Lucarini Elena, Benvenuti Laura, Di Salvo Clelia, D'Antongiovanni Vanessa, Pellegrini Carolina, Valdiserra Giulia, Ciampi Clara, Antonioli Luca, Lambiase Christian, Cancelli Lorenzo, Grosso Antonio, Di Cesare Mannelli Lorenzo, Bellini Massimo, Ghelardini Carla, Fornai Matteo
Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health, Neurofarba, University of Florence, Florence, Italy.
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Front Pharmacol. 2024 Sep 20;15:1466824. doi: 10.3389/fphar.2024.1466824. eCollection 2024.
Visceral pain represents the most common digestive issue, frequently resulting from long-term inflammation, such as inflammatory bowel diseases. The lack of effective drugs prompted search of new therapeutic approaches. In this regard, gamma-aminobutyric acid (GABA) and (Mo) appear as excellent candidates as they were recognized to have several positive effects on the digestive system. The aim of this research was to evaluate the effects of a compound containing GABA and Mo (GABA-Mo 5:1) in inflammation-induced intestinal damage and visceral pain.
Colitis was induced in rats by intrarectal 2,4-dinitrobenzenesulfonic acid (DNBS) administration. DNBS-treated animals received GABA-Mo (80 mg/kg BID), starting 3 days before DNBS administration, until 14 days after colitis induction (preventive protocol), or starting 7 days after DNBS until day 21 (curative protocol). Visceral pain was assessed by measuring the viscero-motor response (VMR) and the abdominal withdrawal reflex (AWR) to colorectal distension on day 7, 14 (both protocols) and 21 (curative protocol) after DNBS administration.
In the preventive protocol, GABA-Mo reduced AWR at day 14 but had no effect on VMR. In the spinal cord, treatment with GABA-Mo significantly prevented microglia reactivity (Iba-1 positive cells). In the colon, the supplement significantly decreased malondialdehyde (MDA, index of oxidative stress) and IL-1β levels and counteracted the decreased expression of claudin-1. Moreover, GABA-Mo normalized the increased levels of plasma lipopolysaccharide binding protein (LBP, index of altered intestinal permeability). In the curative protocol, GABA-Mo significantly counteracted visceral hypersensitivity persistence in DNBS-treated animals (day 14 and 21). In the spinal cord, GABA-Mo significantly reduced GFAP positive cell density (astrocytes). Histological evaluations highlighted a mild but significant effect of GABA-Mo in promoting healing from DNBS-induced colon damage. Colonic MDA and myeloperoxidase (index of leukocyte infiltration) levels were reduced, while the decreased colonic claudin-1 expression was normalized. In addition, the increased levels of plasma LBP were normalized by GABA-Mo administration.
In conclusion GABA-Mo, particularly in the curative protocol, was able to reduce visceral pain and intestinal inflammation, likely through a reinforcement of intestinal barrier integrity, thus representing a suitable approach for the management of abdominal pain, especially in the remission stages of colitis.
内脏痛是最常见的消化系统问题，常由长期炎症引起，如炎症性肠病。缺乏有效的药物促使人们寻找新的治疗方法。在这方面，γ-氨基丁酸（GABA）和钼（Mo）似乎是很好的候选物质，因为它们被认为对消化系统有多种积极作用。本研究的目的是评估一种含有GABA和Mo（GABA-Mo 5:1）的化合物对炎症诱导的肠道损伤和内脏痛的影响。
通过直肠内给予2,4-二硝基苯磺酸（DNBS）诱导大鼠结肠炎。接受DNBS处理的动物在DNBS给药前3天开始接受GABA-Mo（80mg/kg，每日两次），直至结肠炎诱导后14天（预防方案），或在DNBS给药后7天开始直至第21天（治疗方案）。在DNBS给药后第7天、14天（两种方案）和21天（治疗方案），通过测量对结肠扩张的内脏运动反应（VMR）和腹部退缩反射（AWR）来评估内脏痛。
在预防方案中，GABA-Mo在第14天降低了AWR，但对VMR没有影响。在脊髓中，GABA-Mo治疗显著预防了小胶质细胞反应性（Iba-1阳性细胞）。在结肠中，该补充剂显著降低了丙二醛（MDA，氧化应激指标）和IL-1β水平，并抵消了claudin-1表达的降低。此外，GABA-Mo使血浆脂多糖结合蛋白（LBP，肠道通透性改变指标）升高的水平恢复正常。在治疗方案中，GABA-Mo显著抵消了DNBS处理动物内脏超敏反应的持续存在（第14天和21天）。在脊髓中，GABA-Mo显著降低了GFAP阳性细胞密度（星形胶质细胞）。组织学评估突出了GABA-Mo在促进DNBS诱导的结肠损伤愈合方面的轻微但显著的作用。结肠MDA和髓过氧化物酶（白细胞浸润指标）水平降低，而结肠claudin-1表达降低恢复正常。此外，通过给予GABA-Mo使血浆LBP升高的水平恢复正常。
总之，GABA-Mo，特别是在治疗方案中，能够减轻内脏痛和肠道炎症，可能是通过增强肠道屏障完整性，因此是管理腹痛的合适方法，尤其是在结肠炎的缓解期。
