中 GLT-1、xCT 和神经炎症因子(IL-6 和 TGF-β)表达的影响方面的功效。由于阿片类药物对小鼠的运动敏感性有影响,本研究还调查了吗啡和β-内酰胺类药物对小鼠运动活动、自发交替率(SAP)和进入Y迷宫次数的影响。小鼠在第1、3、5、7天暴露于中等剂量的吗啡(20毫克/千克,静脉注射),在第9天暴露于较高剂量的吗啡(150毫克/千克,静脉注射),然后对这些小鼠进行行为测试,并在第10天安乐死。Western印迹分析表明,接触吗啡会降低NAc中GLT-1和xCT的表达,而MC-100093和头孢曲松均可减轻这些影响。此外,吗啡还增加了NAc中IL-6 mRNA和TGF-β mRNA的表达,而MC-100093和头孢曲松只减弱了对IL-6 mRNA表达的影响。此外,接触吗啡会导致行走距离增加,而MC-100093和头孢曲松会减弱这种效应。此外,暴露于吗啡会降低Y迷宫中的SAP并增加进入臂的次数,但MC-100093和头孢曲松均未显示出任何减弱作用。我们的研究结果首次证明,MC-100093和头孢曲松可减轻吗啡诱导的GLT-1和xCT表达下调、吗啡诱导的神经炎症因子IL-6增加以及过度活跃。这些发现揭示了MC-100093和头孢曲松对暴露于递增剂量吗啡的影响具有有益的治疗作用。
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Effects of novel beta-lactam, MC-100093, and ceftriaxone on astrocytic glutamate transporters and neuroinflammatory factors in nucleus accumbens of C57BL/6 mice exposed to escalated doses of morphine

Chronic exposure to opioids can lead to downregulation of astrocytic glutamate transporter 1 (GLT-1), which regulates the majority of glutamate uptake. Studies from our lab revealed that beta-lactam antibiotic, ceftriaxone, attenuated hydrocodone-induced downregulation of GLT-1 as well as cystine/glutamate antiporter (xCT) expression in central reward brain regions. In this study, we investigated the effects of escalating doses of morphine and tested the efficacy of novel synthetic non-antibiotic drug, MC-100093, and ceftriaxone in attenuating the effects of morphine exposure in the expression of GLT-1, xCT, and neuroinflammatory factors (IL-6 and TGF-β) in the nucleus accumbens (NAc). This study also investigated the effects of morphine and beta-lactams in locomotor activity, spontaneous alternation percentage (SAP) and number of entries in Y maze since opioids have effects in locomotor sensitization. Mice were exposed to moderate dose of morphine (20 mg/kg, i.p.) on days 1, 3, 5, 7, and a higher dose of morphine (150 mg/kg, i.p.) on day 9, and these mice were then behaviorally tested and euthanized on Day 10. Western blot analysis showed that exposure to morphine downregulated GLT-1 and xCT expression in the NAc, and both MC-100093 and ceftriaxone attenuated these effects. In addition, morphine exposure increased IL-6 mRNA and TGF-β mRNA expression, and MC-100093 and ceftriaxone attenuated only the effect on IL-6 mRNA expression in the NAc. Furthermore, morphine exposure induced an increase in distance travelled, and MC-100093 and ceftriaxone attenuated this effect. In addition, morphine exposure decreased the SAP and increased the number of arm entries in Y maze, however, neither MC-100093 nor ceftriaxone showed any attenuating effect. Our findings demonstrated for the first time that MC-100093 and ceftriaxone attenuated morphine-induced downregulation of GLT-1 and xCT expression, and morphine-induced increase in neuroinflammatory factor, IL-6, as well as hyperactivity. These findings revealed the beneficial therapeutic effects of MC-100093 and ceftriaxone against the effects of exposure to escalated doses of morphine.

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来源期刊
Saudi Pharmaceutical Journal
Saudi Pharmaceutical Journal PHARMACOLOGY & PHARMACY-
CiteScore
6.10
自引率
2.40%
发文量
194
审稿时长
67 days
期刊介绍: The Saudi Pharmaceutical Journal (SPJ) is the official journal of the Saudi Pharmaceutical Society (SPS) publishing high quality clinically oriented submissions which encompass the various disciplines of pharmaceutical sciences and related subjects. SPJ publishes 8 issues per year by the Saudi Pharmaceutical Society, with the cooperation of the College of Pharmacy, King Saud University.
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