Store-operated calcium entry (SOCE) is crucial for cellular processes, including cellular calcium homeostasis and signaling. However, uncontrolled activation of SOCE is implicated in neurological disorders and CNS trauma, but underlying mechanisms remain unclear. We hypothesized that inhibiting SOCE enhances neurological recovery following contusive spinal cord injury (SCI). To investigate key SOCE effectors, stromal interaction molecules (STIM) and Orai channels on neurological recovery following spinal cord injury (SCI), we utilized male and female conditional neuronal Stim1KO mice to investigate the role of neuronal STIM1 in SCI outcome following a mild (30 kdyn) contusion at T13. To investigate Ca2+ store mediated Ca2+ store depletion, and SOCE-mediated refilling in SCI outcome, we inhibited the IP3R with 2-APB, and uncoupled STIM/Orai activation with DPB162-AE, respectively. Intravital microscopy demonstrated that neuron specific Stim1KO increased axonal survival post-SCI. Likewise, pharmaceutical uncoupling of STIM1/Orai activation, alone or combined with IP3R inhibition, enhanced axon survival 24 h after T13 contusion in male and female Thy1YFP+ mice. Behavioral evaluation of female C57BL/6 J mice revealed that DPB162-AE, alone or combined with 2-APB, improved neurological recovery 4-6 weeks following a moderate (50 kdyn) T9 contusion. Immunohistochemical analysis showed that combined treatment improves axonal sparing, increases astrogliosis, and reduces microglia/macrophage density at the injury epicenter 6 weeks post-SCI. These findings reveal a novel role for neuronal STIM1 in "bystander" secondary axonal degeneration, and introduce STIM/Orai functional uncoupler DPB162-AE, combined with IP3R inhibitor 2-APB, as a novel therapeutic approach for improving neurological recovery following SCI.

Ryanodine receptors (RyRs) mediate calcium release from calcium stores and have been implicated in axonal degeneration. Here, we use an intravital imaging approach to determine axonal fate after spinal cord injury (SCI) in real-time and assess the efficacy of ryanodine receptor inhibition as a potential therapeutic approach to prevent intra-axonal calcium-mediated axonal degeneration. Adult 6-8 week old Thy1YFP transgenic mice that express YFP in axons, as well as triple transgenic Avil-Cre:Ai9:Ai95 mice that express the genetically-encoded calcium indicator GCaMP6f in tdTomato positive axons, were used to visualize axons and calcium changes in axons, respectively. Mice received a mild SCI at the T12 level of the spinal cord. Ryanodine, a RyR antagonist, was given at a concentration of 50 μM intrathecally within 15 min of SCI or delayed 3 h after injury and compared with vehicle-treated mice. RyR inhibition within 15 min of SCI significantly reduced axonal spheroid formation from 1 h to 24 h after SCI and increased axonal survival compared with vehicle controls. Delayed ryanodine treatment increased axonal survival and reduced intra-axonal calcium levels at 24 h after SCI but had no effect on axonal spheroid formation. Together, our results support a role for RyR in secondary axonal degeneration.

Secondary axonal loss contributes to the persistent functional disability following trauma. Consequently, preserving axons following spinal cord injury (SCI) is a major therapeutic goal to improve neurological outcome; however, the complex molecular mechanisms that mediate secondary axonal degeneration remain unclear. We previously showed that IP₃R-mediated Ca²⁺ release contributes to axonal dieback and axonal loss following an ex vivo laser-induced SCI. Nevertheless, targeting IP₃R in a clinically relevant in vivo model of SCI and determining its contribution to secondary axonal degeneration has yet to be explored. Here we used intravital two-photon excitation microscopy to assess the role of IP₃R in secondary axonal degeneration in real-time after a contusive-SCI in vivo. To visualize Ca²⁺ changes specifically in spinal axons over time, adult 6-8 week-old triple transgenic Avil-Cre:Ai9:Ai95 (sensory neuron-specific expression of tdTomato and the genetic calcium indicator GCaMP6f) mice were subjected to a mild (30 kdyn) T12 contusive-SCI and received delayed treatment with the IP₃R blocker 2-APB (100 μM, intrathecal delivery at 3, and 24 h following injury) or vehicle control. To determine the IP₃R subtype involved, we knocked-down IP₃R3 using capped phosphodiester oligonucleotides. Delayed treatment with 2-APB significantly reduced axonal spheroids, increased axonal survival, and reduced intra-axonal Ca²⁺ accumulation within dorsal column axons at 24 h following SCI in vivo. Additionally, knockdown of IP₃R3 yielded increased axon survival 24 h post-SCI. These results suggest that IP₃R-mediated Ca²⁺ release contributes to secondary axonal degeneration in vivo following SCI.

Ryanodine receptors (RyRs) are highly conductive intracellular Ca²⁺ release channels and are widely expressed in many tissues, including the central nervous system. RyRs have been implicated in intracellular Ca²⁺ overload which can drive secondary damage following traumatic injury to the spinal cord (SCI), but the spatiotemporal expression of the three isoforms of RyRs (RyR1-3) after SCI remains unknown. Here, we analyzed the gene and protein expression of RyR isoforms in the murine lumbar dorsal root ganglion (DRG) and the spinal cord lesion site at 1, 2 and 7 d after a mild contusion SCI. Quantitative RT PCR analysis revealed that RyR3 was significantly increased in lumbar DRGs and at the lesion site at 1 and 2 d post contusion compared to sham (laminectomy only) controls. Additionally, RyR2 expression was increased at 1 d post injury within the lesion site. RyR2 and -3 protein expression was localized to lumbar DRG neurons and their spinal projections within the lesion site acutely after SCI. In contrast, RyR1 expression within the DRG and lesion site remained unaltered following trauma. Our study shows that SCI initiates acute differential expression of RyR isoforms in DRG and spinal cord.

Spinal cord injury is a complex cascade of reactions secondary to the initial mechanical trauma that puts into action the innate properties of the injured cells, the circulatory, inflammatory, and chemical status around them, into a non-permissive and destructive environment for neuronal function and regeneration. Priming means putting a cell, in a state of "arousal" towards better function. Priming can be mechanical as trauma is known to enhance activity in cells.

A comprehensive review of the literature was performed to better understand the possible chemical primers used for spinal cord injuries.

Taken together, many studies have shown various promising results using the substances outlined herein for treating SCI.

Acute spinal cord injury (ASCI) occurs as a result of physical disruption of spinal cord axons through the epicenter of injury leading to deficits in motor, sensory, and autonomic function. This is a debilitating neurological disorder common in young adults that often requires life-long therapy and rehabilitative care, placing a significant burden on our healthcare system. While no cure exists, research has identified various pharmacological compounds that specifically antagonize primary and secondary mechanisms contributing to the etiology of ASCI. Several compounds including methylprednisolone (MPSS), GM-1 ganglio-side, thyrotropin releasing hormone (TRH), nimodipine, and gacyclidine have been tested in prospective randomized clinical trials of ASCI. MPSS and GM-1 ganglioside have shown evidence of modest benefits. Clearly trials of improved neuroprotective agents are required. Promising potential therapies for ASCI include riluzole, minocycline, erythropoietin, and the fusogen polyethylene glycol, as well as mild hypothermia.

Traumatic spinal cord injury is a consequence of a primary mechanical insult and a sequence of progressive secondary pathophysiological events that confound efforts to mitigate neurological deficits. Pharmacotherapy aimed at reducing the secondary injury is limited by a narrow therapeutic window. Thus, novel drug strategies must target early pathological mechanisms in order to realize the promise of efficacy for this form of neurotrauma. Research has shown that an accumulation of intracellular sodium as a result of trauma-induced perturbation of voltage-sensitive sodium channel activity is a key early mechanism in the secondary injury cascade. As such, voltage-sensitive sodium channels are an important therapeutic target for the treatment of spinal cord trauma. This review describes the evolution of acute spinal cord injury and provides a rationale for the clinical utility of sodium channel blockers, particularly riluzole, in the management of spinal cord trauma.

Because of its potential for augmentation of blood flow and protection of neurons after neurological insult, nimodipine has been investigated as a treatment of spinal cord injury (SCI). The results have been inconsistent, possibly because of poor delivery of nimodipine to the injured spinal cord. The following study was designed to determine the delivery of nimodipine to the injured spinal cord. It was also hoped that information about the temporal and spatial pattern of binding of nimodipine after SCI might further elucidate the relationship between calcium channel activation and injury. Fourteen female Wistar rats were divided into three groups: control (n = 3), 30 min post-SCI (n = 6); and 4 h post-SCI (n = 5). The injury was produced by acute clip compression for 1 min at T1. [3H]Nimodipine was administered 5 min after laminectomy in the control group, and at the above-specified times after injury in the SCI groups. The drug was then allowed to equilibrate for 30 min before the animals were killed. The spatial patterns and concentrations of [3H]nimodipine in various segments of the spinal cord were autoradiographically determined. The highest concentrations of [3H]nimodipine were at the injury site after SCI. Also, the mean [3H]nimodipine concentrations in all sites in each animal were higher in the injury groups than in the control group (p < 0.05). This study indicates that delivery of this agent to the injured cord is possible, and provides evidence of widespread Ca2+ channel activation in the first 4 h after injury.

The effectiveness of nimodipine and N-acetylcysteine in experimental spinal cord injury was evaluated by measuring tissue lipid peroxidation levels of the damaged spinal cords 1 hour after the injury We used the clip compression method to produce acute spinal cord injury in 40 female Sprague-Dawley rats were used. The rats were divided into four groups of 10 each. Lipid peroxidation was assessed by measuring the tissue content of malonil dialdehyde (MDA). In group 3, nimodipine, and in group 4, N-acetylcysteine, was administered i.p. as a single dose immediately after the injury. The rats were sacrificed 1 hour after clip application. The tissue mean MDA content was 3,992 micromol MDA/gww in group 1 (sham operated), 10,192 micromol MDA/gww in group 2 (trauma), 10,449 micromol MDA/gww in group 3 (nimodipine treatment) and 9,009 micromol MDA/gww in group 4 (N-acetylcysteine treatment). These results demonstrated that a single dose of nimodipine and N-acetylcysteine had no effect on peroxidation of lipid membranes in the early period of experimental spinal cord injury.

Most of the numerous experimental studies to research pathophysiological changes following acute spinal cord injury suggest a two-step mechanism of damage to the spinal cord in which the primary (direct) or mechanical injury caused by the trauma initiates secondary (indirect) or progressive autodestructive injury of the cord. During recent years, free oxygen radical generation and lipid peroxidation have been considered to be responsible for secondary autodestructive injury. Alpha tocopherol occupies an important and unique position in the overall antioxidant defense. Alpha tocopherol-depleted animals are generally more susceptible to the adverse effects of environmental agents than are supplemented animals. This study was planned to study the effectiveness in counteracting this autodestructive process by supplementing alpha-tocopherol in rats maintained on a nutritionally adequate diet, and also to evaluate whether it will provide additional protection or not. Eighty healthy Wistar rats (treatment and controls) were included. The treatment group received 100 mg/kg alpha tocopherol each day, intraperitoneally for seven days. Using a standard acute spinal cord trauma model in Wistar rats trauma was applied, an malondialdehyde (MDA) which is a lipid peroxidation product was measured in the traumatized spinal cord at various times following the trauma in order to indirectly evaluate the lipid peroxidation and generation of free oxygen radicals in a time sequence. Statistical analysis of the values demonstrated that malondialdehyde formation in the alpha-tocopherol administered group was significantly lower than in the control group. These findings indicate that longterm administration of alpha-tocopherol may be useful to decrease lipid peroxidation following acute spinal cord trauma.

A reversible middle cerebral artery occlusion was performed in rats to determine whether nicardipine, a dihydropyridine voltage-sensitive Ca++ channel (VSCC) antagonist, exerts neuroprotective effects when administered 10 minutes following an ischemic insult, and if it does, whether this is due to its vasodilatory action and effect on cerebral blood flow (CBF) or to direct blockade of Ca++ entry into ischemic brain cells. An increase in the intracellular calcium, [Ca++]i, plays a major role in neuronal injury during cerebral ischemia. Although a large amount of Ca++ enters neurons through the VSCC during ischemia, inconsistent neuroprotective effects have been reported with the antagonists of the VSCC. An intraperitoneal injection of nicardipine (1.2 mg/kg) was administered to rats 10 minutes after the onset of ischemia, and 8, 16, and 24 hours after occlusion. Cortical CBF was determined by laser-Doppler flowmetry. Neurological and neuropathological examinations were performed after 72 hours. Neuron-specific enolase, a specific marker for the incidence of neuronal injury, was measured in plasma. The CBF and other physiological parameters were not affected by nicardipine during occlusion or reperfusion. However, nicardipine treatment significantly improved motor neurological outcome by 29%, and the infarction and edema volume in the pallium as well as the edema volume in the striatum were significantly reduced by 27%, 37%, and 52%, respectively. Nicardipine also reduced the neuron-specific enolase plasma levels by 50%, 42%, and 59% at 24, 48, and 72 hours after the occlusion, respectively. It is concluded that nicardipine may attenuate focal ischemic brain injury by exerting direct neuroprotective and antiedematous effects that do not depend on CBF.

Clinical recovery after central nervous system (CNS) trauma or ischemia may be limited by a neural injury process that is triggered and perpetuated at the cellular level, rather than by a lesion amenable to surgical repair. It is widely thought that one such process, a fundamental pathological mechanism initiated by CNS injury, is a disruption of cellular Ca2+ homeostasis. Because of the critical role of Ca2+ ions in regulating innumerable cellular functions, this major homeostatic disturbance is thought to trigger neuronal and axonal degeneration and produce clinical disability. We review those aspects of normal and pathological Ca2+ homeostasis in neurons that relate to neurodegeneration and to the application of neuroprotective strategies for the treatment of CNS injury. In particular, we examine the contribution of Ca(2+)-permeable ionic channels, Ca2+ pumps, intracellular Ca2+ stores, intracellular Ca2+ buffering systems, and the roles of secondary, Ca(2+)-dependent processes in neurodegeneration. A number of hypotheses linking Ca2+ ions and Ca2+ permeable channels to neurotoxicity are discussed with an emphasis on strategies for lessening Ca(2+)-related damage. A number of these strategies may have a future role in the treatment of traumatic and ischemic CNS injury.

Calcium ion entry following mechanical neurite transection was examined in cultured sympathetic neurons loaded with the Ca2+ indicator fluo-3. Neurite transection produced a rapid [Ca2+]i rise in the cell soma which preceded any [Ca2+]i rise in the neurite (n = 30). Blocking sodium channels with tetrodotoxin had no effect on the Ca2+ rise, but inactivating voltage-sensitive Ca2+ channels by bath-applying 140 mM potassium prior to the transection, and the simultaneous application of nimodipine and omega-conotoxin GVIA, blockers of L-type and N-type Ca2+ channels, respectively, considerably attenuated the Ca2+ rise in the soma and neurites. These data contradict the intuitive hypothesis that Ca2+ entry following mechanical neurite transection occurs via non-specific influx pathways produced by cell-membrane disruption and provide direct evidence in mammalian neurons that immediate, traumatically-induced, increases in neuronal [Ca2+]i are amenable to pharmacological manipulation.

The purpose of the present study was to examine the behavioral, electrophysiologic, and anatomic responses to nimodipine or methylprednisolone treatment of acute experimental spinal cord injury. Four groups of rats were injured at T1 by compressing the cord with a 52-g clip for 1 minute. The treatments were begun 15 minutes after injury, and the animals were observed thereafter for 8 weeks. Nimodipine 0.02 mg/kg/h intravenously (iv) for 8 hours with adjuvant albumen volume expansion, followed by 20 mg/kg nimodipine enterally three times per day for 7 days, produced a moderately better composite score comprising four endpoint parameters than the other treatments which consisted of nimodipine iv for 8 hours only, methylprednisolone 30 mg/kg iv bolus followed by 5.4 mg/kg/h iv for 8 hours, or control.

The lipophilic calcium channel antagonist flunarizine has been demonstrated to be neuroprotective in several models of cerebral ischemia. Ischemic spinal cord injury may have a similar pathophysiology and hence may respond in a similar fashion. This study was designed to investigate the effects of pretreatment with flunarizine on systemic hemodynamics, spinal cord blood flow, and neurological recovery in a rabbit model of ischemic spinal cord injury.

New Zealand White rabbits were anesthetized with ketamine and xylazine and instrumented for systemic blood pressure monitoring and spinal cord blood flow measurements using the microsphere method. After pretreatment with flunarizine or vehicle, ischemic spinal cord injury was created selectively in the caudal regions of the spinal cord by cross-clamping the abdominal aorta for a period of 25 minutes. Spinal cord blood flow was measured before, during, and 15 minutes after cross-clamp removal. Animals were allowed to recover and were graded neurologically at 18 and 24 hours after ischemia.

Flunarizine injection was associated with hypotension that was both transient and dose related. Animals pretreated with flunarizine 0.4 mg/kg had significantly improved neurological recovery scores at 18 hours after ischemia (P = .017) compared with vehicle controls. At 24 hours this effect was lessened (P = .095); however, 60% of flunarizine-treated animals retained their ability to hop, whereas all of the vehicle-treated animals were nonambulatory.

Flunarizine has a protective effect on neurological recovery after experimental ischemic spinal cord injury. The therapeutic window is narrow, and dosing is limited by untoward hypotension. The mechanism of protection likely involves inhibition of pathological cytosolic calcium accumulation rather than a direct effect on vascular smooth muscle.

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)

The cortical somatosensory evoked potentials (CSEPs) were recorded to determine if the administration of nimodipine improves axonal function after spinal cord injury. Animals receiving a 52 g compression injury (a moderately severe injury) for 5 minutes were randomly allocated to one of five treatment groups. Each group was given an infusion of one of the following nimodipine regiments over 2 hours, commencing 1 hour before compression: placebo (n = 20), 0.5 micrograms/kg (n = 10), 0.25 micrograms/kg (n = 20), 0.125 micrograms/kg (n = 10), and 0.25 micrograms/kg + Hetstarch (n = 10). In the control group, 65% of animals lost the CSEPs immediately after the injury with almost all (95%) of these regaining the CSEPs within 15 minutes after decompression of the spinal cord. In the treated groups, the rate of the CSEP loss was highest in the 0.5 micrograms/kg group. This group also had the lowest CSEP recovery. The proportion of the CSEP loss was essentially the same for the other nimodipine-treated groups, although it seemed that there was an increasing number of nonresponses with increasing the nimodipine dose. Our data indicate lack of any beneficial effects of nimodipine on axonal function as measured by evoked activities in experimental spinal cord injury.

The effects of nimodipine and thyrotropin-releasing hormone (TRH) were compared in a clip-compression model of experimental spinal cord injuries (SCI) in rats. Thirty rats received a 50-g clip-compression injury on the cord at T9. Ten rats were given 0.02 mg/kg nimodipine and dextran 40 (3 ml) i.v. 1 h after injury. Ten rats were given 2 mg/kg TRH and dextran 40 (3 ml) i.v. 1 h after injury followed by 1 mg/kg per hour for 4 h. The remaining ten rats were given only saline. TRH treatment significantly improved somatosensory-evoked potentials (SEPs) and mean arterial blood pressures (MABPs), whereas nimodipine treatment had no effect on these variables (Fisher's exact test (P less than 0.01).

In patients with spinal cord injury, the primary or mechanical trauma seldom causes total transection, even though the functional loss may be complete. In addition, biochemical and pathological changes in the cord may worsen after injury. To explain these phenomena, the concept of the secondary injury has evolved for which numerous pathophysiological mechanisms have been postulated. This paper reviews the concept of secondary injury with special emphasis on vascular mechanisms. Evidence is presented to support the theory of secondary injury and the hypothesis that a key mechanism is posttraumatic ischemia with resultant infarction of the spinal cord. Evidence for the role of vascular mechanisms has been obtained from a variety of models of acute spinal cord injury in several species. Many different angiographic methods have been used for assessing microcirculation of the cord and for measuring spinal cord blood flow after trauma. With these techniques, the major systemic and local vascular effects of acute spinal cord injury have been identified and implicated in the etiology of secondary injury. The systemic effects of acute spinal cord injury include hypotension and reduced cardiac output. The local effects include loss of autoregulation in the injured segment of the spinal cord and a marked reduction of the microcirculation in both gray and white matter, especially in hemorrhagic regions and in adjacent zones. The microcirculatory loss extends for a considerable distance proximal and distal to the site of injury. Many studies have shown a dose-dependent reduction of spinal cord blood flow varying with the severity of injury, and a reduction of spinal cord blood flow which worsens with time after injury. The functional deficits due to acute spinal cord injury have been measured electrophysiologically with techniques such as motor and somatosensory evoked potentials and have been found proportional to the degree of posttraumatic ischemia. The histological effects include early hemorrhagic necrosis leading to major infarction at the injury site. These posttraumatic vascular effects can be treated. Systemic normotension can be restored with volume expansion or vasopressors, and spinal cord blood flow can be improved with dopamine, steroids, nimodipine, or volume expansion. The combination of nimodipine and volume expansion improves posttraumatic spinal cord blood flow and spinal cord function measured by evoked potentials. These results provide strong evidence that posttraumatic ischemia is an important secondary mechanism of injury, and that it can be counteracted.

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.

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 greater than 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 less than 0.0001) as well as significant changes in the MEP recorded from the spinal cord (MEP-C) (p less than 0.0001), the MEP recorded from the sciatic nerve (MEP-N) (p less than 0.0001), and the SSEP (p less than 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 less than 0.003) and improved the MEP-C (p less than 0.0001), MEP-N (p less than 0.04), and SSEP (p less than 0.002) following SCI. With this combination, the changes in SCBF were significantly related to improvement in axonal function in the motor tracts (p less than 0.0001) and somatosensory tracts (p less than 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.