Federal University of São Paulo, São Paulo, São Paulo, Brazil.
Naunyn Schmiedebergs Arch Pharmacol. 2013 Jul;386(7):575-87. doi: 10.1007/s00210-013-0853-4. Epub 2013 Apr 14.
Valproic acid (VA) is a major antiepileptic drug, used for several therapeutic indications. It has a wide activity spectrum, reflecting on mechanisms of action that are not fully understood. The objectives of this work were to study the effects of VA on acute models of nociception and inflammation in rodents. VA (0.5, 1, 10, 25, and 50 mg/kg, p.o.) effects were evaluated on the carrageenan-induced paw edema, carrageenan-induced peritonitis, and plantar tests in rats, as well as by the formalin test in mice. The HE staining and immunohistochemistry assay for TNF-α in carrageenan-induced edema, from paws of untreated and VA-treated rats, were also carried out. VA decreased paw edema after carrageenan, and maximum effects were seen with doses equal to or higher than 10 mg/kg. VA also preserved the tissue architecture as assessed by the HE staining. Immunohistochemical studies revealed that VA significantly reduced TNF-α immunostaining in carrageenan-inflamed rat paws. In addition, the anti-inflammatory action of VA was potentiated by pentoxifylline (a phosphodiesterase inhibitor, known to inhibit TNF-α production), but not by sodium butyrate or by suberoylanilide hydroxamic acid (SAHA), nonspecific and specific inhibitors, respectively, of histone deacetylase. However, the decrease in the number of positive TNF-α cells in the rat paw was drastically potentiated in the VA + SAHA associated group. VA also reduced leukocytes and myeloperoxidase (MPO) releases to the peritoneal exudate, in the carrageenan-induced peritonitis. Although in the formalin test, VA inhibited both phases, the inhibition was mainly on the second phase. Furthermore, VA significantly increased the reaction time to thermal stimuli, as assessed by the plantar test. VA is a multi-target drug, presenting potent antinociceptive and anti-inflammatory properties at a lower dose range. These effects are partly dependent upon its inhibitory action on TNF-α-related pathways. However, the participation of the HDAC inhibition with the VA anti-inflammatory action cannot be ruled out. Inflammatory processes are associated with free radical damage and oxidative stress, and their blockade by VA could also explain the present results.
丙戊酸（VA）是一种主要的抗癫痫药物，用于多种治疗适应症。它具有广泛的活性谱，反映了其作用机制尚不完全清楚。本工作的目的是研究 VA 对啮齿动物急性痛觉和炎症模型的影响。评估了 VA（0.5、1、10、25 和 50mg/kg，口服）对卡拉胶诱导的爪肿胀、卡拉胶诱导的腹膜炎和大鼠足底测试以及小鼠福尔马林测试的影响。还进行了未经处理和 VA 处理大鼠爪肿胀中 TNF-α的 HE 染色和免疫组织化学测定。VA 降低了卡拉胶后的爪肿胀，且在剂量等于或高于 10mg/kg 时出现最大作用。VA 还通过 HE 染色评估保存了组织结构。免疫组织化学研究表明，VA 显著减少了卡拉胶致炎大鼠爪中的 TNF-α免疫染色。此外，VA 的抗炎作用被己酮可可碱（一种磷酸二酯酶抑制剂，已知能抑制 TNF-α的产生）增强，但不能被丁酸钠或 SAHA（分别是非特异性和特异性组蛋白去乙酰化酶抑制剂）增强。然而，在 VA+SAHA 相关组中，大鼠爪中 TNF-α阳性细胞的数量急剧增加。VA 还减少了白细胞和髓过氧化物酶（MPO）向腹膜炎渗出液中的释放。虽然在福尔马林试验中，VA 抑制了两个阶段，但主要是在第二阶段。此外，VA 显著增加了热刺激的反应时间，通过足底试验评估。VA 是一种多靶点药物，在较低的剂量范围内表现出强大的镇痛和抗炎作用。这些作用部分依赖于其对 TNF-α相关途径的抑制作用。然而，不能排除 HDAC 抑制与 VA 抗炎作用的参与。炎症过程与自由基损伤和氧化应激有关，VA 对其的阻断也可以解释目前的结果。
