Comparison of a Serotonin Antagonist, Opioid Antagonist, and TRH Analog for the Acute Treatment of Experimental Spinal Trauma

Abstract

The therapeutic efficacies of a serotonin antagonist (mianserin), an opioid antagonist (nalmefene), and a TRH analog (YM-14673) were compared in a well-characterized model of experimental spinal trauma in the rat. Injury was produced by the weight-drop method at T10 and confirmed by the disappearance of the somatosensory evoked response during the subsequent 15 minutes. Drug or vehicle treatments were administered randomly as a single intravenous bolus 15 minutes after injury. Functional outcome was blindly assessed for 2 weeks postinjury using a modified Tarlov scale and the Rivlin-Tator angleboard test. The survival of descending raphe-spinal axons was determined by measurement of serotonin in postmortem spinal tissues located above and below the injury, and histopathologic studies were carried out at the site of injury. All agents displayed similar and significant efficacies with respect to Tarlov and Rivlin-Tator measures of motor recovery and preservation of raphe-spinal fibers below the lesion site. In contrast, none of the agents were effective for preserving the central gray matter or myelin staining in the white matter in slices of tissue from the site of injury. Results are discussed in terms of the early treatment of spinal cord injury and future clinical trials.

Neuroprotective and Nootropic Actions of a Novel Cyclized Dipeptide after Controlled Cortical Impact Injury in Mice

“…(C) A significant correlation was detected between lesion volume values obtained with the two methods (P < 0.05, regression ANOVA). a variety of experimental models of CNS trauma in a number of species (Akdemir et al, 1993;Arias MJ, 1987;Behrmann et al, 1994;Ceylan et al, 1990Ceylan et al, , 1992Faden, 1989Faden, , 1993Faden et al, 1981Faden et al, , 1990Fukuda et al, 1979;Puniak et al, 1991;Takami et al, 1991;Wang and Zhu, 1991). A small clinical study confirmed these beneficial effects in human spinal cord injury (Pitts et al, 1995).…”

Actual Aspects of Treatment Strategies in Spinal Cord Injury

“…The disadvantage of opiate antagonists is the fact that they block the analgesic effects of endogenous or exogenous opiates. Therefore, TRH and analogs were thought to be more effective, by acting in vivo as partial physiologic opiate antagonists that spare analgesic systems [4,49,56,59,124]. Moreover, it was shown that TRH but not naloxone treatment starting 24 h and as late as 7 days after injury is effective in rats with severe neurologic impairment following SCI.…”

“…Thus, it is suggested that the duration of the effectiveness of late treatment with TRH on the neurologic impairment in rats with SCI is > 1 week, while the duration with naloxone is < 24 h [93]. In contrast to the neurologic recovery described by Faden et al for opioid antagonists [58] and TRH analogs [59], Puniak et al [124] found that none of the agents was effective in preserving the central gray matter or the white matter at the site of injury.…”

Effects of serotonin 1A agonist on acute spinal cord injury

“…4 ± 6 Further, mianserin (5-HT2A antagonist) has been reported to be neuroprotective in acute spinal cord injuries. 7,8 Thus, 5-HT receptors may play a role in the pathological responses of axons to injury. However, in the absence of any previous evidence for 5-HT receptors existing on axons, most hypotheses regarding 5-HT mediated secondary axonal injury have focused on indirect mechanisms, such as posttraumatic ischemia.…”

“…7,8 However, the mechanisms by which 5-HT causes secondary tissue damage, especially with axons, are not well understood. Most investigators have focused on the possible indirect eects of 5-HT, such as posttraumatic ischemia, and it has been demonstrated that some peripheral and central axon terminals have 5-HT autoreceptors.…”