Single-Dose Oral Administration of Theophylline in Institute of Cancer Research Mice: A Central Nervous System Safety Pharmacology Evaluation using the Modified Irwin Test

Theophylline, a methylxanthine-class bronchodilator that has anti-inflammatory properties, is clinically used to manage chronic respiratory disorders such as asthma and chronic obstructive pulmonary disease. Although theophylline demonstrates therapeutic efficacy, it has a narrow therapeutic index and central nervous system (CNS) activity, which requires a detailed safety assessment. This study investigated the acute neurobehavioral and thermophysiological effects of orally administered theophylline in male Institute of Cancer Research (ICR) mice using the modified Irwin test. Single doses of 10, 30, or 100 mg/kg of theophylline were administered, followed by structured behavioral observations at 0, 1, 2, 4, 6, and 24 h post-dosing. Administration at concentrations of 30 and 100 mg/kg induced transient hyperthermia, increased spontaneous locomotion, and reversible motor coordination deficits between 1 and 6 h, with full recovery by 24 h. Tail elevation was observed only at concentrations of 30 mg/kg, whereas partial eyelid closure occurred exclusively in mice receiving 100 mg/kg administered doses. However, doses of 10 mg/kg did not produce measurable changes in any of these parameters. No notable alterations were detected in the abdominal tone, tremors, convulsions, respiration, righting reflex, salivation, lacrimation, skin color, or exophthalmos, thereby indicating the absence of systemic or generalized CNS toxicity. The modified Irwin test captured the subtle, regionally selective neurofunctional responses induced by theophylline, thus emphasizing its relevance in CNS safety pharmacology and supporting continued mechanistic investigations under clinically relevant exposure conditions.