Skeletal muscle atrophy induced by intramuscular repeated dose of botulinum toxin type A in rats

Botulinum toxin type A was intramuscularly administered to Sprague-Dawley rats once a day for 28 days at doses of 1, 3, and 9 ng kg-1 day-1 to investigate the possibility of unanticipated toxicity of repeated dose. A dose-related decrease in body weight gain was noted and lasted throughout the 4-week recovery period. Paralytic gait was a common clinical sign observed in the animals dosed at >or=3 ng kg-1 day-1 and muscle atrophy at 9 ng kg-1 day-1. Decreased creatinine was monitored in both males and females treated at 9 ng kg-1 day-1. Microscopic examination of the quadriceps femoris muscle, the test article application site, confirmed the muscle atrophy with a decrease in myofiber diameter and an increase of myofiber nuclei and intermyofiber connective tissue. Although antibody against botulinum toxin type A was detected in the sera from both males and females at 9 ng kg-1 day-1, no immunogenicity-related changes or lesions were noted. In conclusion, no other side effects of the botulinum toxin type A injection except the decrease in body weight gain and the muscle atrophy at the administration site were noted in the 28-day intramuscular repeated dose study.