Journal of neurotrauma
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Journal of neurotrauma · Aug 2002
NBQX treatment improves mitochondrial function and reduces oxidative events after spinal cord injury.
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. ⋯ 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.
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Journal of neurotrauma · Aug 2002
Association between cerebrospinal fluid interleukin-6 concentrations and outcome after severe human traumatic brain injury.
Acute inflammation plays a significant role in the pathophysiology of traumatic brain injury (TBI). However, the specific relationships between inflammatory mediators and patient outcome following TBI have not been fully established. In this study, we measured plasma and cerebrospinal fluid interleukin-1 (IL-1) and interleukin-6 (IL-6) concentrations in 36 patients, following severe TBI. ⋯ Multiple regression analysis identified that age (p = 0.0072), pupillary abnormality (p = 0.021), the presence of mass lesion (p = 0.023), and peak CSF IL-6 concentrations (p = 0.026) were all statistically significant predictors of clinical outcome following TBI. These results suggest that peak CSF IL-6 concentrations correlate with improved outcome following TBI. This finding helps to characterize the inflammatory reaction associated with TBI and may help to develop improved treatment strategies for patients with TBI.
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Journal of neurotrauma · Aug 2002
Improved recovery and delayed cytokine induction after closed head injury in mice with central overexpression of the secreted isoform of the interleukin-1 receptor antagonist.
The acute inflammatory response following traumatic brain injury (TBI) has been shown to play an important role in the development of secondary tissue damage. The proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNFalpha), are induced early after brain injury and have been implicated in the delayed damage. The IL-1 receptor antagonist (IL-1ra) has been shown to modulate the proinflammatory cytokine cascade by blocking the binding of IL-1 to its signaling receptor. ⋯ After 4 h significant increases in the levels of IL-1beta and IL-6 were observed in the wild type mice. In the transgenic mice, on the other hand, no effect on TNFalpha levels was observed and no significant increases in IL-1beta and IL-6 levels could be detected until 6 h after injury. Thus, it can be concluded that blockage of IL-1 signaling by elevated levels of IL-1ra has a neuroprotective effect, in agreement with previous reports, and that central overexpression of IL-1ra results in delayed proinflammatory cytokine induction and improved neurological recovery after traumatic brain injury.
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Journal of neurotrauma · Aug 2002
LF 16-0687 Ms, a bradykinin B2 receptor antagonist, reduces brain edema and improves long-term neurological function recovery after closed head trauma in rats.
Bradykinin is an endogenous inflammatory agent that enhances vascular permeability and produces tissue edema. We investigated whether LF 16-0687 Ms, a potent nonpeptide antagonist of bradykinin type-2 (B(2)) receptor, was able to reduce brain swelling and to improve the recovery of neurological function following closed head trauma (CHT) in rats. In dose-effect studies, LF 16-0687 Ms doses of 0.75-4.5 mg/kg given 1 h after trauma significantly reduced the development of edema in the injured hemisphere by a maximum of 70%. ⋯ In duration of treatment studies, rats tended to recover normal neurological function over 14 days after CHT. However, time to recovery was longer in severely than in moderately injured animals, unless they were treated with LF 16-0687 Ms. This study provides further evidence that blockade of bradykinin B(2) receptors represents a potential effective approach to the treatment of focal cerebral contusions.
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Journal of neurotrauma · Aug 2002
Relationship between NOC/oFQ, dynorphin, and COX-2 activation in impaired NMDA cerebrovasodilation after brain injury.
Previous studies have observed that the recently described endogenous opioid, nociceptin/orphanin FQ (NOC/oFQ), contributes to impairment of N-methyl-D-aspartate (NMDA)-induced cerebrovasodilation following fluid percussion brain injury (FPI) via a cyclooxygenase (COX)-dependent generation of superoxide anion (O(2)(-)). This study was designed to investigate the relationship between NOC/oFQ, another opioid, dynorphin, and activation of the COX-2 isoform of the enzyme in such impaired dilation to NMDA after FPI in piglets equipped with a closed cranial window. Superoxide dismutase (SOD)-inhibitable nitroblue tetrazolium (NBT) reduction was determined as an index of O(-)(2) generation. ⋯ These data also show that dynorphin contributes to O(2)(-) generation after FPI via COX-2 activation. These data additionally indicate that dynorphin and COX-2 activation contribute to impairment of NMDA pial artery dilation after FPI. Finally, these data suggest that NOC/oFQ impairs NMDA dilation postinsult via the sequential release of dynorphin, activation of COX-2, and generation of O(2)(-).