Neuroprotective effect of MK-801 and U-50488H after contusive spinal cord injury

doi:10.1016/S0014-4886(89)80004-4

Experimental Neurology

Volume 104, Issue 2, May 1989, Pages 118-124

https://doi.org/10.1016/S0014-4886(89)80004-4 Get rights and content

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 < 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.

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Traumatic spinal cord injury (SCI) is a major problem in clinical medicine. Etiology depends on several factors such as mechanism of injury and level of injury. The result is a very heterogeneous population of SCI patients. The characteristics of this pathology make for high levels of inter-patient variability. The validation of pharmacological neuroprotective therapy in the acute phase of traumatic SCI has been a treacherous road. Today, there are no FDA-approved therapies for medical management of acute SCI. The clinician depends on recommendations from the AANS/CNS suggesting that the use of methylprednisolone or GM-1 ganglioside is permissible but no real benefits have been observed. Several poorly designed prospective randomized controlled trials have obscured the real value of these promising therapies. This review systematically revises the current treatment protocols while also analyzing the validity and feasibility of the most cutting-edge basic and clinical treatment strategies. With this in mind, the objective is to inform healthcare providers of the present state of acute SCI pharmacological neuroprotective treatment and where is it going in the future.
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This increased activation of NMDARs has been implicated in excitotoxic cell death following experimental injury. Indeed, administration of an NMDAR antagonist, or other agents that block glutamate receptors, soon after injury improves functional outcome following SCI (Faden et al., 1981, 1988; Gómez-Pinilla et al., 1989; Mills et al., 2000, 2001; Wrathall et al., 1994, 1996, 1997). Increased extracellular glutamate levels, and the subsequent NMDAR activation, can lead to the induction of central sensitization, one mechanism thought to underlie the development of neuropathic pain, in the spinal cord (Artola and Singer, 1987; Woolf and Thompson, 1991).
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Citation Excerpt :
Glutamate, the major central nervous system (CNS) excitatory neurotransmitter, is toxic to neurons [23,25] and oligodendrocytes [56] at the elevated concentrations it attains following spinal cord injury (SCI). Furthermore, agents that block glutamate receptors improve functional outcomes and reduce damage to traumatized spinal cord tissue [10,11,14,29,30,52–54]. Thus, release of glutamate clearly contributes to secondary damage following SCI.
It is widely hypothesized that excitotoxicity of released glutamate following a CNS insult is propagated by the cyclic cascade: glutamate release → damage → glutamate release → further damage → etc. We tested this hypothesis by determining the effects of attempting to interrupt the loop by administering glutamate receptor antagonists and Na⁺-channel blockers on glutamate release following spinal cord injury (SCI). The effects of administering the NMDA receptor blockers MK-801 and memantine, the AMPA/kainate receptor blockers NBQX and GYKI 52466, the AMPA receptor desensitization blocker cyclothiazide and the sodium channel blockers riluzole, mexiletine and QX-314 on post-SCI were determined. Agents were administered into the site of injury by direct injection, by microdialysis or systemically. None of these agents had an appreciable effect on glutamate release following SCI. Thus, it is unlikely that the above cascade produces significant secondary glutamate release and ongoing damage following SCI, although such cascades may worsen other CNS insults. We attribute our results to overwhelming effects of much greater release by direct mechanical damage and reversal of transport following SCI.
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To investigate the possibility that glutamate receptor levels in the spinal cord are altered following injury to young rats, we used a previously characterized model of spinal cord contusion that produces a reliable injury in rats at postnatal day 14–15. Quantitative Western blot analysis was used to measure relative amounts of protein for several glutamate receptor subunits acutely (24 h) and chronically (28 days) after spinal cord injury (SCI). Acutely after injury significant decreases were observed in the GluR1, GluR2, and GluR4 subunits of the α-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA) receptor, and the NR2A and NR2B subunits, but not the NR1 subunit, of the N-methyl-d-aspartate (NMDA) receptor. However, 28 days after injury only one subunit (GluR4) was shown to be altered. These widespread changes that occur acutely in receptor subunit expression may be an attempt to protect cells from glutamate-induced death. The injured spinal cord in these young animals, however, appears to have the capacity to regulate receptor subunit levels to normal within a month of injury.
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Excitotoxic mechanisms have been implicated in the pathophysiology of spinal cord injury (SCI). The authors have studied the protection against secondary damage to rat spinal cord with magnesium sulphate, a well-known N-methyl-d-aspartate antagonist. Rats were randomly allocated into 5 groups. Group 1 rats were controls and normal spinal cord samples were obtained after clinical examination. 50 g–cm contusion injury was introduced to Group 2. Group 3 was vehicle, 1 cc of physiologic saline was injected posttrauma. Group 4 and 5 were treatment groups and 100 mg/kg and 600 mg/kg of Magnesium sulphate was given immediately after trauma, intraperitoneally. Animals were evaluated with inclined plane, Tarlov motor scale and Basso–Beattie–Bresnahan scale 24 h after SCI. Spinal cord samples for ultrastructural evaluations were obtained following clinical examinations. Magnesium treatment improved neurological outcome. Electron microscopic results showed obvious neuroprotection in the treatment groups. Application of 600 mg/kg of magnesium revealed better ultrastructural findings and clinical results than 100 mg/kg. These findings demonstrated that magnesium sulphate possesses neuroprotection on spinal cord ultrastructure and on functional scores after acute contusion injury to the rat spinal cord.

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Neuroprotective effect of MK-801 and U-50488H after contusive spinal cord injury

Trends Neurosci

Neurosci. Lett.

Exp. Neurol.

Brain Res

Brain Res

Trends Neurosci

Brain Res. Rev.

Exp. Neurol.

Trends Neurosci

Brain Res

Exp. Neurol.

Exp. Neurol.

Brain Res

Surgery of experimental lesion of spinal cord equivalent to crush injury of fracture dislocation of spinal column. A preliminary report

JAMA

Drug may protect brains of heart attack victims

Science

Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis

J. Neurochem.

Therapeutic approaches in subjects with brain lesions