Clinical benefits of thyrotropin-releasing hormone (TRH) were tested in wobbler mice, an animal model of motor neuron disease. After the disease was clinically recognized at 3-4 weeks, the animals were divided into two groups, each group consisting of 5 pairs of wobbler mice and normal littermates. TRH (50 mg/kg) and normal saline (NS) were injected intraperitoneally daily, 6 times per week for 9 weeks, in a double-blind study. Weekly assessments consisted of front paw grip strength, push walking, body weight, and semiquantitative grading. At the end of the trial, the brain and spinal cord were sampled to measure TRH and cyclo (His-Pro) concentrations. Progression of motor neuron disease was evident in wobbler mice, regardless of treatment. Descriptive semiquantitative gradings showed the tendency of improvement in TRH-treated wobbler mice. In saline-injected controls, TRH levels in the cervical spinal cord were significantly increased (P less than 0.01) in wobbler mice compared to littermates. However, with TRH treatment, there was no significant difference in TRH and cyclo (His-Pro) levels in any neural tissue between wobbler and controls. The lack of clinical benefits with TRH in wobbler mice may be due to increased TRH levels found in diseased spinal cord in murine motor neuron disease.