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) antagonist mianserin was examined with respect to optimal dosage, route of administration and time of treatment after a moderate spinal impact 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 outcome when given 15 min after injury, whereas higher doses (5 and 10 mg/kg i.v.) displayed lesser therapeutic actions as well as pulmonary depressant effects. In these studies, lower dosages of minanserin (0.5 and 0.1 mg/kg i.v.) also were not associated with neuroprotection. Although the 1-mg/kg i.v. dosage again displayed significant efficacy when administered at 15 min delaying treatment to 30 min resulted in only marginal therapeutic actions. Nonetheless, i.p. dosage of 10 mg/kg (but not 2.5 mg/kg) at 15 min retained therapeutic efficacy, suggesting a pharmacodynamic influence. In support of this conclusion, the intrathecal administration of a 50-fold lower dose of minanserin (0.006 mg) at 15 min after injury resulted in neuroprotection that was superior to that 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 spinal edema but its ability to reverse the decrease in central 5-HT oxidative metabolism after injury.(ABSTRACT TRUNCATED AT 250 WORDS)
Salzman
S K
SK
Department of Medical Cell Biology, Alfred I. duPont Institute, Wilmington, Delaware.
Kelly
G
G
Chavin
J
J
Wang
L
L
Puniak
M A
MA
Agresta
C A
CA
Azim
S
S
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004487:Edema / Q000209:etiology / Q000517:prevention & control; D007650:Ketanserin / Q000627:therapeutic use; D008297:Male; D008803:Mianserin / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000145:classification; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists; D013118:Spinal Cord Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D008803:Mianserin; D012701:Serotonin; D007650:Ketanserin