Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio)- Grupo de Pesquisa em Neurobiotecnologia, CCQFA, Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil.
Laboratório de Síntese Orgânica Limpa (LASOL), CCQFA, Universidade Federal de Pelotas (UFPel), Pelotas, RS, Brazil.
Chem Biol Interact. 2019 Sep 25;311:108790. doi: 10.1016/j.cbi.2019.108790. Epub 2019 Aug 7.
Preclinical assays play a key role in research in research on the neurobiology of pain and the development of novel analgesics. Drugs available for the treatment of inflammatory pain are not fully effective and show adverse effects. Thus, we investigated the antinociceptive, anti-inflammatory and anti-hyperalgesic effects of bis(3-amino-2-pyridine) diselenide (BAPD), a new analgesic drug prototype. BAPD effects were investigated using nociception models induced by chemical (glutamate), immunologic (Freund's Complete Adjuvant - CFA) and thermal stimuli in Swiss mice. Mice were orally (p.o.) treated with BAPD (0.1-50 mg/kg) 30 min prior to the glutamate and hot-plate tests and a time-course (0.5 up to 8 h) of the antinociceptive effect of BAPD (50 mg/kg, p. o.) was evaluated in a CFA model. In the CFA model, BAPD effects on cyclooxygenase-2 (COX-2), tumor necrosis factor (TNFα) and interferon-γ (INF-γ) expression, myeloperoxidase (MPO) activity, oxidative (2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels) and histological parameters were evaluated. The safety of the compound (50 and 300 mg/kg, p. o.) was verified for 72 h. BAPD reduced the licking time induced by glutamate and caused an increase in latency response to thermal stimulus. Naloxone reversed the antinociceptive effect of BAPD. Paw edema formation induced by glutamate or CFA injection was reduced by BAPD. Mechanical hyperalgesia induced by CFA was attenuated by BAPD. BAPD did not protect against the increase in MPO activity and decrease of the 2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid and 2,2-diphe- nyl-1-picrylhydrazyl levels induced by CFA. BAPD protected against histological alterations and reduction on the levels of gene expression COX-2 and INF-γ in the paw of mice exposed to CFA. BAPD was safe at the doses and time evaluated. BAPD exerts acute antinociceptive, anti-inflammatory and anti-hyperalgesic actions, suggesting that it may represent an alternative in the future development of new therapeutic strategies.
临床前检测在疼痛神经生物学研究和新型镇痛药的开发中起着关键作用。可用于治疗炎症性疼痛的药物并非完全有效，且具有不良反应。因此，我们研究了新型镇痛药物原型双（3-氨基-2-吡啶）二硒化物（BAPD）的镇痛、抗炎和抗痛觉过敏作用。我们使用化学（谷氨酸）、免疫（完全弗氏佐剂-CFA）和热刺激诱导的痛觉模型来研究 BAPD 的作用，在瑞士小鼠中进行。在谷氨酸和热板试验前 30 分钟，小鼠经口（p.o.）给予 BAPD（0.1-50mg/kg），并评估 50mg/kg（p.o.）BAPD 的时间进程（0.5 至 8 小时）在 CFA 模型中的抗伤害作用。在 CFA 模型中，评估了 BAPD 对环氧化酶-2（COX-2）、肿瘤坏死因子（TNFα）和干扰素-γ（INF-γ）表达、髓过氧化物酶（MPO）活性、氧化（2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid 和 2,2-diphe- nyl-1-picrylhydrazyl 水平）和组织学参数的影响。验证了化合物（50 和 300mg/kg，p.o.）72 小时的安全性。BAPD 减少了谷氨酸诱导的舔舐时间，并增加了对热刺激的潜伏期反应。纳洛酮逆转了 BAPD 的镇痛作用。BAPD 减少了由谷氨酸或 CFA 注射引起的爪肿胀形成。CFA 引起的机械性痛觉过敏也被 BAPD 减弱。BAPD 不能防止 CFA 引起的 MPO 活性增加、2,2'-Azino-bis-3-ethylbenzothiazoline 6-sulfonic acid 和 2,2-diphe- nyl-1-picrylhydrazyl 水平降低。BAPD 可防止暴露于 CFA 的小鼠爪组织学改变和 COX-2 和 INF-γ 基因表达水平降低。在评估的剂量和时间内，BAPD 是安全的。BAPD 具有急性镇痛、抗炎和抗痛觉过敏作用，表明它可能成为未来开发新治疗策略的一种选择。
