The serotonin antagonist mianserin improves functional recovery following experimental spinal trauma

Abstract

The ability of the serotonin antagonist mianserin to improve neurological recovery after graded impact trauma to the thoracic region of the spinal cord was compared to that of cyproheptadine and ketanserin in pentobarbital-anesthetized rats. Spinal cord injury was produced at T-10 by the weight-drop method and confirmed by the disappearance of the somatosensory-evoked response during the subsequent 15 minutes. In all experiments, drug or vehicle treatments were randomly administered as a single intravenous bolus 15 minutes after injury. Functional outcome was blindly assessed for 2 weeks after injury using a modified Tarlov scale, and in some cases, the Rivlin-Tator angleboard test. The survival of descending raphe-spinal axons was determined by the measurement of serotonin in postmortem spinal tissues located above and below the site of injury. In separate acute experiments, the physiological and hemodynamic correlates of a 50 gm cm injury and either mianserin or vehicle injection were examined, as were the effects on serotonin content and metabolism in spinal tissues harvested 30 minutes after injury. All doses of mianserin were associated with some index of improved recovery following a 50 gm cm injury, with a 1-mg/kg dose being clearly superior. Both ketanserin (0.1 mg/kg) and cyproheptadine (2 mg/kg) displayed marginal therapeutic actions for 50 gm cm injuries. In acute studies, mianserin at 1 mg/kg was associated with the preservation of posttraumatic spinal cord blood flow at T-12 as well as a pronounced alteration in postmortem spinal serotonin content and metabolism, in contrast to vehicle control treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Novel Pharmacologic Strategies in the Treatment of Experimental Traumatic Brain Injury: 1998

“…Although voltage-sensitive calcium channel blockers have been used with some success in treating subarachnoid hemorrhage in nonhuman primate (Dorsch et al, 1987) and in humans (Allen et al, 1983;Philippon et al, 1986;Baethmann and Jansen, 1986;Pikard et al, 1989;Robinson and Teasdale, 1990), only recently have studies been initiated to examine the therapeutic efficacy of these compounds in models of experimental brain trauma (McBumey et al, 1992). Administration of the combined phenylalkylamine calciumchannel blocker (S)-emopamil (which also possesses 5-HT2 receptor antagonist effects) has been reported to improve cerebrovascular and electrophysiological variables following traumatic spinal cord injury (Salzman et al, 1992) and attenuate regional cerebral edema, as well as both cognitive and motor deficits, following lateral FP brain injury in rats (Okiyama et al, 1992). Subsequently, these authors reported that (S)-emopamil also reduced the posttraumatic fall in rCBF observed in critically injured brain regions after FP brain injury (Okiyama et al, 1994).…”

A Model of Experimental Spinal Cord Trauma Based on Computer-Controlled Intervertebral Distraction: Characterization of Graded Injury

“…The skull was then exposed and implanted with stainless steel screw electrodes (Small Parts, Miami, FL) for the recording of somatosensory-evoked potentials (SEPs), as described previously. [7][8][9][10] The amplitude of the major negative wave (latency ϭ 16 -22 milliseconds) was recorded five times before the initial incision and one to three times after laminectomy, after the insertion of each sublaminar hook, and at 2, 5, 10, and 15 minutes after the application of distraction force. Only those animals that displayed a SEP with a stable latency and amplitude (coefficient of variation Ͻ5 and Ͻ10%, respectively, calculated as the standard deviation divided by the mean of five prior recordings) were subjected to further study.…”

Actual Aspects of Treatment Strategies in Spinal Cord Injury

“…The serotoninergic transmitter system is also involved in the development of spinal cord edema following trauma, and the edema formation could be blocked after prior depletion of serotonin (5-HT) with the synthesis inhibitor fenclonine [141]. Administration of a combination of receptor antagonists of 5-HT 2/5 -HT 1 mianserin and (s)-emopamil improves motor function and preserves descending tracts [124,133,134]. Puniak et al [124] found preservation of descending raphe-spinal axons below the lesion site after mianserin treatment.…”