Excessive manganese (Mn) accumulation in the brain may induce an extrapyramidal disorder known as manganism. Inflammatory processes play a critical role in neurodegenerative diseases. Therapeutically, non-steroidal anti-inflammatory drugs or analogous anti-inflammatory therapies have neuroprotective effects. As a non-steroidal anti-inflammatory drug, p-aminosalicylic acid (PAS) has anti-inflammatory effects, which are mediated by decreased prostaglandins E2 (PGE2) levels. The aim of the current study was to investigate whether PAS-Na treatment prevents Mn-induced behavioral changes and neuroinflammation in vivo. Male Sprague-Dawley rats were intraperitoneally (i.p.) injected with MnCl₂·4H₂O (15 mg/kg) for 12 weeks, followed by 6 weeks PAS-Na treatment. Sub-chronic Mn exposure increased Mn levels in the whole blood, cortex, hippocampus and thalamus, and induced learning and memory deficits, concomitant with astrocytes activation in the cortex, hippocampus and thalamus. Moreover inflammatory cytokine levels in serum and brain of Mn-treated group were increased, including IL-1β, IL-6, TNF-αand PGE2, especially in the hippocampus and thalamus. Furthermore, sub-chronic Mn exposure also increased inflammatory cytokines and COX-2 in transcription levels concomitant with increased MAPK signaling and COX-2 in the same selected brain regions. PAS-Na treatment at the highest doses also decreased Mn levels in the whole blood and selected brain tissues, and reversed the Mn-induced learning and memory deficits. PAS-Na inhibited astrocyte activation as well as the Mn-induced increase in inflammatory cytokine levels, reducing p38, ERK MAPK pathway and COX-2 activity. In contrast PAS-Na had no effects on the JNK MAPK pathway. These data establish the efficacy of PAS-Na not only as a chelating agent to mobilize whole blood Mn, but also as an anti-inflammatory agent.

大脑中过多的锰（Mn）可能会导致锥体外系疾病，称为锰症。炎症过程在神经退行性疾病中起关键作用。在治疗上，非甾体抗炎药或类似的抗炎疗法具有神经保护作用。作为一种非甾体类抗炎药，对氨基水杨酸（PAS）具有抗炎作用，其作用是通过降低前列腺素E2（PGE2）的水平来实现的。本研究的目的是研究PAS-Na治疗是否能预防Mn诱导的行为改变和体内神经炎症。对雄性Sprague-Dawley大鼠腹膜内（ip）注射MnCl ₂ ·4H ₂O（15 mg / kg）持续12周，然后进行6周PAS-Na处理。亚慢性锰暴露会增加全血，皮质，海马和丘脑中的锰水平，并导致学习和记忆障碍，并伴随皮质，海马和丘脑中星形胶质细胞的活化。此外，锰治疗组的血清和脑中炎性细胞因子水平升高，包括IL-1β，IL-6，TNF-α和PGE2，尤其是在海马和丘脑。此外，亚慢性锰暴露还增加了转录水平的炎性细胞因子和COX-2，同时在相同的选定大脑区域中增加了MAPK信号传导和COX-2。最高剂量的PAS-Na处理还降低了全血和某些脑组织中的Mn水平，并逆转了Mn引起的学习和记忆缺陷。PAS-Na抑制星形胶质细胞活化以及Mn诱导的炎性细胞因子水平增加，从而降低p38，ERK MAPK途径和COX-2活性。相反，PAS-Na对JNK MAPK途径没有影响。这些数据证明了PAS-Na不仅作为一种螯合剂来动员全血Mn，而且还作为一种抗炎药。