Spinal cord blood flow and evoked potential responses after treatment with nimodipine or methylprednisolone in spinal cord-injured rats.

This study examined the effect of nimodipine or methylprednisolone on spinal cord blood flow (SCBF) and electrophysiological function after spinal cord injury in rats. Three groups of male rats (n = 10 per group) were injured by compression of the cord at T1 for 1 minute with a 52-g clip. The hydrogen clearance technique was used to measure SCBF at the T1 segment. Motor and somatosensory evoked potentials were recorded. SCBF and evoked potentials were measured before injury and again at approximately 1 and 2.5 hours after injury. The methylprednisolone group received a bolus of methylprednisolone (30 mg/kg) at 5 minutes after injury and then at 15 minutes after injury, the group received an infusion of methylprednisolone at 5.4 mg/kg per hour. The nimodipine group received placebo at 5 minutes and then received an infusion of nimodipine at 0.02 mg/kg per hour at 15 minutes. The placebo group received placebo at both times. Physiological parameters were closely monitored and maintained within the normal range. Albumin was administered after injury to maintain mean arterial blood pressure at or above 80 mm Hg. The infusions were continued for approximately 3 hours after spinal cord injury. SCBF was not significantly different between the experimental groups at either 1 or 2.5 hours postinjury (P = 0.16 and 0.71, respectively), and evoked potential responses did not return in any rat at any time after injury. Thus, this experiment failed to demonstrate an improvement in SCBF or electrophysiological function with either drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Further studies of nimodipine in experimental spinal cord injury in the rat.

Previously in our laboratory, nimodipine was effective in reversing posttraumatic ischemia and promoting electrophysiologic recovery in a rat spinal cord injury (SCI) model. However, these beneficial effects were achieved when nimodipine was combined with adjuvant therapy to reverse posttraumatic hypotension, by either volume expansion or vasopressor therapy. The present experiments determined if nimodipine alone can increase spinal cord blood flow (SCBF) and improve function after SCI. The hydrogen clearance technique was used to measure SCBF, and motor and somatosensory evoked potentials (MEP and SSEP) were used to quantitate electrophysiologic function. SCBF, MEP, and SSEP were recorded before and after a 52 g clip compression injury at the T1 segment and then repeated after a 35 minute infusion of nimodipine. Twenty-five rats were allocated randomly to five equal groups, each of which received 35 minute infusions of one of the following doses of nimodipine: (1) 0 mg/kg, (2) 0.005 mg/kg, (3) 0.01 mg/kg, (4) 0.025 mg/kg, or (5) 0.05 mg/kg. SCBF decreased after injury in all groups, and there was no increase in SCBF after nimodipine infusion in any group. MEP and SSEP were abolished by the injury in all rats, and there was no recovery of the evoked potentials in any group. It is concluded that adjuvant therapy for posttraumatic hypotension may be necessary for nimodipine to improve SCBF and promote recovery of function in the injured spinal cord.

Improvement in post-traumatic spinal cord blood flow with a combination of a calcium channel blocker and a vasopressor.

We have recently shown that nimodipine, a calcium channel blocker, can increase spinal cord blood flow (SCBF) in normal rats and can improve SCBF after spinal cord trauma if the mean systemic arterial pressure (mSAP) is restored to normal levels by the vasopressor, adrenalin. The present study is a further analysis of the improvement in post-traumatic SCBF (measured with the hydrogen clearance technique) with the combination of adrenalin and nimodipine. In addition, image analysis was used to study the potential risk of this combination for exacerbating intramedullary hemorrhage in the injured spinal cord. SCBF, mSAP, and other physiologic parameters were measured preinjury, postinjury, and post-treatment. A 53.0-gram clip compression injury at the T1 spinal segment was delivered for 1 minute to three treatment groups (saline, adrenalin, and adrenalin plus nimodipine) comprised of five rats each. Injury caused a marked decline in SCBF and mSAP. Treatment with adrenalin alone or combined with nimodipine (1.5 micrograms/kg/min IV) improved mSAP to 100-125 mm Hg. However, adrenalin alone failed to improve SCBF, whereas nimodipine plus adrenalin produced a marked improvement of approximately 60% in post-traumatic SCBF. Morphometric analysis showed no significant difference between per cent area or volume of hemorrhage between the three treatment groups, although there was a trend for increased hemorrhage in the adrenalin-alone group perhaps due to the higher post-traumatic mSAP in this group. Further studies are required to find the minimal elevation in mSAP produced by a vasopressor that would still cause an improvement in post-traumatic SCBF by nimodipine, and to determine whether this combination improves function after spinal cord injury.

Effect of a direct current field on axons after experimental spinal cord injury.

There is evidence that direct current (DC) stimulation promotes neurologic recovery in spinal cord injury. The authors conducted a morphometric analysis of axons at the site of spinal cord injury in adult rats treated with a DC field. Ten rats received a 17-g and 15 rats a 53-g clip compression injury and were treated with either a sham (control) or a functioning DC stimulator for 8 weeks. Five normal rats were also assessed. There was a significant relation (p less than 0.0001) between the severity of injury and the number of axons at the injury site. After the 17-g injury, there was no significant difference in the number of axons between control and treated rats. However, after the 53-g injury, there were significantly (p less than 0.05) more axons in treated than control rats. Both degrees of injury caused preferential destruction of large-calibre axons. Subsequent analysis showed that the axon diameter of treated rats with 17-g or 53-g injury was significantly greater (p less than 0.05) than that of control rats with 17-g or 53-g injury. These data, for the first time, show that the application of a DC field increases the number and calibre of axons at the site of a spinal cord injury and enhances the survival or regrowth of axons following spinal cord injury in the rat.

The effect of direct-current field on recovery from experimental spinal cord injury.

Recent work has indicated that direct-current (DC) fields may promote recovery after acute spinal cord injury. In the present experiments, the therapeutic value of an applied DC field was studied in 40 rats with clip compression injuries of the cord at C7-T1. The rats were randomly allocated to one of four groups including 10 rats each: two groups received a 17-gm cord injury and two groups a 53-gm injury. One group at each injury severity received implantation of a treatment (14 microA) DC stimulator and the other group a control (0 microA) stimulator. Clinical neurological function was assessed weekly by the inclined-plane technique. At 8 weeks after injury, motor and somatosensory evoked potentials (MEP's and SSEP's) were recorded, and the axonal tracer horseradish peroxidase (HRP) was introduced into the cord at T-6. The total number of HRP-labeled cells was counted in every sixth coronal section through the brain stem and motor cortex. All outcome parameters were assessed blindly. In the 17-gm group, there were no significant differences in any outcome measure between control and treated rats. In contrast, in the 53-gm group, the inclined-plane scores, the amplitude of the MEP's, and the number of labeled cells in the red nucleus, raphé nuclei, and vestibular nuclei were greater in treated than in control rats. These data strongly indicate that an applied DC field can produce functional neurological and anatomical improvement in rats with acute spinal cord injuries.

Effect of alternating current stimulation of the spinal cord on recovery from acute spinal cord injury in rats.

The therapeutic value of electrical stimulation of the spinal cord was studied in rats injured by acute compression of the spinal cord. Twenty adult Wistar rats underwent cord compression at T6-7 by the extradural clip compression technique at a force of 125 g for 1 minute. After injury and group randomization, stimulating electrodes were placed extradurally, proximal and distal to the injury site, and attached to a small, implantable receiver-stimulator. The receiver was secured to the paraspinal muscles and implanted subcutaneously, overlying the thoracic spine. The animals were maintained in specially designed cages with encircling antennae attached to radio frequency transmitters. The 10 treatment animals were subjected to a 460-kHz electromagnetic field, pulsed at a frequency of 10 Hz. The receivers converted the pulsed radio frequency into square-wave pulses at the cord electrodes (width 1 ms, frequency 10 Hz). The 10 control animals were exposed to a similar field but with a frequency below the range of the tuned receiver, and therefore they did not receive the square-wave pulse. Clinical recovery was assessed by the inclined plane technique which measures the maximum angle of inclination attained without falling. After 15 weeks of continuous spinal cord stimulation, the inclined plane performance was not significantly different between the two groups (treatment group mean, 44.4 +/- 5.4; control group mean, 41.7 +/- 7.9). This is the first experimental study of the effect of long-term continuous electrical stimulation on spinal cord recovery in mammals. The methods required and the technical aspects involved in achieving continuous stimulation, and the guidelines for future study of this modality are discussed.

Recovery of spinal cord function induced by direct current stimulation of the injured rat spinal cord.

Direct current stimulation has been shown by others to enhance the regeneration of several types of tissues, including nervous tissue in some species. The purpose of the present experiment was to assess the value of direct current stimulation for enhancing the recovery of spinal cord function after clip compression injury of the rat spinal cord. Twenty Wistar rats underwent a 1-minute, 50-g clip compression injury at T-1, after which electrodes were placed epidurally with the anode proximal and the cathode distal to the injury site. These electrodes were attached to a stimulator implanted subcutaneously. Ten animals received stimulators that produced a constant current of 14 microA, and the remainder received stimulators with no electrical output and served as controls. Assignment of stimulators was random, and the treatment group was not identified until sacrifice. Neurological function was tested weekly for 15 weeks by the inclined plane technique, after which the animals were killed and the injured cords were examined for histological evidence of regeneration. The mean inclined plane result for the treatment group (39 +/- 5 degrees) was significantly better than that for the control group (31 +/- 6 degrees) (P less than 0.02), although there was no significant difference in histological findings between the two groups. Thus, direct current stimulation of the injured mammalian spinal cord produced improvement in neurological function and warrants further investigation.

Intraneoplastic injection of CCNU for experimental brain tumor chemotherapy.

Chemotherapy experiments were performed with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in an experimental mouse brain tumor model. Cell suspensions of a transplantable mouse ependymoblastoma were injected intracerebrally by means of a stereotactic frame. CCNU was given either intraperitoneally or by direct intraneoplastic injection beginning the fifth day after tumor cell implantation. Intraneoplastic injection beginning the fifth day after tumor cell implantation. Intraneoplastic injections of drugs were made with the stereotactic frame. A single intraneoplastic injection of CCNU was found to be highly effective in increasing the median day of death and in yielding large numbers of long-term survivors. In some experiments CCNU injected into the neoplasm produced increased numbers of long-term survivors and less systemic toxicity than when injected intraperitoneally.