PT  - JOURNAL ARTICLE
AU  - Stacey Meeker
AU  - Megan Beckman
AU  - Kevin M. Knox
AU  - Piper M. Treuting
AU  - Melissa Barker-Haliski
TI  - Repeated Intraperitoneal Administration of Low-Concentration Methylcellulose Leads to Systemic Histologic Lesions Without Loss of Preclinical Phenotype
AID  - 10.1124/jpet.119.257261
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.119.257261
4099  - http://jpet.aspetjournals.org/content/early/2019/08/02/jpet.119.257261.short
4100  - http://jpet.aspetjournals.org/content/early/2019/08/02/jpet.119.257261.full
AB  - 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 an FDA "generally recognized as safe" compound. Yet, there is limited data pertaining to the tolerability and impact on model fidelity of repeated intraperitoneal (IP) 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 IP administration of antiseizure drugs delivered in MC revealed similar widespread lesions. This study thus tested the hypothesis that chronic administration of IP, but not PO, MC incites histologic lesions without effects on preclinical phenotype. Male CF-1 mice (n=2-14/group) were randomized to receive either 6 weeks of twice weekly 0.5% MC or saline (IP 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 IP MC-treated mice (n=7/7). Kindled mice that received MC PO (n=5) or saline (IP n=6, PO n=3) had no lesions. There were no effects of IP MC treatment on body weight, appearance, seizure stability, or behavior. Nonetheless, our findings suggest that repeated IP, 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 (MC; 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.