Department of Comparative Medicine, School of Medicine (S.M., P.M.T.), Department of Biology, College of Arts and Sciences (M.B.), and Department of Pharmacy, School of Pharmacy (M.B., K.M.K., M.B.-H.), University of Washington, Seattle, Washington.
Department of Comparative Medicine, School of Medicine (S.M., P.M.T.), Department of Biology, College of Arts and Sciences (M.B.), and Department of Pharmacy, School of Pharmacy (M.B., K.M.K., M.B.-H.), University of Washington, Seattle, Washington
J Pharmacol Exp Ther. 2019 Oct;371(1):25-35. doi: 10.1124/jpet.119.257261. Epub 2019 Aug 2.
Methylcellulose (MC; 0.5% concentration) is commonly used when evaluating investigational agents for efficacy in preclinical models of disease. When administered by the oral (PO) route, MC is considered a Food and Drug Administration "generally recognized as safe" compound. Yet, there is limited data pertaining to the tolerability and impact on model fidelity of repeated intraperitoneal administration of 0.5% MC. Chronic administration of high-concentration MC (2%-2.5%) has been used to induce anemia, splenomegaly, and lesions in multiple organ systems in several preclinical species. Histopathological findings from a diagnostic pathologic analysis of a single mouse from our laboratory with experimentally induced chronic seizures that had received repeated intraperitoneal administration of antiseizure drugs delivered in MC revealed similar widespread lesions. This study thus tested the hypothesis that chronic administration of intraperitoneal, but not PO, MC incites histologic lesions without effects on preclinical phenotype. Male CF-1 mice ( = 2-14/group) were randomized to receive either 6 weeks of twice weekly 0.5% MC or saline (intraperitoneal or PO) following induction of chronic seizures. Histology of a subset of mice revealed lesions in kidney, liver, mediastinal lymph nodes, mesentery, aorta, and choroid plexus only in intraperitoneal MC-treated mice ( = 7/7). Kindled mice that received MC PO ( = 5) or saline (intraperitoneal = 6, PO = 3) had no lesions. There were no effects of intraperitoneal MC treatment on body weight, appearance, seizure stability, or behavior. Nonetheless, our findings suggest that repeated intraperitoneal, but not PO, MC elicits systemic organ damage without impacting the model phenotype, which may confound interpretation of investigational drug-induced histologic lesions. SIGNIFICANCE STATEMENT: Methylcellulose (0.5% concentration) is commonly used when evaluating investigational agents for efficacy in preclinical models of disease. Herein, we demonstrate that repeated administration of 0.5% methylcellulose by the intraperitoneal, but not oral, route results in systemic inflammation and presence of foam-laden macrophages but does not impact the behavioral phenotype of a rodent model of neurological disease.
甲基纤维素（MC；0.5%浓度）常用于评估疾病的临床前模型中治疗效果的研究药物。当通过口服（PO）途径给药时，MC 被认为是一种“通常被认为是安全的”FDA 化合物。然而，关于重复腹腔内给予 0.5%MC 的耐受性和对模型真实性的影响的数据有限。在几种临床前物种中，高浓度 MC（2%-2.5%）的慢性给药已被用于诱导贫血、脾肿大和多个器官系统的病变。我们实验室的一只患有实验性慢性癫痫发作的老鼠接受了抗癫痫药物的腹腔内给予，并用 MC 递送，对其进行了诊断性病理分析，发现其广泛的病变。因此，本研究检验了这样一个假设，即腹腔内而非 PO 给予慢性 MC 给药会引起组织学病变，而不会影响临床前表型。雄性 CF-1 小鼠（每组 2-14 只）随机分为腹腔内或 PO 给予 0.5%MC 或生理盐水，接受慢性癫痫发作诱导后，每周两次，共 6 周。对一小部分老鼠的组织学检查显示，只有腹腔内 MC 治疗组的老鼠（7/7）的肾脏、肝脏、纵隔淋巴结、肠系膜、主动脉和脉络丛有病变。腹腔内给予 MC PO（5/5）或生理盐水（腹腔内 6/6，PO 3/3）的点燃老鼠没有病变。腹腔内 MC 治疗对体重、外观、癫痫发作稳定性或行为没有影响。尽管如此，我们的研究结果表明，重复腹腔内而非 PO 给予 MC 会引起全身器官损伤，而不会影响模型表型，这可能会混淆对研究药物引起的组织学病变的解释。意义：当评估疾病的临床前模型中的治疗效果时，通常使用甲基纤维素（0.5%浓度）。在此，我们证明了通过腹腔内而非口服途径重复给予 0.5%甲基纤维素会导致全身性炎症和泡沫状巨噬细胞的存在，但不会影响神经疾病啮齿动物模型的行为表型。
