Neuroprotective Effects of Interleukin-10 Following Excitotoxic Spinal Cord Injury

Intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Inflammatory responses appear to be a major component of the secondary neuronal injury initiated by SCI and play a role in the pathogenesis of QUIS-induced injury. IL-10 is a potent antiinflammatory cytokine that has been shown to reduce inflammation and improve functional outcome in human and animal models of inflammatory diseases. We propose the administration of IL-10 following excitotoxic SCI will attenuate the inflammatory response, thus resulting in increased neuronal survival. Female, Sprague–Dawley rats were given intraspinal injections of QUIS followed by either intraspinal (5 ng, n=8) or systemic injections (5 μg, n=14) of IL-10. Survival times were varied (2–3 days) in order to produce a range of injury states and inflammatory involvement. When administered intraspinally, IL-10 significantly exacerbated the QUIS damage (P<0.05), resulting in an 11.2% increase in lesion volume. When given systemically, IL-10 significantly decreased lesion volume by 18.1% in the more advanced injury (P<0.05), but did not effect the more acute injury. These divergent effects were attributed to the modest inflammatory response in the short-term injury compared to the more robust inflammatory response in the more chronic injury. In conclusion, reducing the inflammatory response to SCI by systemic administration of IL-10 resulted in a significant reduction in neuronal damage, suggesting that targeting injury-induced inflammation may be an effective treatment strategy for acute SCI

Diffusion-Weighted MR Imaging in a Rat Model of Syringomyelia after Excitotoxic Spinal Cord Injury

BACKGROUND AND PURPOSE: Recent experimental data have shown that an increase of excitatory amino acids and the initiation of inflammatory responses within the injured spinal cord may play a role in post-traumatic syringomyelia. The purpose of this study was to determine whether diffusion-weighted MR imaging with apparent diffusion coefficient (ADC) maps could provide earlier evidence of spinal cord cavitation in a rat model of syringomyelia than available with conventional MR imaging. METHODS: The spinal cord gray matter of four rats was injected with the α-amino-3 hydroxy-5 methyl-4 isoxazole propionic acid/metabotropic receptor agonist quisqualic acid. Animals were sacrificed at 1, 4, or 8 weeks after injection, and the spinal cords were fixed in formalin for 1 week and imaged with T1-, T2-, and diffusion-weighted sequences. One control specimen was also imaged. ADC maps were constructed from the diffusion-weighted data. Histopathologic analyses of sections stained with cresyl violet were compared with the MR images. RESULTS: By 1 week after injection, ADC maps at the level of injection showed areas within the gray matter of increased intensity and increased ADC values as compared with the control specimen. These bright areas corresponded to cysts or cavities within the cord parenchyma on the histopathologic sections. The ADC values within affected gray matter areas progressively increased at 4 and 8 weeks, also corresponding to cyst formation. Conventional T1- and T2-weighted images showed corresponding lesions with cystic characteristics at 4 and 8 weeks, but not at 1 week. CONCLUSION: In an animal model of syringomyelia, diffusion-weighted imaging with ADC maps detected cystic lesions within spinal cord gray matter before they were seen on conventional T1- and T2-weighted images

Neuronal Damage following Intraspinal Injection of a Nitric Oxide Synthase Inhibitor in the Rat

Intraspinal microinjection of the nonspecific nitric oxide synthase (NOS) inhibitor N-nitro-L-arginine methyl ester (L-NAME) was used to determine if inhibition of NOS results in morphological changes in the rat spinal cord. Following spinal injections of 100–750 m M L-NAME (pH 7.0), 1.0–500 m M L-NAME (pH 2.5–5.4), or L-NAME + L-arginine, quantitative analysis of morphological changes revealed a positive dose-response relationship between L-NAME and neuronal loss. This effect was blocked by L-arginine and was inversely related to spinal levels of NOS enzyme activity. Results of this study have shown the importance of basal NOS activity in maintaining the structural integrity of spinal neurons. It is proposed that the effects of L-NAME on nitric oxide (NO) production leads to decreased blood flow, secondary to vasoconstriction, and a hypoxic–ischemic reaction in spinal tissue. The results suggest that a potential contributing factor to neuronal damage in pathological conditions such as spinal cord injury may be the decreased production of nitric oxide

Perceived difficulty in dealing with consequences of spinal cord injury

Objectives: To determine the perceived difficulty in dealing with consequences of spinal cord injury (SCI) and to explore patterns of how these complications are perceived. Design: Postal survey. Setting: General community. Participants: Individuals with traumatic SCI ( n = 430). Methods: Subjects ( n = 877) were selected from The Miami Project database and were sent a questionnaire in which they were asked to rate their difficulty in dealing with 10 consequences of SCI, on a scale ranging from 0 (not hard at all) to 10 (extremely hard). Results: The questionnaire was returned by 430 individuals (49%). Five consequences (decreased ability to walk or move, decreased control of bowel, decreased control of bladder, decreased sexual function, and pain) were rated highest (means, 8.2 to 6.2). High ratings of feeling sad were associated with high ratings of most other consequences, and a cluster analysis revealed interrelationships between the ways the various consequences were perceived. Conclusions: Several consequences of SCI are frequently perceived as being very difficult to deal with. Sadness may influence how well a person deals with other consequences of SCI. The observed patterns in perceived difficulty dealing with complications of SCI need to be explored further because they are important in our understanding and treatment of the medical conditions that may follow SCI

Dermatomal Scratching After Intramedullary Quisqualate Injection: Correlation With Cutaneous Denervation

Central nervous system lesions cause peripheral dysfunctions currently attributed to central cell death that compromises function of intact peripheral nerves. Injecting quisqualate (QUIS) into the rat spinal cord models spinal cord injury (SCI) and causes at-level scratching and self-injury. Such overgrooming was interpreted to model pain until patients with self-injurious scratching after SCI reported itch motivated scratching that was painless because of sensory loss. Because self- injurious scratching is difficult to explain by central mechanisms alone, we hypothesized that QUIS injections damage peripheral axons of at-level afferents. QUIS was injected into thoracic spinal cords of 18 Long-Evans rats. Animals were killed 3 days after overgrooming began or 14 days after injection. Spinal cord lesions were localized and DRG-immunolabeled for ATF-3. At- level and control skin samples were PGP9.5-immunabeled to quantify axons. Eighty-four percent of QUIS rats overgroomed. Skin in these regions had lost two-thirds of epidermal innervation as compared with controls (P < .001). Rats that overgroomed had 47% less axon-length than nongrooming rats (P = .006). The presence of ATF-3 immunolabeled neurons within diagnosis- related groups of QUIS rats indicated death of afferent cell bodies. Overgrooming after QUIS injections may not be due entirely to central changes. As in humans, self-injurious neuropathic scratching appeared to require loss of protective pain sensations in addition to peripheral denervation