Cilostazol, a selective Type III phosphodiesterase inhibitor: prevention of cervical myelopathy in a rat chronic compression model

Abstract

Regional blood flow is decreased in experimental models of chronic spinal cord compression, and the alteration presumably contributes to the development of myelopathy. Cilostazol (Otsuka Pharmaceuticals Co.), a selective Type III phosphodiesterase inhibitor, has been shown to be neuroprotective in cerebral hypoperfusion animal models and clinically effective in preventing the recurrence of cerebral infarction. To investigate the neuroprotective effect of cilostazol on cervical spondylotic myelopathy, the preventive effect against progressive motor dysfunction and the loss of anterior horn motor neurons were assessed using a chronic cord compression model in rats. To produce chronic cervical cord compression in male Wistar rats, thin polyurethane sheets (3 × 5 × 0.7 mm) that gradually expand over 48-72 hours by absorbing water were implanted under the C5-6 laminae. In sham operations, the sheets were momentarily placed and then immediately removed. This model has been shown to reproduce characteristic features of clinical cervical myelopathy, with progressive motor disturbances after a latency period and insidious neuronal loss preceding the onset of symptoms. In the treatment group, cilostazol (30 mg/kg/day) was orally administered to the rats once a day, starting the day after surgery and continuing through the entire observation period of 25 weeks. In the control group, vehicle solution was administered under the same protocol. Changes in motor function were monitored by measuring bilateral forepaw grip strength and the duration of forced running on a treadmill. Twenty-five weeks after surgery, cervical spinal cords were examined histopathologically. Cilostazol preserved both forepaw grip strength and forced running capability. The drug also preserved anterior horn motor neurons in the C5-6 spinal cord segment, which diminished in number in the untreated chronic compression group. The drug decreased the number of TUNEL-positive apoptotic cells. These results indicate that cilostazol is neuroprotective in the chronically compressed cervical cord and is potentially useful in the treatment of cervical spondylotic myelopathy.