dizocilpine-maleate and Spinal-Cord-Injuries

Ischemic damage, chiefly of the focal type, and axonal disruption (diffuse axonal injury) are the major factors causing brain damage after human head injury. About one third of this damage may be delayed hours or days after the injury. Evidence from four animal models, each relevant to different aspects of human head injury, has shown that excitatory amino acid-induced changes are responsible for a proportion of the posttraumatic sequelae and that these effects can be blocked by EAA antagonists. This evidence is reviewed, and the implications for the conduct of human trials with EAA antagonists are discussed.

Topics: Animals; Brain Damage, Chronic; Brain Injuries; Brain Ischemia; Central Nervous System Depressants; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Humans; Ischemic Attack, Transient; Spinal Cord Injuries

Background and aims The clinical management of neuropathic pain remains a challenge. We examined the interaction between gabapentin and NMDA receptor antagonists dextromethrophan and MK-801 in alleviating neuropathic pain-like behaviors in rats after spinal cord or sciatic nerve injury. Methods Female and male rats were produced with Ischemic spinal cord injury and sciatic nerve injury. Gabapentin, dextromethorphan, MK-801 or drug combinations were injected with increasing doses. Mechanical response thresholds were tested with von Frey hairs to graded mechanical touch/pressure, and ethyl chloride spray was applied to assess the cold sensitivity before and after injuries. Results In spinally injured rats, gabapentin and dextromethorphan did not affect allodynia-like behaviors at doses of 30 and 20 mg/kg, respectively. In contrast, combination of 15 or 30 mg/kg gabapentin with dextromethorphan at 10 mg/kg produced total alleviation of allodynia to mechanical or cold stimulation. Further reducing the dose of gapapentin to 7.5 mg/kg and dextromethorphan to 5 mg/kg still produced significant effect. MK-801, another NMDA receptor antagonist, also enhanced the effect of gabapentin in spinally injured rats. Similar synergistic anti-allodynic effect between dextromethorphan and gabapentin was also observed in a rat model of partial sciatic nerve injury. No increased side effect was seen following the combination between gabapentin and dextromethorphan. Conclusions In conclusion, the present study suggested that combining NMDA receptor antagonists with gabapentin could provide synergistic effect to alleviate neuropathic pain and reduced side effects. Implications Combining NMDA receptor antagonists with gabapentin may provide a new approach in alleviating neuropathic pain with increased efficacy and reduced side effects.

Topics: Animals; Behavior, Animal; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Gabapentin; Hyperalgesia; Male; Neuralgia; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Spinal Cord Injuries; Touch

In this study, we examined whether topical treatment of glutamate receptor antagonists attenuate hyperexcitability of lumbar spinal dorsal horn neurons following low thoracic hemisection spinal cord injury in rats. Four weeks after spinal hemisection, neuronal activity in response to mechanical stimuli applied on the peripheral receptive field was significantly increased in three different phenotypes of lumbar spinal dorsal horn neurons: wide dynamic range (WDR), low threshold (LT) and high threshold (HT). Topical application of MK-801 (NMDA receptor antagonist, 50 microg) significantly attenuated the activity of WDR, but not LT and HT neurons; whereas, NBQX (AMPA receptor antagonist, 0.5 and 1 microg) significantly attenuated neuronal activity in all three phenotypes of neurons (*p<0.05). However, MCPG (group I/II metabotropic glutamate receptor antagonist, 100 microg) had no effect. The present study, in the context of previous work, suggests that ionotropic glutamate receptor activation play critical roles in the maintenance of neuronal hyperexcitability and neuropathic "below-level" pain behavior following spinal hemisection injury.

Topics: Action Potentials; Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Male; Physical Stimulation; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Spinal Cord Injuries; Thoracic Vertebrae

Adenosine 2a (A2a) receptor agonists elicit persistent increases in phrenic nerve activity by transactivating the neurotrophin receptor, TrkB, near phrenic motoneurons. Our working model proposes that A2a receptor-mediated TrkB receptor activation strengthens glutamatergic synapses onto phrenic motoneurons. Activation of glutamate N-methyl d-aspartate (NMDA) receptors has been implicated in other models of phrenic motor plasticity. Thus we hypothesized that NMDA receptor activation also would contribute to A2a receptor-mediated phrenic motor facilitation. Adult male Sprague-Dawley rats were anesthetized with urethane, mechanically ventilated, neuromuscularly paralyzed, and bilaterally vagotomized. The A2a receptor agonist CGS-21680 and the NMDA receptor-channel blocker MK-801 were administered intrathecally over the C4 spinal segment. Phrenic nerve activity was recorded before, during, and after drug administration. MK-801 (concentration range 0.1, 1.0, 10.0, and 100 microM) was administered 30 min before CGS-21680 (50 microM). MK-801 dose-dependently blocked A2a receptor-mediated phrenic motor facilitation. When administered at 60 min post-CGS-21680, MK-801 prevented further increases in phrenic nerve activity compared with the CGS-21680 alone (CGS-21680 alone at 120 min: 114 +/- 19%; CGS-21680 and MK-801 at 60 min post-CGS-21680: 61 +/- 11%, above baseline, P < 0.05) but did not return phrenic motor output to baseline values. Our data suggest that NMDA receptor activation is necessary for de novo A2a receptor-mediated phrenic motor facilitation and that the maintenance of preexisting phrenic motor facilitation does not involve NMDA receptor-dependent mechanisms.

Topics: Adenosine; Adenosine A2 Receptor Antagonists; Animals; Antihypertensive Agents; Disease Models, Animal; Dizocilpine Maleate; Drug Interactions; Male; Motor Neurons; Neuroprotective Agents; Phenethylamines; Phrenic Nerve; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A; Receptor, trkB; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Cord Injuries

Characterizing connectivity in the spinal cord of zebrafish embryos is not only prerequisite to understanding the development of locomotion, but is also necessary for maximizing the potential of genetic studies of circuit formation in this model system. During their first day of development, zebrafish embryos show two simple motor behaviors. First, they coil their trunks spontaneously, and a few hours later they start responding to touch with contralateral coils. These behaviors are contemporaneous until spontaneous coils become infrequent by 30 h. Glutamatergic neurons are distributed throughout the embryonic spinal cord, but their contribution to these early motor behaviors in immature zebrafish is still unclear. We demonstrate that the kinetics of spontaneous coiling and touch-evoked responses show distinct developmental time courses and that the touch response is dependent on AMPA-type glutamate receptor activation. Transection experiments suggest that the circuits required for touch-evoked responses are confined to the spinal cord and that only the most rostral part of the spinal cord is sufficient for triggering the full response. This rostral sensory connection is presumably established via CoPA interneurons, as they project to the rostral spinal cord. Electrophysiological analysis demonstrates that these neurons receive short latency AMPA-type glutamatergic inputs in response to ipsilateral tactile stimuli. We conclude that touch responses in early embryonic zebrafish arise only after glutamatergic synapses connect sensory neurons and interneurons to the contralateral motor network via a rostral loop. This helps define an elementary circuit that is modified by the addition of sensory inputs, resulting in behavioral transformation.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Dizocilpine Maleate; Electrophysiology; Embryo, Nonmammalian; Escape Reaction; Excitatory Amino Acid Antagonists; Glutamic Acid; Immunohistochemistry; Neural Pathways; Neurons; Receptors, AMPA; Reflex; Spinal Cord; Spinal Cord Injuries; Swimming; Synapses; Zebrafish

C2 hemisection results in paralysis of the ipsilateral hemidiaphragm. Recent data indicate that an upregulation of the N-methyl-D-aspartate (NMDA) receptor 2A subunit following chronic C2 hemisection is associated with spontaneous hemidiaphragmatic recovery following injury. MK-801, an antagonist of the NMDA receptor, upregulates the NR2A subunit in neonatal rats.. We hypothesized that administration of MK-801 to adult, acute C2-hemisected rats would result in an increase of NR2A in the spinal cord. Furthermore, we hypothesized that upregulation of NR2A would be associated with recovery of the ipsilateral hemidiaphragm as in the chronic studies.. To develop a dose-response curve, adult rats were treated with varying doses of MK-801 and their spinal cords harvested and assessed for NR2A as well as AMPA GluR1 and GluR2 subunit protein levels. In the second part of this study, C2-hemisected animals received MK-801. Following treatment, the animals were assessed for recovery of the hemidiaphragm through electromyographic recordings and their spinal cords assessed for NR2A, GluR1, and GluR2.. Treatment with MK-801 leads to an increase of the NR2A subunit in the spinal cords of adult noninjured rats. There were no changes in the expression of GluR1 and GluR2 in these animals. Administration of MK-801 to C2-hemisected rats resulted in recovery of the ipsilateral hemidiaphragm, an increase of NR2A, and a decrease of GluR2.. Our findings strengthen the evidence that the NR2A subunit plays a substantial role in mediating recovery of the paralyzed hemidiaphragm following C2 spinal cord hemisection.

Topics: Analysis of Variance; Animals; Diaphragm; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electromyography; Female; Functional Laterality; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recovery of Function; Spinal Cord Injuries; Time Factors; Up-Regulation

Spinal plasticity is known to play a role in central neurogenic pain. Over the last 100 years researchers have found that the spinal cord is also capable of supporting other forms of plasticity including several forms of learning. To study instrumental (response-outcome) learning in the spinal cord, we use a preparation in which spinally transected rats are given shock to the hind leg when the leg is extended. The spinal cord rapidly learns to hold the leg in a flexed position when given this controllable shock. However, if shock is independent of leg position (uncontrollable shock), subjects fail to learn. Uncontrollable shock also impairs future learning. As little as 6 min of uncontrollable shock to either the leg or the tail generates a learning deficit that lasts up to 48 h. Recent data suggest links between the learning deficit and the sensitization of pain circuits associated with inflammation or injury (central sensitization). Here, we explored whether central sensitization and the spinal learning deficit share pharmacological and behavioral features. Central sensitization enhances reactivity to mechanical stimulation (allodynia) and depends on the N-methyl-d-aspartate receptor (NMDAR). The uncontrollable shock stimulus that generates a learning deficit produced a tactile allodynia (Exp. 1) and administration of the NMDAR antagonist MK-801 blocked induction of the learning deficit (Exp. 2). Finally, a treatment known to induce central sensitization, intradermal carrageenan, produced a spinal learning deficit (Exp. 3). The findings suggest that the induction of central sensitization inhibits selective response modifications.

Topics: Analysis of Variance; Animals; Behavior, Animal; Carrageenan; Conditioning, Psychological; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Functional Laterality; Inhibition, Psychological; Male; Models, Biological; Neuronal Plasticity; Nociceptors; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries

This study aimed to investigate the effect of tonic nociception on spinal withdrawal reflexes including (1) long lasting spontaneous responses elicited by subcutaneous (s.c.) administration of formalin (2.5%, 50 microl) and bee venom (BV, 0.2 mg/50 microl) into the hind paw and (2) corresponding ipsilateral (primary) and contralateral (secondary) hypersensitivity to noxious pinch and repetitive supra-threshold (1.5 x T) electrical stimuli at different frequencies (3 Hz: wind-up; 20 Hz: after-discharge) in anesthetized spinal rats. Spinal withdrawal reflexes were studied by simultaneously assessing single motor units (SMUs) electromyographic (EMG) activities from the bilateral medial gastrocnemius (MG) muscles. Subcutaneous formalin-induced persistent spontaneous SMU EMG responses were in typical biphasic manner with an apparent silent period (about 13-18 min), but in contrast, BV elicited monophasic long lasting (about 1 h) SMU EMG responses without any resting state. The mechanically and electrically evoked responsiveness of SMUs were enhanced significantly by ipsilateral BV injection, whereas enhanced electrically, but not mechanically, evoked responses (including wind-up and after-discharge) were found at the non-injection site of the contralateral hind paw. However, s.c. administration of formalin was only able to establish ipsilateral hypersensitivity of the SMUs to repeated electrical, not mechanical, stimulation. Neither mechanically nor electrically evoked contralateral hypersensitivity of the SMUs was found during the ipsilateral formalin-induced nociception. For pharmacological intervention, intrathecal administration of the non-N-methyl-d-aspartate (non-NMDA) receptor antagonist CNQX (40 nmol/10 microl), but not the non-competitive NMDA receptor antagonist MK-801 (40 nmol/10 microl), significantly depressed BV-induced contralateral hypersensitivity of the SMUs to repeated 3 Hz (wind-up) and 20 Hz (after-discharge) frequencies of electrical stimulation. Using the extracellular SMU recording technique, we found that s.c. administration of formalin and BV shows a significant difference in long lasting spontaneous firing of SMUs. This is consistent with previous observations in animal behavioral studies. Additionally, contralateral electrically evoked hypersensitivity of the SMUs was found only following BV injection, not in the formalin test. The maintenance and development of BV-induced contralateral hypersensitivity of the spinal withdrawal refl

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Action Potentials; Analysis of Variance; Anesthesia; Animals; Bee Venoms; Dizocilpine Maleate; Dose-Response Relationship, Radiation; Drug Interactions; Electric Stimulation; Electromyography; Excitatory Amino Acid Antagonists; Formaldehyde; Functional Laterality; Injections, Subcutaneous; Male; Muscle, Skeletal; Pain Measurement; Physical Stimulation; Rats; Rats, Wistar; Reflex; Spinal Cord; Spinal Cord Injuries; Time Factors

Windup, the frequency dependent build-up of spinal neuronal responses, is implicated in the development of central sensitization of nociceptive pathways. N-methyl-D-aspartate (NMDA) receptors have been shown to be involved in these processes but the role of various receptor subtypes at the spinal level is not fully understood. In our experiments, we compared the inhibitory effect of MK-801 (a nonselective NMDA receptor antagonist, 0.01-3 mg/kg i.v.) and CI-1041 (an NR2B subunit specific NMDA receptor antagonist, 0.3-10 mg/kg i.v.) on the formation of dorsal horn neuronal windup in spinalized rats, in vivo. Both types of antagonist blocked windup considerably at doses not affecting the normal synaptic transmission. These results are in agreement with the well-documented effectivity of NR2B subtype selective NMDA receptor antagonists in chronic pain models and give the first direct evidence that spinal mechanisms are involved in this effect.

Topics: Action Potentials; Analysis of Variance; Animals; Benzoxazoles; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Electric Stimulation; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Male; Nerve Fibers; Piperidines; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Cord Injuries

Experimental laboratory investigation of the effects of serotonergic and glutamatergic drugs in early paraplegic mice.. To examine whether NMDA and 5-HT receptors synergistically participate to generate basic stepping movements in paraplegic mice.. Laval University Medical Center, Quebec, Canada.. Adult mice completely spinalized at the low-thoracic level 1 week earlier were suspended in harnesses for experiments. Acute drug-induced effects were examined on hindlimb movements filmed with a digital video camera. Detailed kinematic analyses included stick diagrams reconstructions of hindlimb movements and analysis of bilateral coordination, angular excursion, stepping amplitude and frequency.. A single treatment with the 5-HT2 agonist quipazine (>0.7 mg/kg, i.p.) induced episodes of air-stepping movements in the hindlimbs of paraplegic mice. In contrast, injection of the glutamatergic agonist NMDA (1-45 mg/kg i.p.) failed to induce rhythmicity, although nonlocomotor rhythmic movements were observed with higher doses (45-60 mg/kg i.p.). Subthreshold doses of NMDA (22-30 mg/kg) could induce episodes of hindlimb air-stepping if combined with subthreshold doses of quipazine (0.3-0.7 mg/kg). Air-stepping was entirely blocked by administration of the selective NMDA antagonist MK-801.. A single treatment with quipazine can trigger episodes of locomotor-like movements in early chronic spinal mice. Even though NMDA alone could not generate bilaterally coordinated air-stepping, NMDA receptor activation was nonetheless critical for spinal locomotor rhythmogenesis induced by 5-HT agonists in awake behaving animals.

Topics: Animals; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Male; Mice; Motor Activity; N-Methylaspartate; Paraplegia; Quipazine; Receptors, N-Methyl-D-Aspartate; Serotonin Receptor Agonists; Signal Transduction; Spinal Cord Injuries; Thoracic Vertebrae

The present study aimed to investigate the role of central N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the spinal withdrawal reflex assessed by recording single motor unit (SMU) electromyogram (EMG) response to peripheral mechanical (pressure, pinch) stimuli and repeated electrical stimuli at 3 and 20 Hz. During normal conditions, intrathecal administration of MK-801 and CNQX apparently depressed mechanically and electrically (3 Hz) evoked EMG responses in a dose-dependent manner (10, 20 and 40 nmol in 10 microl). In contrast, the after-discharges to 20 Hz electrical stimuli were suppressed only by CNQX treatment, not by MK-801 treatment. This indicates that the central mechanisms underlying the different frequencies of electrically evoked withdrawal reflex may be different. During peripheral bee venom (BV, 0.2 mg/50 microl) induced inflammation and central sensitization, the enhanced SMU EMG responses including after-discharges to pinch stimuli and 3 Hz electrical stimuli were depressed significantly by treatments with both MK-801 and CNQX. However, the enhanced SMU activities to innocuous pressure stimuli were depressed only by treatment with CNQX. Likewise, enhanced long lasting after-discharges elicited by 20 Hz electrical stimuli were also only depressed by CNQX, indicating that different central mechanisms are involved in the persistent hyperexcitability during BV-induced inflammation. The data suggest that both central NMDA and non-NMDA receptors play important roles in the transmission of nociceptive information under normal conditions. In BV-induced inflammation, however, central non-NMDA receptors, but not NMDA receptors, play a pivotal role in the generation of persistent hyperexcitability to mechanical and electrical stimuli at different frequencies (3 Hz, 20 Hz).

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Analysis of Variance; Anesthesia; Animals; Bee Venoms; Central Nervous System; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electric Stimulation; Electromyography; Evoked Potentials, Motor; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Hindlimb; Inflammation; Male; Muscle, Skeletal; N-Methylaspartate; Pain Measurement; Pain Threshold; Physical Stimulation; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reflex; Spinal Cord; Spinal Cord Injuries

The purpose of this study was to examine the effects of inhibiting ionotropic glutamate receptor subtypes on measures of oxidative stress events at acute times following traumatic spinal cord injury (SCI). Rats received a moderate contusion injury and 15 min later were treated with one of two doses of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzol[f]quinoxaline-7-sulfonamide disodium (NBQX), MK-801, or the appropriate vehicle. At 4 h following injury, spinal cords were removed and a crude synaptosomal preparation obtained to examine mitochondrial function using the MTT assay, as well as measures of reactive oxygen species (ROS), lipid peroxidation, and glutamate and glucose uptake. We report here that intraspinal treatment with either 15 or 30 nmol of NBQX improves mitochondrial function and reduces the levels of ROS and lipid peroxidation products. In contrast, MK-801, given intravenously at doses of 1.0 or 5.0 mg/kg, was without effect on these same measures. Neither drug treatment had an effect on glutamate or glucose uptake, both of which are reduced at acute times following SCI. Previous studies have documented that drugs acting on non-N-methyl-D-aspartate (NMDA) receptors exhibit greater efficacy compared to NMDA receptor antagonists on recovery of function and tissue sparing following traumatic spinal cord injury. The results of this study provide a potential mechanism by which blockade of the non-NMDA ionotropic receptors exhibit positive effects following traumatic SCI.

Topics: Animals; Dizocilpine Maleate; Female; Glucose; Glutamic Acid; Injections, Spinal; Lipid Peroxidation; Mitochondria; Neuroprotective Agents; Quinoxalines; Rats; Rats, Long-Evans; Reactive Oxygen Species; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Spinal Cord Injuries; Synaptosomes; Thiobarbituric Acid Reactive Substances; Thoracic Vertebrae

Spinal cord injury (SCI)-induced neurodegeneration leads to irreversible and devastating motor and sensory dysfunction. Post-traumatic outcomes are determined by events occurring during the first 24 hours after SCI. An increase in extracellular glutamate concentration to neurotoxic levels is one of the earliest events after SCI. We used Affymetrix DNA oligonucleotide microarrays (with 1,322 DNA probes) analysis to measure gene expression in order to test the hypothesis that SCI-induced N-methyl-D-aspartate (NMDA) receptor activation triggers significant postinjury transcriptional changes. Here we report that SCI, 1 hour after trauma, induced change in mRNA levels of 165 genes and expression sequence tags (ESTs). SCI affected mRNA levels of those genes that regulate predominantly transcription factors, inflammation, cell survival, and membrane excitability. We also report that NMDA receptor inhibition (with -(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate [MK-801]) reversed the effect of SCI on about 50% of the SCI-affected mRNAs. Especially interesting is the finding that NMDA receptor activation participates in the up-regulation of inflammatory factors. Therefore, SCI-induced NMDA receptor activation is one of the dominant, early signals after trauma that leads to changes in mRNA levels of a number of genes relevant to recovery processes. The majority of MK-801 effects on the SCI-induced mRNA changes reported here are novel. Additionally, we found that the MK-801 treatment also changed the mRNA levels of 168 genes and ESTs that had not been affected by SCI alone, and that some of their gene products could have harmful effects on SCI outcome.

Topics: Animals; Cluster Analysis; Contusions; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluorescent Antibody Technique; Gene Expression Profiling; Injections, Spinal; Male; Neuroprotective Agents; Oligonucleotide Array Sequence Analysis; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; RNA, Messenger; Spinal Cord Injuries

We determined if bilateral section of the hypogastric nerves (HGN), which provide the major sympathetic input to the urinary bladder neck/proximal urethra, could improve voiding by reducing urethral resistance in conscious, female spinal-cord-injured (SCI) rats 2-3 weeks after T(7-9) transection of the spinal cord. Cystometry was performed in animals with HGN intact and with HGN sectioned bilaterally 1-2 h before the experiment. Residual volume (RV), volume threshold for inducing micturition (VT), maximal voiding pressure, and bladder compliance were significantly lower (71, 35, 33, and 31%, respectively) in SCI rats with sectioned HGN than in rats with intact HGN, whereas voided volume (VV), pressure threshold for micturition, and bladder contraction duration (BCD) in the two groups were similar. Voiding efficiency (VE) in the HGN-sectioned group was 36% greater than that in the HGN-intact group. Antagonists for AMPA and NMDA glutamatergic receptors (LY215490 and MK-801, respectively) were administered to rats with sectioned HGN, to determine if activity in the HGN contributes to the previously reported inhibitory effects of these drugs, on voiding function after SCI. MK-801 (3 mg/kg iv) significantly reduced VV (75%) and VE (85%) and increased RV (8-fold), VT (87%), and bladder compliance (60%), whereas LY215490 (10 mg/kg iv) significantly increased VT and BCD by 15 and 19%, respectively. It is concluded that bilateral section of HGN reduces voiding dysfunction in the SCI rat but does not alter the effects of AMPA and/or NMDA glutamatergic receptor antagonists on the micturition reflex in the SCI rat. Thus the effects of these drugs are not dependent on changes in activity of sympathetic axons in the HGN.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Drug Therapy, Combination; Female; Isoquinolines; Muscle Contraction; Neuroprotective Agents; Peripheral Nerves; Rats; Receptors, AMPA; Spinal Cord Injuries; Sympathectomy; Tetrazoles; Treatment Outcome; Urination; Urination Disorders; Urine

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.

Topics: Animals; Cerebellum; Dizocilpine Maleate; Evoked Potentials; Evoked Potentials, Motor; Evoked Potentials, Somatosensory; Excitatory Amino Acid Antagonists; Male; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Regional Blood Flow; Spinal Cord; Spinal Cord Injuries

We report here that activation of the caspase-3 apoptotic cascade in spinal cord injury is regulated, in part, by calcineurin-mediated BAD dephosphorylation. BAD, a proapoptotic member of the bcl-2 gene family, is rapidly dephosphorylated after injury, dissociates from 14-3-3 in the cytosol, and translocates to the mitochondria of neurons where it binds to Bcl-x(L). Pretreatment of animals with FK506, a potent inhibitor of calcineurin activity, or MK801, an NMDA glutamate receptor antagonist, blocked BAD dephosphorylation and abolished activation of the caspase-3 apoptotic cascade. These findings extend previous in vitro observations and are the first to implicate the involvement of glutamate-mediated calcineurin activation and BAD dephosphorylation as upstream, premitochondrial signaling events leading to caspase-3 activation in traumatic spinal cord injury.

Topics: 14-3-3 Proteins; Animals; Apoptosis; bcl-Associated Death Protein; bcl-X Protein; Calcineurin; Calcineurin Inhibitors; Carrier Proteins; Caspase 3; Caspases; Contusions; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluorescent Antibody Technique; Immunoblotting; Immunosuppressive Agents; Mitochondria; Neurons; Neuroprotective Agents; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Rats; Signal Transduction; Spinal Cord Injuries; Tacrolimus; Tyrosine 3-Monooxygenase

Prevention of the immediate excitotoxic phase occurring in response to spinal cord injury (SCI) is a major issue to reduce the neuronal damage responsible for any ensuing motor deficits. The present study evaluated the neuroprotective efficacy of three noncompetitive NMDA receptor antagonists: Gacyclidine (GK-11), a new compound, Dizocilpine (MK-801), and Cerestat (CNS-1102) in a rat spinal cord contusion model. To mimic human SCI, a standardized model of rat spinal cord closed contusion in which animals spontaneously and progressively recover from the induced paraplegia was employed. Such model, characterized by a slow recovery of hindlimb locomotor function enables easy quantification of the neuroprotection at both the behavioral and cellular level. The animals were treated intravenously with the respective drugs 10 min after the spinal contusion. The dose range study suggested that 1 mg/kg of Gacyclidine was the most effective dose to promote functional recovery in reducing by half the time needed to reach full locomotor recovery. Racemate and enantiomers of Gacyclidine showed similar neuroprotective effects, but treatment with the enantiomers were not as efficacious in promoting full functional recovery. Similarly, a prolonged treatment with the racemate was not as efficious as a single dose, suggesting that a prolonged blockade of the amino-excitatory neurotransmission may be deleterious. Finally, Dizocilpine and Cerestat treatments induced only a partial and delayed neuroprotective effect compared to Gacyclidine. Neuroprotection characterized by a reduction of the cystic cavity and of the astrogliosis was observed with all treatments. As Gacyclidine is already in clinical trials, the present findings suggest the premise that it is a promising agent for limiting the initial neuronal damage induced by CNS trauma leading to better functional recovery.

Topics: Animals; Astrocytes; Cyclohexanes; Cyclohexenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Administration Schedule; Excitatory Amino Acid Antagonists; Female; Gliosis; Guanidines; Neuroprotective Agents; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recovery of Function; Spinal Cord; Spinal Cord Injuries; Stereoisomerism

An experimental study was conducted to evaluate the effects of methylprednisolone and MK-801 after the compressive injury of spinal cord in rats.. To investigate the effect of methylprednisolone and non-competitive NMDA antagonist MK-801 in long-term functional outcome after spinal cord injury (SCI).. A randomized group A of Sprague-Dawley rats were treated with MK-801 (1.0 mg/kg, n=10; Group A) after a compression injury. A group of methylprednisolone (MP)-treated (30 mg/kg, n=10; Group B) and non-treated animals (n=9; Group C) were included for comparison. The functional motor outcome such as inclined plane (IP), toe spreading reflex (TSR), and modified Tarlov scale (TS) were measured in each animal at regular time points up to 8 weeks post-treatment. Histologically the injury site was scored in four groups and immunohistochemically Wallerian Degeneration (WD), astrocytosis and expression of beta-amyloid protein was identified.. In examining the IP data, no significant difference was recognized between the group means (P-value>0.5). For the TSR, there were no differences in the group responses. For the TS, the differences were not statistically significant. Only group B showed significance in cavitation scores compared to group A (P>0.0094), WD was significantly different than group C (P>0.03), astrocytosis was significantly higher than group A (P>0.001) and modest presence of beta-amyloid protein.. Our data indicate that one time bolus administration of MK-801 lacks any significant effect on axonal function in chronically injured rats. Daily bolus administration of MP at 30 mg/kg also did not ensure a better functional outcome. Immunohistochemically we have been able to show significant differences in WD, astrocytosis and small insignificant changes in beta-amyloid protein.

Topics: Amyloid beta-Peptides; Animals; Anti-Inflammatory Agents; Axons; Chronic Disease; Dizocilpine Maleate; Drug Therapy, Combination; Gliosis; Male; Methylprednisolone; Nerve Degeneration; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recovery of Function; Spinal Cord; Spinal Cord Injuries

The aims of this study were to clarify the histological and histochemical changes associated with cell death in the spinal cord after acute traumatic injury and to examine the role of excitatory amino acid release mediated by N-methyl-D-aspartate (NMDA) receptors.. Following laminectomy, the spinal cord in 70 rats was injured at the T-9 level by applying extradural static weight-compression, in which a cylindrical compressor was used to induce complete and irreversible transverse spinal cord injury (SCI) with paralysis of the lower extremities. The injured rats were killed between 30 minutes and 14 days after injury, and the injured cord was removed en bloc. Rats that received NMDA receptor antagonist (MK-801) were killed at the same time points as those that received saline. The specimens were stained with hematoxylin and eosin, Nissl, and Klüver-Barrera Luxol fast blue and subjected to in situ nick-end labeling, a specific in situ method used to allow visualization of apoptosis. Thirty minutes post-SCI, a large hematoma was observed at the compressed segment. Six hours after injury, large numbers of dead cells that were not stained by in situ nick-end labeling were observed. Between 12 hours and 14 days postinjury, nuclei stained by using the in situ nick-end labeling technique were observed not only at the injury site but also in adjoining segments that had not undergone mechanical compression, suggesting that the delayed cell death was due to apoptosis. The number of cells stained by in situ nick-end labeling was maximum at 3 days postinjury. The results of electron microscopic examination were also consistent with apoptosis. In the MK-801-treated rats, the number of cells stained by in situ nick-end labeling was smaller than in nontreated rats at both 24 hours and 7 days after injury.. These findings suggest that NMDA-receptor activation promotes delayed neuronal and glial cell death due to apoptosis.

Topics: Animals; Apoptosis; Cell Count; Cell Death; Cell Nucleus; Coloring Agents; Demyelinating Diseases; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fluorescent Dyes; Hematoma; In Situ Nick-End Labeling; Laminectomy; Male; Microscopy, Electron; N-Methylaspartate; Nerve Fibers, Myelinated; Neurons; Neuroprotective Agents; Paralysis; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Spinal Cord Compression; Spinal Cord Injuries

This study was undertaken to determine if an AMPA (LY215490) or an NMDA (MK-801) glutamatergic receptor antagonist can reduce urinary tract dysfunctions related to detrusor hyperreflexia and detrusor-sphincter dyssynergia in awake, spinal cord-injured (SCI) rats. Experiments were performed on female Sprague-Dawley rats in which the spinal cord was completely transected at T(8-10) level, 2-3 weeks prior to performing an intravesical continuous infusion cystometrogram (CMG). Bladder volume threshold (VT) for inducing voiding and voiding efficiency (VE) were determined by measuring voided volumes and residual volumes (RV). After control CMGs were performed, cumulative intravenous doses of LY215490 (0.1, 1, and 10 mg/kg) or MK-801 (0.03, 0.3, and 3 mg/kg) were administered at 120-min intervals. Small doses of LY215490 (0.1 mg/kg) or MK-801 (0. 03 and 0.3 mg/kg) did not affect any parameters. A large dose (10 mg/kg) of LY215490 decreased maximal voiding pressure (MVP) by 27% and increased RV by 119% and VT by 58% but did not decrease VE. The highest cumulative dose (3 mg/kg) of MK-801 significantly increased RV by 134% and VT by 44% and markedly decreased VE by 60% and MVP by 18%. The effects of LY215490 to reduce MVP and increase VT without changing VE suggest that an AMPA receptor antagonist might be useful in treating detrusor-sphincter dyssynergia and bladder hypertrophy after SCI. The effect of MK-801 to markedly reduce VE indicates that NMDA receptor antagonists may exacerbate neurogenic bladder dysfunction in SCI patients.

Topics: Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Isoquinolines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Reflex; Spinal Cord Injuries; Tetrazoles; Urethra; Urinary Bladder; Urinary Catheterization; Urination; Urodynamics

Spinal cord injury can lead to an exaggeration of transmission through spinal pathways, resulting in muscle spasticity, chronic pain, and abnormal control of blood pressure and bladder function. These conditions are mediated, in part, by N-methyl-D-aspartate (NMDA) receptors on spinal neurons, but the effects of cord injury on the expression or function of these receptors is unknown. Therefore, antibodies to the NMDA-R1 receptor subunit and binding of [3H]MK-801 were used to assess NMDA receptors in the spinal cord. Receptor density in rats with intact spinal cords was compared to that in rats 1 and 2 weeks after spinal cord transection (SCT) at the mid-thoracic level. At 1 and 2 weeks after SCT, [3H]MK-801 binding was reduced in most laminae in cord segments caudal to the injury, whereas no decrease in amount of R1 subunit immunoreactivity was observed. No significant changes in [3H]MK-801 binding and NMDA-R1 immunoreactivity could be seen rostral to the transection. Since [3H]MK-801 binding requires an open ion channel, the discrepancy between [3H]MK-801 binding and immunocytochemistry may indicate a loss of functional receptors without a consistent change in their total number. Therefore, the exaggerated reflexes that are well established in rats 2 weeks after cord injury must be mediated by a mechanism that withstands attenuation of NMDA receptor function.

Topics: Animals; Autonomic Nervous System Diseases; Autoradiography; Chronic Disease; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Immunohistochemistry; Male; Muscle Spasticity; Nociceptors; Pain; Radioligand Assay; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Reflex, Abnormal; Spinal Cord; Spinal Cord Injuries; Tritium

We have investigated the effect of memantine, a clinically used NMDA receptor antagonist, in two experimental animals models of spinal cord injury. The lesions were laser-induced photothrombosis to induce focal spinal cord ischemia and clip compression to mimic traumatic spinal cord injury. Pre- or posttreatment of rats with a dose of memantine (20 mg/kg ip) previously shown to be neuroprotective in cerebral ischemia, failed to affect both the neurological and morphological outcome of ischemic spinal cord injury. Likewise, memantine had no effects on neurological and morphological outcome after experimental traumatic injury. In view of the regional heterogeneity of NMDA receptors, the affinity of memantine for spinal cord NMDA receptors was also determined by studying displacement of [3H] (+)-5-methyl-10,11-dihydro-5-H-dibenzo[a,d]cyclohepten-5-10-imine (MK-801) to rat and human spinal cord homogenates. We found that memantine had an affinity for NMDA receptors in the spinal cord (Ki = 0.58 microM) that was significantly lower compared to that of the cerebral cortex (Ki = 0.23 microM) and that the affinity for NMDA receptors in human spinal cord was even lower. We conclude that in view of available data, memantine should not be chosen for clinical studies on neuroprotection in spinal cord injuries and that the lack of protective effect is most likely due to insufficient affinity of memantine for spinal cord NMDA receptors.

Topics: Adult; Animals; Anti-Inflammatory Agents; Behavior, Animal; Binding, Competitive; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Humans; In Vitro Techniques; Kinetics; Memantine; Membranes; Methylprednisolone; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Cord Compression; Spinal Cord Injuries

A chronic allodynia-like response to mechanical stimulation was observed in rats after severe spinal cord ischemia. This allodynia-like response was not relieved by most conventional analgesics used for treating chronic neuropathic pain. The present experiments evaluated the effects of systemically administered excitatory amino acid receptor antagonists, including the non-competitive N-methyl-D-aspartate (NMDA) receptor/channel blockers MK-801 and dextromethorphan, the competitive NMDA receptor antagonist CGS 19755 and a competitive antagonist of the alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) receptor NBQX, on the chronic allodynia-like response in spinally injured rats. Systemic MK-801, dextromethorphan and CGS 19755 dose-dependently relieved the mechanical allodynia-like response. Systemic MK-801 and CGS 19755, but not dextromethorphan, also induced severe motor impairment at analgesic doses. All three NMDA antagonists increased spontaneous motor activity. Systemic NBQX reduced muscle tone and caused sedation. The mechanical allodynia was only relieved by NBQX at a sedative dose. It is concluded that systemic NMDA, but not AMPA, receptor antagonists may have an analgesic effect upon the chronic allodynia-like response. However, the analgesic effect of all NMDA antagonists was associated with side effects. Dextromethorphan, which is clinically tolerated and produced less side effects, may be useful for treating chronic pain associated with central nervous system injury.

Topics: Animals; Behavior, Animal; Chronic Disease; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Hyperalgesia; Ischemia; Motor Activity; Pipecolic Acids; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Regional Blood Flow; Spinal Cord; Spinal Cord Injuries

The post-traumatic release of excitatory amino acids (EAA) and their actions on N-methyl-D-aspartate (NMDA) receptors plays a major role in the spinal cord secondary injury process. The neuronal damage caused by the release of EAA may be reduced by NMDA-receptor channel blockers. To investigate the involvement of NMDA receptors in spinal cord injury (SCI), we pretreated animals with the noncompetitive NMDA antagonist MK801 (1.0 mg kg-1) before a compressive acute SCI. Pretreated animals with MK801 significantly (p = 0.038) improved the recovery of function as measured by evoked potential activities. Morphologically, specimens from rats treated with MK801 were characterized by milder and more localized hemorrhage in the gray matter. Immunohistochemical staining for glial fibrillary acidic protein (GFAP) and neurofilament (NF) histochemistry showed leakage of these antigens in traumatized cord while characteristic staining of astrocytes and neurons and their processes was observed in morphologically preserved tissue. The loss of NF immunoreactivity was reduced by MK801 treatment.

Topics: Animals; Blood Pressure; Dizocilpine Maleate; Evoked Potentials, Somatosensory; Immunohistochemistry; Nerve Compression Syndromes; Neural Conduction; Neurologic Examination; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Cord Injuries; Treatment Outcome

To clarify the role of N-methyl-D-aspartate (NMDA) receptors in acute spinal cord injury, changes in the intraspinal microcirculation after acute spinal cord injury in rabbits were examined. Systemic administration of MK-801, an NMDA receptor antagonist, at a dose of 5 mg/kg, significantly improved motor recovery after injury and significantly reduced edema formation at the injured site without altering spinal cord blood flow or vascular permeability at the injured site. These findings indicate that excitatory amino acids contribute to secondary spinal cord damage, especially edema formation, mediated by NMDA receptors in the early stage after injury.

Topics: Acute Disease; Animals; Blood Pressure; Capillary Permeability; Dizocilpine Maleate; Edema; Excitatory Amino Acid Antagonists; Microcirculation; Rabbits; Receptors, N-Methyl-D-Aspartate; Regional Blood Flow; Spinal Cord; Spinal Cord Diseases; Spinal Cord Injuries

N-methyl-D-aspartate (NMDA) receptor-mediated events have been implicated in the pathophysiology of posttraumatic spinal cord injury. In the present study, [3H]MK801 was used to analyse the changes in NMDA receptor-binding sites in rat spinal cord after impact trauma at T9. In contrast to brain, which showed only a single binding site, spinal cord showed both high-affinity (Kd1 = 0.47 +/- 0.24 nM) and low-affinity (Kd2 = 7.75 +/- 1.82 nM) binding sites with relatively low binding density (Bmax1 = 0.11 +/- 0.04 pmol/mg protein and Bmax2 = 0.84 +/- 0.11 pmol/mg protein). Time-course studies demonstrated significant decreases in the binding of [3H]MK801 at the thoracic and lumbar segments at 4 h after spinal cord injury with recovery by 24 h. Scatchard analyses indicate that these changes likely involve both high- and low-affinity binding sites. The transitory reduction in [3H]MK801-binding after trauma may reflect downregulation of NMDA receptors as a consequence of posttraumatic glutamate release and may serve to limit excitotoxin-induced injury.

Topics: Animals; Dizocilpine Maleate; Down-Regulation; Kinetics; Male; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Spinal Cord Injuries

The potential role of excitatory amino acid (EAA) receptors in spinal cord trauma was examined in a standardized rat model of contusive injury. EAA antagonists were administered in a split-dose protocol with half given 5 min prior to and the remainder 15 min after contusion produced at the T8 vertebral level. Hindlimb function was assessed using a battery of tests of reflex and more complex behaviors at 1 day after injury and weekly thereafter through 4-8 weeks. Functional deficits were compared for groups administered intravenous MK 801 (1 mg/kg), dextromethorphan (10 mg/kg) and kynurenate (300 mg/kg) or the vehicle, saline, alone. In addition, possible effect of the drugs themselves on hindlimb function were assessed in uninjured controls. None of the drugs produced more than transient effect on uninjured rats. In contused rats, only kynurenate produced significant reductions in functional deficits as compared to saline controls. Significant improvement of hindlimb function was also observed when the thoracic cord was locally perfused with kynurenate via intrathecal cannulas and when kynurenate was directly infused into the contusive injury site by stereotaxic microinjection. Using the latter route of administration, a dose-dependent effect of kynurenate (100, 200 and 400 nmol) on the ability of contused rats to use their hindlimbs in locomotion was demonstrated. The highest dose also resulted in a significant reduction in overall functional deficits from 1 week through 1 month and at 2 months after injury. Our results support the hypothesis that EAA receptors at or near the injury site are involved in producing a proportion of the overall functional deficits stemming from traumatic injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Amino Acids; Analysis of Variance; Animals; Dextromethorphan; Dizocilpine Maleate; Female; Infusions, Intravenous; Injections, Spinal; Kynurenic Acid; Rats; Rats, Inbred Strains; Spinal Cord Injuries

Damage to the central nervous system is followed by local release of excitatory amino acids, e.g. glutamate. These have been claimed to increase the metabolic need of already hypoxic neurons, and thereby to promote cell death. To investigate whether N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms are involved in the damage consequent to spinal cord injury, 20 rats were exposed to 5-min compression of the thoracic spinal cord produced with a load of 35 g on a 2.2 x 5 mm sized plate. One group of animals was given a noncompetitive NMDA channel blocker, MK-801, in a dose of 10 mg/kg b.w and one group saline alone. The neurologic function was evaluated on the inclined plane for 4 days when spinal cord blood flow (SCBF) was measured with the 14C-iodoantipyrine autoradiographic technique. One day after trauma the animals in both groups were paraparetic and exhibited a significantly decreased capacity angle at the inclined plane test (about 35 degrees compared with about 63 degrees before compression). Thereafter, the motor function improved slightly, but to a similar extent in the two groups. On Day 4, gray and white matter SCBF was similar in the two groups. The results indicate that MK 801 in the dose used does not prevent the development of neurologic dysfunction or the reduction in SCBF after spinal cord compression.

Topics: Animals; Dizocilpine Maleate; Male; Motor Skills; Nerve Regeneration; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Regional Blood Flow; Spinal Cord; Spinal Cord Compression; Spinal Cord Injuries

Prolonged (2-6 h) cooling of monolayer cultures of dissociated murine spinal cord at temperatures below 17 degrees C caused pronounced swelling of neuronal perikarya and dendrites. The numbers of swollen neurons in a culture increased as the temperature was reduced, and at 7 degrees C-10 degrees C all of the neurons were swollen. On rewarming the cultures to 37 degrees C, the majority of the swollen neurons died (up to 74% at 10 degrees C). Glial cells were not affected. Addition of the NMDA antagonists D-2-amino-5-phosphonovalerate (DAPV, 100 microM), ketamine (100 microM), and dibenzocyclohepteneimine (MK801, 10 microM) to spinal cord cultures before lowering the temperature to 10 degrees C minimized the dendrosomatic swelling and reduced neuronal mortality from 74% to 10%. These data show a surprising sensitivity of some neurons to nonfreezing low temperatures and suggest direct involvement of the NMDA receptor in hypothermia-related neuronal death.

Topics: 2-Amino-5-phosphonovalerate; Animals; Cell Survival; Dizocilpine Maleate; Female; Freezing; Hypothermia, Induced; Ketamine; Mice; N-Methylaspartate; Neurons; Pregnancy; Spinal Cord Injuries

One hour before a contusive spinal cord injury either compound MK-801 or compound U-50488H was injected intraperitoneally, and a 14-day-delivery osmotic minipump containing the same drug was placed subcutaneously at the time of surgery. The motor and sensory behavior of the animals was measured over the following 30 days. Both MK-801 and U-50488H treatments had a statistically significant neuroprotective effect. The number of neurons per unit area outside the lesion epicenter was significantly (P less than 0.01) greater in the drug-treated animals (MK-801, 298.9 +/- 74.8 neurons/mm2; U-50488H, 242.7 +/- 16.5 neurons/mm2) than in untreated controls (73.3 +/- 9.3 neurons/mm2). Recovery of sensory and motor behavior was limited but significant differences were observed when drug-treated rats were compared with untreated controls. The effects of the two drugs were not additive for any of the variables studied.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Cell Survival; Contusions; Dibenzocycloheptenes; Dizocilpine Maleate; Female; Neurons; Psychomotor Performance; Pyrrolidines; Rats; Rats, Inbred Strains; Spinal Cord Injuries

It has been proposed that endogenously released excitatory amino acids may contribute to injury of the central nervous system in a variety of disorders including certain neurodegenerative diseases, epilepsy, and cerebral ischemia. In the present studies we evaluated the hypothesis that excitatory amino acids, acting at the N-methyl-D-aspartate (NMDA) receptor, contribute to secondary tissue damage following traumatic spinal cord injury. Administration of NMDA, adjacent to the trauma site, significantly worsened the outcome after thoracic cord injury in rats, whereas its stereoisomer, N-methyl-L-aspartate (NMLA), was without effect. Systemic treatment with MK-801--a selective, centrally active, NMDA antagonist--significantly improved neurological outcome after trauma. These findings extend the excitotoxin concept to central nervous system trauma and indicate that NMDA antagonists may be beneficial in the treatment of traumatic spinal cord injury.

Topics: Animals; Anticonvulsants; Aspartic Acid; Dibenzocycloheptenes; Disease Models, Animal; Dizocilpine Maleate; Male; Motor Activity; N-Methylaspartate; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Spinal Cord Injuries; Stereoisomerism; Toxins, Biological

Antagonism of N-methyl-D-aspartate (NMDA) excitatory amino acid receptors limits tissue damage after experimental cerebral ischemia. Spinal cord trauma leads to a progressive decline in blood flow that is associated with secondary tissue damage. In the present studies, we evaluated the hypothesis that NMDA receptor activation contributes to the pathophysiology of spinal cord injury by examining the effects of the NMDA antagonist MK801 after impact trauma to rat thoracic spinal cords. MK801, in doses of 1.0 and 5.0 mg/kg administered intravenously (IV) at 15 min after trauma, improved long-term neurologic recovery. At a dose of 1.0 mg/kg, the drug reduced histologic changes as well as alterations in certain tissue cations found after spinal trauma. These findings suggest that excitotoxins contribute to the pathophysiology of spinal cord injury and that early treatment with NMDA antagonists may reduce posttraumatic tissue damage.

Topics: Animals; Aspartic Acid; Blood Pressure; Dibenzocycloheptenes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Injections, Intravenous; Male; N-Methylaspartate; Rats; Rats, Inbred Strains; Serotonin; Spinal Cord Injuries; Time Factors