The effect of nimodipine and dextran on axonal function and blood flow following experimental spinal cord injury

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✓ There is evidence that posttraumatic ischemia is important in the pathogenesis of acute spinal cord injury (SCI). In the present study spinal cord blood flow (SCBF), measured by the hydrogen clearance technique, and motor and somatosensory evoked potentials (MEP and SSEP) were recorded to evaluate whether the administration of nimodipine and dextran 40, alone or in combination, could increase posttraumatic SCBF and improve axonal function in the cord after acute SCI. Thirty rats received a 53-gm clip compression injury on the cord at T-1 and were then randomly and blindly allocated to one of six treatment groups (five rats in each). Each group was given an intravenous infusion of one of the following over 1 hour, commencing 1 hour after SCI: placebo and saline; placebo and dextran 40; nimodipine 0.02 mg/kg and saline; nimodipine 0.02 mg/kg and dextran 40; nimodipine 0.05 mg/kg and saline; and nimodipine 0.05 mg/kg and dextran 40.

The preinjury physiological parameters, including the SCBF at T-1 (mean ± standard error of the mean: 56.84 ± 4.51 ml/100 gm/min), were not significantly different (p > 0.05) among the treatment groups. Following SCI, there was a significant decrease in the SCBF at T-1 (24.55 ± 2.99 ml/100 gm/min; p < 0.0001) as well as significant changes in the MEP recorded from the spinal cord (MEP-C) (p < 0.0001), the MEP recorded from the sciatic nerve (MEP-N) (p < 0.0001), and the SSEP (p < 0.002). Only the combination of nimodipine 0.02 mg/kg and dextran 40 increased the SCBF at T-1 (43.69 ± 6.09 ml/100 gm/min; p < 0.003) and improved the MEP-C (p < 0.0001), MEP-N (p < 0.04), and SSEP (p < 0.002) following SCI. With this combination, the changes in SCBF were significantly related to improvement in axonal function in the motor tracts (p < 0.0001) and somatosensory tracts (p < 0.0001) of the cord. This study provides quantitative evidence that an increase in posttraumatic SCBF can significantly improve the function of injured spinal cord axons, and strongly implicates posttraumatic ischemia in the pathogenesis of acute SCI.

Article Information

Address reprint requests to: Michael G. Fehlings, M.D., Lab 12-423, Playfair Neuroscience Unit, Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.

Dr. Fehlings is a Fellow of the Medical Research Council of Canada.

© AANS, except where prohibited by US copyright law.

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Figures

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    A schematic representation of the experimental protocol. For description see text.

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    Left: Computer-derived grand mean of the motor evoked potentials recorded from the spinal cord (MEP-C) of 20 normal rats at T-10 (average of 20,480 responses). The normal MEP-C consists of a series of positive deflections: an initial d (direct) wave which reflects direct pyramidal cell activation, and a series of subsequent i waves which result from indirect activation of pyramidal cells by cortical inter-neurons as well as activation of nonpyramidal tracts. Right: Computer-derived grand mean of somatosensory evoked potentials (SSEP) recorded from 16 normal rats from the sensorimotor cortex following sciatic nerve stimulation (average of 32,768 responses). The normal rat SSEP consists of four positive (P) and three negative (N) peaks.

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    Spinal cord blood flow (SCBF) recorded from the injury site at T-1 in 30 rats. The preinjury SCBF (56.83 ± 3.82 ml/100 gm/min) did not differ significantly among the groups. Following spinal cord injury, there was a significant decrease in SCBF in all groups (mean ± standard error of the mean: 24.55 ± 2.99 ml/100 gm/min). In the group treated with nimodipine (Nim) 0.02 mg/kg and dextran 40, there was a significant increase in SCBF immediately after infusion (43.69 ± 6.09 ml/100 gm/min) and at 1 hour postinfusion (30.54 ± 3.47 ml/100 gm/min) in comparison with the other groups (mean: 17.30 ± 1.50 ml/100 gm/min). At 2 hours postinfusion, the SCBF was similar for all groups.

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    Spinal cord blood flow (SCBF) data recorded adjacent to the injury site from the cord at C-6 in 30 rats. The preinjury SCBF was similar in all groups (mean ± standard error of the mean: 51.88 ± 3.72 ml/100 gm/min). With injury, the SCBF at C-6 declined significantly in each group (30.43 ± 1.99 ml/100 gm/min). Infusion of dextran alone or in combination with nimodipine (Nim) at 0.02 mg/kg or 0.05 mg/kg resulted in a significant increase in SCBF in comparison with the postinjury values. At 1 and 2 hours postinfusion the improvement in SCBF at C-6 in these groups had abated and there was no difference in SCBF among the six treatment groups.

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    Spinal cord blood flow (SCBF) data recorded distal to the injury site from the cord at T-10 in 30 rats. The SCBF remained constant in all groups throughout the experiment with the exception of the group treated with nimodipine (Nim) 0.02 mg/kg and dextran 40. In the latter, there was a significant increase in the postinfusion SCBF at T-10 to 81.49 ± 8.45 ml/100 gm/min (mean ± standard error of the mean).

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    Upper: Representative evoked potential recordings from a control rat which received placebo and saline. After cord injury, the motor evoked potentials recorded at the spinal cord (MEP-C) and at the sciatic nerve (MEP-N) and the somatosensory evoked potentials (SSEP) were abolished and did not recover postinfusion. The spinal evoked potentials (SEP) recorded from the cord at T-10 (caudal to the injury site) following stimulation of the sciatic nerve were unchanged pre- and postinjury, confirming the physiological integrity of the experimental preparation. Lower: Representative evoked potential recordings from a rat treated with nimodipine 0.02 mg/kg and dextran 40. After cord injury, the MEP-C and MEP-N were abolished and the amplitude of the SSEP was significantly attenuated. Postinfusion, there was a significant recovery of the MEP-C, MEP-N, and SSEP. The SEP recorded from the cord at T-10 (caudal to the injury site) following stimulation of the sciatic nerve were unchanged pre- and postinjury, confirming the physiological integrity of the experimental preparation.

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    The amplitude of the d wave of the motor evoked potential recorded at the spinal cord and plotted as a function of time. Preinjury, the d wave amplitude was similar in all groups. After spinal cord injury, there was a significant reduction in d wave amplitude in all groups. With the exception of the groups treated with nimodipine (Nim) 0.02 mg/kg or 0.05 mg/kg in combination with dextran 40, there was a progressive attenuation of d wave amplitude after injury. After treatment with nimodipine 0.02 mg/kg and dextran 40, there was a significant recovery of d wave amplitude which persisted until the conclusion of recording. In the group that received nimodipine 0.05 mg/kg and dextran 40, there was transient delayed recovery of d wave amplitude at 1 hour postinfusion.

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    Upper: Superimposed postinfusion motor evoked potential (MEP) traces from the spinal cord of rats treated with placebo and saline (left) or nimodipine 0.02 mg/kg and dextran 40 (right). Lower: The respective grand mean MEP's are shown. These data illustrate a significant return of axonal function in the motor tracts of the cord after infusion of nimodipine 0.02 mg/kg and dextran 40.

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    The amplitude of the N2 wave of the somatosensory evoked potentials plotted as a function of time. Preinjury, the N2 amplitude was similar for all groups. After spinal cord injury, there was a significant reduction of N2 wave amplitude in all groups. With the exception of the group treated with nimodipine (Nim) 0.02 mg/kg and dextran 40, there was a progressive attenuation of N2 amplitude after injury. Following treatment with nimodipine 0.02 mg/kg and dextran 40, however, there was a significant recovery of the N2 amplitude which persisted at 1 hour but was no longer apparent at 2 hours postinfusion.

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    Relationship between the d wave amplitude of the motor evoked potentials recorded at the spine and the spinal cord blood flow (SCBF) in 30 rats (five observations per rat: 150 observations in total).

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    Changes in mean arterial blood pressure (MABP), spinal cord blood flow at T-1 (SCBF T1), d wave amplitude of the motor evoked potentials recorded at the spine (MEP D), and the somatosensory evoked potential (SSEP) N2 wave amplitude with drug infusion (postinfusion-preinfusion value). Although the infusion of saline, dextran, and nimodipine (Nim) 0.02 mg/kg with dextran 40 increased the MABP, only the latter increased the SCBF and promoted a recovery of axonal function.

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