We investigated the histological effects of ciliary neurotrophic factor on degenerating motor neurons, their axons, and skeletal muscles in 68 wobbler mice with motor neuron disease. Treatment consisted of recombinant rat or human ciliary neurotrophic factor (or a vehicle solution), 1-mg/kg subcutaneous injection, three times per week for 4 weeks after the clinical diagnosis. The number of motor neurons immunoreactive for calcitonin gene-related peptide was higher in mice receiving rat ciliary neurotrophic factor ( p < 0.031, although the number of choline acetyltransferasereactive neurons was the same in both treated and untreated control groups. Treatment did not prevent vacuolar degeneration of motor neurons. In mice treated with human ciliary neurotrophic factor, the percentage of axons undergoing acute axonal degeneration (myelin ovoids) was smaller in the entire C5 ventral root ( p < 0.02) and in the musculocutaneous nerve ( p < 0.04), and the number of myelinated nerve fibers was 30% higher in both nerves ( p < 0.01 and p < 0.04, respectively) than in controls. In ciliary neurotrophic factor-treated mice, the biceps muscle weight was 20% greater, the mean muscle fiber diameter was 30% larger, and the number of atrophied muscle fibers was From the Departments of "Neurology, ?Neuroscience, and %Biostatistics and Epidemiology, The Cleveland Clinic Foundation, Cleveland, OH, and SRegeneron Pharmaceuticals, Tarrytown, NY. Drs holders in Regeneron Pharmaceuticals.