Repeated Intraperitoneal Administration of Low-Concentration Methylcellulose Leads to Systemic Histologic Lesions Without Loss of Preclinical Phenotype

Abstract

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 (n 5 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 (n 5 7/7). Kindled mice that received MC PO (n 5 5) or saline (intraperitoneal n 5 6, PO n 5 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 STATEMENTMethylcellulose (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.

Chronic Seizures Induce Sex-Specific Cognitive Deficits with Loss of Presenilin 2 Function

“…Open Field (OF) -In this assay, each mouse was placed into an OF Plexiglass chamber (40L × 40W × 30H cm) equipped with infrared sensors to detect animal movement for 10 min. During the 10-min period, the total distance travelled (cm), vertical activity counts, and horizontal activity counts in both the center and perimeter of the OF were automatically recorded by the computer system, consistent with our reported methods with kindled mice (Barker-Haliski et al, 2016b;Barker-Haliski et al, 2016a;Koneval et al, 2018;Meeker et al, 2019;Koneval et al, 2020).…”

Antiseizure drug efficacy and tolerability in established and novel drug discovery seizure models in outbred vs inbred mice

“…First, the present protocol does not require chronic ASD administration during the kindling process to elicit pharmacoresistance, unlike our previously developed LTG‐resistant CKM 6 . Repeated administration of formulation vehicles like 0.5% MC may themselves elicit pathological changes 29 ; thus the fact that the presently described pharmacoresistant kindling protocol does not require drug administration is of high value to ASD discovery. Second, the present pharmacoresistant kindling model is characterized by Racine stage seizures that progress through an easily differentiated escalation in seizure severity (ie, Racine stages 1‐5; Figure 2), whereas the 6 Hz CKM elicits early focal seizures that are difficult to differentiate and do not initially present on the Racine scale 5 .…”

“…This stimulation intensity was determined to be initially benign and pilot studies of CF-1 mice that were similarly stimulated with a 10-fold reduction in voltage (9.0 V) did not lead to kindled seizures or the expression of Racine stage seizures in over 3 weeks of twice-daily stimulations (not shown). Based on our history with CKM, 13,19,26,28,29 we sought to characterize the pharmacology of this stimulation protocol to determine whether it demonstrated a differentiated profile from traditional 60 Hz kindling (ie, 3 seconds, 3.0 mA stimulation). As noted below, this novel stimulation protocol results in a kindling model that is resistant to several of the ASDs tested.…”

Impaired Meningeal Lymphatic Flow in NMOSD Patients With Acute Attack

“…Numerous studies have demonstrated that mLVs played an important role in maintaining brain tissue homeostasis and dysfunction of mLVs was involved in the progression of neurodegenerative diseases (6,9,27). Dysfunction of mLVs would aggravate deposition of Ab in brain tissue and cognitive impairment in AD mouse model (28)(29)(30).…”