Join Date: Jul 2001
Thanks Bareback, I hope the following response by Dr. Young in August of this year provides some of the answers you're looking for.
Originally posted by Wise Young:
Ischemia damages both gray and white matter in the spinal cord. Much depends on the degree and distribution of white and gray matter damage. If the spinal cord ischemia is due to cardiac failure or low blood pressure, there may be widespread loss of neurons. In such a case, embryonic stem cell transplants that can produce new neurons probably is the best approach for replacing those cells. If the ischemia is localized (for example, due to prolonged compression of the cord), probably the same treatments that are currently being considered for contused spinal cords would be most applicable. In such a case, I think that the currently most promising therapies are OEG, chondroitinase, rolipram, C3, embryonic stem cells, adult stem cells, and alternating currents. As you know, many of these are going into clinical trials.
A number of recent studies of treatments of animal spinal cord ischemia models have shown some promise. For example, there is one recent study that suggests that OEG transplants are beneficial in a rat spinal cord ischemia model (Verdu, et al, 2001). Follis, et al. (1995) had earlier reported the gangliosides improve recovery after a thoracic aorta occluson model of spinal cord ischmia. Celik, et al. (2002) showed the erythropoietin remarkably reduces neuronal damage in a global ischemia model of the spinal cord.
Many studies have reported neuroprotective effects of drugs on spinal cord ischemia models. Lang-Lazdunski, et al. (2001) reported the the immunosuppressant FK506 improve recovery after thoracic aortic occlusion induced spinal cord ischemia. reported that agmantine improves neurological recovery after spinal cord ischmia. Lapchak, et al. (2000) reported neuroprotective effects of dehydroepiandrosterone on an rabbit aortic occlusion spinal cord ischemia model. Several investigators have reported that glutamate receptor blockers (Kanellopoulos, et al., 2000; Li & Tator, 2000; Gaviria, et al., 2000; Gilad & Gilad, 2000), calcium channel blockers (Burns, et al, 1999; Danielisova & Chavko, 1998), and GABA receptor agonist (Farooque, et al. 1999) are neuroprotective in spinal cord ischemia models.
So, there is no dearth of scientists studying spinal cord ischemia and both chronic and acute treatments.
&bull Verdu E, Garcia-Alias G, Fores J, Gudino-Cabrera G, Muneton VC, Nieto-Sampedro M and Navarro X (2001). Effects of ensheathing cells transplanted into photochemically damaged spinal cord. Neuroreport. 12 (11): 2303-9. Summary: Transplantation of olfactory ensheathing cells (OECs) into photochemically damaged rat spinal cord diminished astrocyte reactivity and parenchyma cavitation. The photochemical lesion performed at T12--L1 resulted in severe damage to the spinal cord, so that during the first 15 days postoperation all rats dragged their hindlimbs and did not respond to pinprick. The maximal area and volume of the cystic cavities were lower in transplanted than in non-transplanted rats, not significantly at the T12--L1 lesion site, but significantly at T9--T10 and L4--L6 cord levels. The density of astrocytes in the grey matter was similar at T12--L1 and L4--L6 in non-transplanted and trans- planted rats, but lower in the latter at T9--T10 level. However, in non-transplanted rats all astrocytes showed a hypertrophied appearance, with long and robust processes heavily GFAP-positive, and overexpression of proteoglycan inhibitor of neuritogenesis, whereas in transplanted rats only a few astrocytes showed hypertrophy and the majority had short, thin processes. These results indicate that OECs transplanted into damaged adult rat spinal cord exert a neuroprotective role by reducing astrocytic gliosis and cystic cavitation. Neuroplasticity and Regeneration Group, Department of Cell Biology, Physiology and Immunology, Universitat Autonoma de Barcelona, Edif. M., E-08193 Bellaterra, Spain.
&bull Follis F, Jenson B, Blisard K, Hall E, Wong R, Kessler R, Temes T and Wernly J (1995). Gangliosides and spinal cord ischemia secondary to aortic cross-clamping in the rat model. J Surg Res. 58 (6): 702-6. Summary: Gangliosides, complex glycolipids of the nervous system cell membranes, have been found effective both in reducing the degree of ischemic injury and in stimulating neuronal regeneration during the recovery period. In order to investigate their neuroprotective effect during spinal cord ischemia, 60 male Sprague-Dawley rats underwent occlusion of the thoracic aorta and both subclavian arteries for 13 min. In the postoperative period, function of hindlimbs was appraised, daily for 30 days, by a deficit score (0-15). The animals were then killed and spinal cord injury was assessed by a histologic score (0-3) based on the degree of gray and white matter gliosis, number of motor neurons, and white matter myelination. The rats received intraperitoneal injection of placebo (n = 29) or GM-1 30 mg/kg (n = 31) daily, from 2 days prior to surgery to 15 days after. The scores of each group for each day were analyzed by repeated measures analysis of variance. The rate of recovery was better for GM-1 (P < 0.001) from the 15th to the 30th day. A trend was seen toward lower scores in the GM-1 group [P = 0.056). Mean histologic scores [placebo = 1.14 +/- 0.23 SE, GM-1 = 1.58 +/- 0.22 SE) did not differ [Wilcoxon, P = 0.17). The present data support the hypothesis that functional improvement after spinal cord ischemia due to aortic occlusion is enhanced by the administration of gangliosides. Optical microscopy could document only irreversible injury and might not be sensitive enough to detect subtle changes during recovery of neural elements. Department of Cardiothoracic Surgery, University of New Mexico, Albuquerque 87131, USA.
&bull Celik M, Gokmen N, Erbayraktar S, Akhisaroglu M, Konakc S, Ulukus C, Genc S, Genc K, Sagiroglu E, Cerami A and Brines M (2002). Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury. Proc Natl Acad Sci U S A. 99 (4): 2258-63. Summary: The cytokine erythropoietin (EPO) possesses potent neuroprotective activity against a variety of potential brain injuries, including transient ischemia and reperfusion. It is currently unknown whether EPO will also ameliorate spinal cord injury. Immunocytochemistry performed using human spinal cord sections showed abundant EPO receptor immunoreactivity of capillaries, especially in white matter, and motor neurons within the ventral horn. We used a transient global spinal ischemia model in rabbits to test whether exogenous EPO can cross the blood-spinal cord barrier and protect these motor neurons. Spinal cord ischemia was produced in rabbits by occlusion of the abdominal aorta for 20 min, followed by saline or recombinant human (rHu)-EPO (350, 800, or 1,000 units/kg of body weight) administered intravenously immediately after the onset of reperfusion. The functional neurological status of animals was better for rHu-EPO-treated animals 1 h after recovery from anesthesia, and improved dramatically over the next 48 h. In contrast, saline-treated animals exhibited a poorer neurological score at 1 h and did not significantly improve. Histopathological examination of the affected spinal cord revealed widespread motor neuron injury associated with positive terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling in control but not in rHu-EPO-treated animals. These observations suggest both an acute as well as a delayed beneficial action of rHu-EPO in ischemic spinal cord injury. Because rHu-EPO is currently used widely with an excellent safety profile, clinical trials evaluating its potential to prevent motor neuron apoptosis and the neurological deficits that occur as a consequence of ischemic injury are warranted. Department of Anesthesiology, Dokuz Eylul University School of Medicine, Izmir 35340, Turkey.
&bull Lang-Lazdunski L, Heurteaux C, Dupont H, Rouelle D, Widmann C and Mantz J (2001). The effects of FK506 on neurologic and histopathologic outcome after transient spinal cord ischemia induced by aortic cross-clamping in rats. Anesth Analg. 92 (5): 1237-44. Summary: Spinal cord injury is a devastating complication of thoracoabdominal aortic surgery. We investigated the effect of the immunosuppressant FK506, a macrolide antibiotic demonstrated to have neuroprotective effects in cerebral ischemia models, in a rat model of transient spinal cord ischemia. Spinal cord ischemia was induced in anesthetized rats by using direct aortic arch plus left subclavian artery cross-clamping through a limited thoracotomy. Experimental groups were as follows: sham-operation; control, receiving only vehicle; FK506 A, receiving FK506 (1 mg/kg IV) before clamping; and FK506 B, receiving FK506 (1 mg/kg IV) at the onset of reperfusion. Neurologic status was assessed at 24 h and then daily up to 96 h with a 0 to 6 scale (0, normal function; 6, severe paraplegia). Rats were randomly killed at 24, 48, or 96 h, and spinal cords were harvested for histopathology. Physiologic variables did not differ significantly among experimental groups. All control rats suffered severe and definitive paraplegia. FK506-treated rats had significantly better neurologic outcome compared with control. Histopathologic analysis disclosed severe injury in the lumbar gray matter of all control rats, whereas most FK506-treated rats had less injury. These data suggest that FK506 can improve neurologic recovery and attenuate spinal cord injury induced by transient thoracic aortic cross-clamping. IMPLICATIONS: A single dose-injection of the immunosuppressant FK506 significantly improved neurologic outcome and attenuated spinal cord injury induced by transient thoracic aortic cross-clamping in the rat. Department of Cardiovascular Surgery, Bichat University Hospital and Xavier Bichat Medical University, Paris, France. email@example.com.
&bull Gilad GM and Gilad VH (2000). Accelerated functional recovery and neuroprotection by agmatine after spinal cord ischemia in rats. Neurosci Lett. 296 (2-3): 97-100. Summary: Treatment with agmatine, decarboxylated arginine, proved to be non-toxic and to exert neuroprotective effects in several models of neurotoxic and ischemic brain and spinal cord injuries. Here we sought to find out whether agmatine treatment would also prove beneficial in a rat spinal cord ischemia model (balloon occlusion of the abdominal aorta bellow the branching point of the left subclavian artery for 5 min). Agmatine was injected (100 mg/kg, i.p. ) 5 min after beginning of re-perfusion and again once daily for the next 3 post-operative days. Motor performance ('combined motor score') was recorded for up to 17 days post-operative and motoneuron cell counts (in representative spinal cord sections) performed on the 17th post-operative day. Agmatine treatment was found to accelerate recovery of motor deficits and to prevent the loss of motoneurons in the spinal cord after transient ischemia. Together, the present and previous findings demonstrate that agmatine is an efficacious neuroprotective agent and that this naturally occurring non-toxic compound should be tried for therapeutic use after neurotrauma and in neurodegenerative diseases. Laboratory of Neuroscience, Research and Development, Assaf Harofeh Medical Center, P.O. Beer Yaakov, 70300, Zrifin, Israel. firstname.lastname@example.org.
&bull Lapchak PA, Chapman DF, Nunez SY and Zivin JA (2000). Dehydroepiandrosterone sulfate is neuroprotective in a reversible spinal cord ischemia model: possible involvement of GABA(A) receptors. Stroke. 31 (8): 1953-6; discussion 1957. Summary: BACKGROUND AND PURPOSE: Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) may function as neurotrophic or neuroprotective factors to protect central nervous system (CNS) neurons against a variety of insults, including excitotoxicity. The present study evaluated the pharmacological effects of DHEAS in a reversible spinal cord ischemia model. METHODS: DHEAS was administered (50 mg/kg IV) 5 or 30 minutes after the start of occlusion to groups of rabbits exposed to ischemia induced by temporary (15 to 60 minutes) occlusion of the infrarenal aorta. The group P(50) represents the duration of ischemia (in minutes) associated with 50% probability of resultant permanent paraplegia. RESULTS: The P(50) of the vehicle-treated control group, when behavioral analysis was assessed 18 hours after aortal occlusion, was 28.8+/-2.0 minutes. Neuroprotection was demonstrated if a drug significantly prolonged the P(50) compared with the vehicle-treated control group. Treatment with DHEAS at 5 minutes significantly (P<0.05) prolonged the P[50) of the group to 36.8+/-3.9 minutes. In addition, the DHEAS effect appeared durable, because a significant difference between the control and DHEAS-treated groups was still measurable at the 4-day time point. At 4 days, the P[50) of the control group was 26.1+/-2.2 minutes, whereas the P[50) for the DHEAS-treated group was 38.6+/-5. 9 minutes. DHEAS was not neuroprotective if administered 30 minutes after occlusion. In addition, the GABA[A) antagonist bicuculline abolished the neuroprotective effect of DHEAS. CONCLUSIONS: The present study suggests that neurosteroids may have substantial therapeutic benefit for the treatment of ischemic stroke. University of California San Diego, Department of Neuroscience, La Jolla, CA 92093-0624, USA. email@example.com.
&bull Kanellopoulos GK, Xu XM, Hsu CY, Lu X, Sundt TM and Kouchoukos NT (2000). White matter injury in spinal cord ischemia: protection by AMPA/kainate glutamate receptor antagonism. Stroke. 31 (8): 1945-52. Summary: BACKGROUND AND PURPOSE: Spinal cord ischemia is a serious complication of surgery of the aorta. NMDA receptor activation secondary to ischemia-induced release of glutamate is a major mechanism of neuronal death in gray matter. White matter injury after ischemia results in long-tract dysfunction and disability. The AMPA/kainate receptor mechanism has recently been implicated in white matter injury. METHODS: We studied the effects of AMPA/kainate receptor blockade on ischemic white matter injury in a rat model of spinal cord ischemia. RESULTS: Intrathecal administration of an AMPA/kainate antagonist, 6-nitro-7-sulfamoyl-(f)-quinoxaline-2, 3-dione (NBQX), 1 hour before ischemia reduced locomotor deficit, based on the Basso-Beattie-Bresnahan scale (0=total paralysis; 21=normal) (sham: 21+/-0, n=3; saline: 3.7+/-4.5, n=7; NBQX: 12. 7+/-7.0, n=7, P<0.05) 6 weeks after ischemia. Gray matter damage and neuronal loss in the ventral horn were evident after ischemia, but no difference was noted between the saline and NBQX groups. The extent of white matter injury was quantitatively assessed, based on axonal counts, and was significantly less in the NBQX as compared with the saline group in the ventral [sham: 1063+/-44/200x200 &mgr;m, n=3; saline: 556+/-104, n=7; NBQX: 883+/-103, n=7), ventrolateral [sham: 1060+/-135, n=3; saline: 411+/-66, n=7; NBQX: 676+/-122, n=7), and corticospinal tract [sham: 3391+/-219, n=3; saline: 318+/-23, n=7; NBQX: 588+/-103, n=7) in the white matter on day 42. CONCLUSIONS: Results indicate severe white matter injury in the spinal cord after transient ischemia. NBQX, an AMPA/kainate receptor antagonist, reduced ischemia-induced white matter injury and improved locomotor function. Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
&bull Li S and Tator CH (2000). Action of locally administered NMDA and AMPA/kainate receptor antagonists in spinal cord injury. Neurol Res. 22 (2): 171-80. Summary: NMDA or AMPA/kainate receptor antagonists have been shown to provide neuroprotection following in vitro spinal cord injury, but the mechanisms by which these agents improve behavioral recovery and protect axonal function remains unclear. We hypothesized that treatment of spinal cord injury with these drugs would attenuate glutamate excitatory transmission by blocking the effects of glutamate receptors at the injury site or would improve spinal cord blood flow. To test these hypotheses, we observed the effects of locally administered MK-801 (30 nmol) or NBQX (5 or 15 nmol) into the injured spinal cord on axonal conduction and post-traumatic ischemia of the cord. The outcome measures were multimodality evoked potentials and blood flow in an acute compression injury model in rats. We found that locally administered MK-801 or NBQX 15 min after spinal cord injury attenuated the amplitude, delayed the latency of sensory evoked potentials and increased the sensory conduction time across the injury site, but did not improve blood flow during the 4-h period of observation. These results demonstrate that the NMDA and non-NMDA receptor antagonists produced a blockade of glutamate excitatory transmission in the afferent pathways at the injury site. It is suggested that the neuroprotection provided by these agents following spinal cord injury is mediated through blockade of glutamate ionotropic receptors in the injured spinal cord, but is not related to improvement of SCBF. Division of Neurosurgery, Toronto Western Hospital, Canada.
&bull Gaviria M, Privat A, d'Arbigny P, Kamenka JM, Haton H and Ohanna F (2000). Neuroprotective effects of gacyclidine after experimental photochemical spinal cord lesion in adult rats: dose-window and time-window effects. J Neurotrauma. 17 (1): 19-30. Summary: The aim of this study was to evaluate the efficacy, optimal dose, and optimal time-window of gacyclidine, a novel N-methyl-D-aspartate (NMDA) receptor antagonist, in terms of its functional, histopathological, and electrophysiological effects after experimental spinal cord injury. The spinal cord of rats was damaged by a photochemical method and the animals were treated by saline or gacyclidine at doses of 1, 2.5, or 5 mg/kg 10 min after injury or gacyclidine 1 mg/kg 10, 30, 60, and 120 min after injury. The time-course of the motor score (walking and inclined-plane stability) was evaluated until day 18, and somatosensory evoked potentials were determined on day 18. The animals were then sacrificed, and the cross-sectional area of the spinal cord (at the epicenter of the injury, above and below the injury) was measured. Walking recovery was better in most of the groups treated after injury than in the untreated injured animals. Motor performances were related to preservation of a larger undamaged area of spinal cord at the level of the injury and, interestingly, with prevention of extension of the anatomical lesion above the level of the injury. Somatosensory evoked potential amplitudes were often higher in treated groups. These results confirm that gacyclidine induces dose-dependent and time-dependent attenuation of spinal cord damage after an experimental vascular lesion. Although all three doses induced neuroprotective effects, recovery was greater and very homogeneous in the group treated with 1 mg/kg. Moreover, recovery was slightly better and more homogeneous within the groups treated 10 and 30 min after injury compared to the other groups. It appears that, according to the existing evidence, NMDA antagonists are an essential component in the elaboration of a neuroprotective strategy after spinal cord trauma. Laboratoire de Neurophysiologie Clinique, Centre PROPARA-SEREP, Montpellier, France. firstname.lastname@example.org.
&bull Burns LH, Jin Z and Bowersox SS (1999). The neuroprotective effects of intrathecal administration of the selective N-type calcium channel blocker ziconotide in a rat model of spinal ischemia. J Vasc Surg. 30 (2): 334-43. Summary: PURPOSE: Spinal cord ischemia and resulting paraplegia represent a major complication associated with surgical repair of the thoracoabdominal aorta. Although the mechanism of spinal neuronal degeneration during ischemia is unclear, it may involve excessive calcium influx via N-type voltage-sensitive calcium channels (VSCCs). The neuroprotective capacity of intrathecal (IT) administration of the selective N-type VSCC blocker ziconotide, previously shown to be potently analgesic, was studied. METHODS: In a rat aortic occlusion model, spinal cord ischemia was induced for 8, 9, or 10 minutes by occluding the descending thoracic aorta. Ziconotide was administered IT as (1) a continuous infusion of 300 or 600 ng/kg/h initiated 24 hours before ischemia and continuing an additional 24 hours or (2) a 0.3 microgram bolus injected 45 minutes before the induction of ischemia. Animals were allowed to live for 24 hours, and recovery of motor function was evaluated during this period. Spinal cords were processed using a silver impregnation technique and microtubule-associated protein type II (MAP2) immunohistochemistry. RESULTS: Continuous IT infusion of ziconotide provided significant protection against 8- and 9-minute occlusions, but not 10-minute occlusions, as indicated by recovery of motor function, degree of spinal neuronal degeneration, and loss of MAP2 immunoreactivity. Acute IT pretreatment with ziconotide provided transient protection during the initial 4 hours of reperfusion; however, this protective effect was no longer present at 24 hours. CONCLUSION: These data implicate N-type VSCC activation in spinal neuronal degeneration caused by transient spinal ischemia, because selective blockade of this channel by continuous IT infusion of ziconotide was protective against injurious intervals of spinal ischemia. Based on these findings, ziconotide may provide both neuroprotection and preemptive analgesia for aortic aneurysm surgery. Elan Pharmaceuticals, 3760 Haven Avenue, Menlo Park, CA 94025, USA.
&bull Farooque M, Isaksson J, Jackson DM and Olsson Y (1999). Clomethiazole (ZENDRA, CMZ) improves hind limb motor function and reduces neuronal damage after severe spinal cord injury in rat. Acta Neuropathol (Berl). 98 (1): 22-30. Summary: Clomethiazole (CMZ) has a neuroprotective effect in experimental focal and global forebrain ischemia. This neuroprotective effect may depend on its ability to enhance GABA receptor activity. We have studied the effect of pretreatment with CMZ on motor function recovery and nerve cell damage after spinal cord injury (SCI). Rats were randomized and 30 min before SCI they received a single intraperitoneal dose of CMZ (150 mg/kg) or saline. The spinal cord was injured with a 50 g (4.5 g/mm2) load, applied over the exposed dura, through a curved rectangular plate (2.2 x 5.0 mm) for 5 min at T8-9. The animals became paraplegic 1 day after injury. The rats were evaluated for recovery of hind limb motor function. All animals recovered to some extent over the observation period of 12 weeks. However, hind limb motor function was significantly better in the animals pretreated with CMZ. At 12 weeks the rats were killed and perfused/fixed for morphological investigations. Microtubule-associated protein 2 (MAP2) immunostaining was used to stain neurons and dendrites and Luxol-fast blue to stain myelinated tracts of the white matter. The injured segment of the spinal cord showed severe atrophy, distortion, cavitation and necrosis of grey and white matter. Compared to uninjured controls the transverse sectional area was reduced to 32.7 +/- 4% in untreated animals but only to 38.5% +/- 4.1 in CMZ-treated animals. MAP2 staining showed that, compared to uninjured controls, grey matter was reduced to 7.4 +/- 2.7% in saline-treated injured animals and to 22.7 +/- 5.4% in CMZ-treated rats. Our results thus show that in this model CMZ improves hind limb motor function and attenuates the morphological damage to the spinal cord. Department of Genetics and Pathology, Uppsala University Hospital, Sweden. Mohammad.Farooque@patologi.uu.se.
&bull Danielisova V and Chavko M (1998). Comparative effects of the N-methyl-D-aspartate antagonist MK-801 and the calcium channel blocker KB-2796 on neurologic and metabolic recovery after spinal cord ischemia. Exp Neurol. 149 (1): 203-8. Summary: NMDA receptor antagonists have been demonstrated to be neuroprotective in focal cerebral ischemia and are supposed to prevent neurotoxic intracellular calcium increase. Another mechanism of calcium influx during ischemia involves activation of voltage-activated calcium channels, although the efficacy of calcium channel blockers against ischemia-induced damage varies. The purpose of this study was to determine the contributions of the excitotoxic mechanism and of calcium channel activation to metabolic and functional damage to rabbit spinal cord after ischemia induced by occlusion of the abdominal aorta. All metabolic parameters determined (ATP, energy charge, and lactate) completely recovered at 4 days following 20 min of ischemia when NMDA receptor antagonist MK-801 (1 mg/kg given i.v.) or calcium channel blocker KB-2796 (50 mg/kg given i.p.) was administered either prior to or after ischemia. Significant metabolic recovery was also observed after 30 min of ischemia with MK-801 administered before occlusion and KB-2796 given early in recirculation. Similarly, neurologic functions followed by functional performance in the hindlimbs were completely recovered following 20 and 30 min of ischemia and 4 days of recovery. This study demonstrates that although MK-801 or KB-2796 does not prevent paraplegia due to spinal cord ischemia in the rabbit, both drugs can influence the rate of recovery after ischemic injury. Department of Neurochemistry, Slovak Academy of Sciences, Kosice, Slovak Republic.
[This message was edited by Wise Young on Aug 19, 2002 at 11:48 PM.]