CHARACTERIZATION OF MIANSERIN NEUROPROTECTION IN EXPERIMENTAL SPINAL TRAUMA - DOSE ROUTE RESPONSE AND LATE TREATMENT/

The neuroprotective action of the 5-hydroxytryptamine (5-HT2/5-HT1C) a ntagonist mianserin was examined with respect to optimal dosage, route of administration and time of treatment after a moderate spinal impac t trauma (50 g.cm by the weight-drop method) to the thoracic region of the rat. in a previous study (Salzman et al., 1991b) a single 1-mg/kg i.v. dose of mianserin improved multiple measures of functional outco me when given 15 min after injury, whereas higher doses (5 and 10 mg/k g i.v.) displayed lesser therapeutic actions as well as pulmonary depr essant effects. In these studies, lower dosages of minanserin (0.5 and 0.1 mg/kg i.v.) also were not associated with neuroprotection. Althou gh the 1-mg/kg i.v. dosage again displayed significant efficacy when a dministered at 15 min delaying treatment to 30 min resulted in only ma rginal therapeutic actions. Nonetheless, i.p. dosage of 10 mg/kg (but not 2.5 mg/kg) at 15 min retained therapeutic efficacy, suggesting a p harmacodynamic influence. In support of this conclusion, the intrathec al administration of a 50-fold lower dose of minanserin (0.006 mg) at 15 min after injury resulted in neuroprotection that was superior to t hat of peripheral doses and was retained when this intrathecal dosage was administered at 1 hr after trauma. These results suggest a central mechanism of action for mianserin. Consistent with this was the lack of effect of mianserin (1 mg/kg i.v. at 15 min) upon post-traumatic sp inal edema but its ability to reverse the decrease in central 5-HT oxi dative metabolism after injury. Moreover, the inability of the selecti ve 5-HT2 antagonist ketanserin to produce this action, as well as its lack of neuroprotective efficacy, indicates the role of central 5-HT1C receptors in the therapeutic mechanism of mianserin.