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Gallium Nitrate and Spinal Cord Injury. a Pilot Study of Efficacy Using an Experimental Model

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Gallium Nitrate and Spinal Cord Injury. a Pilot Study of Efficacy Using an Experimental Model Paraplegia 32 (1994) 86-92 © 1994 International Society of Paraplegia Gallium nitrate and spinal cord injury. A pilot study of efficacy using an experimental model S C Colachis MD,l P G Popovich MS,2 B Stokes PhD3 1 Assistant Professor, Department of Physical Medicine and Director, Spinal Cord Injury 2 3 Rehabilitation, Graduate Research Associate. The Department of Physiology. Professor, Departments of Physiology and Surgery and Director, Spinal Cord Injury Research Center, The Ohio State University, College of Medicine, Columbus, Ohio, USA. Gallium (Ga) nitrate has been shown to attenuate immune-mediated tissue destruction in models of neurological autoimmunity. Based upon these observa­ tions, we evaluated the efficacy of Ga nitrate in attenuating the inflammatory response and modifying clinical recovery in an experimental model of traumatic spinal cord injury (SCI). Using a randomized, double-blind, placebo-controlled design, 12 adult female Spraque-Dawley rats received injections of either Ga nitrate (n = 8) or saline (n = 4) following experimental SCI. Ga treated animals received 30 mg/kg elemental Ga followed by weekly injections of 10 mg/kg elemental Ga. There were no observable differences between the Ga treated and the saline control groups using various behavioral paradigms examined during the study period. Histological and immunocytochemical data qualitatively showed no observable differences between Ga treated ( n = 4) and control (n = 2) groups sacrificed 18 days following SCI. Although the efficacy of Ga in this pilot study of experimental SCI was not demonstrated, the potential of Ga to attenuate inflammatory-mediated reactions remains an exciting possibility in the area of SCI. Our preliminary results should not discourage future research endeavors in this regard. A more complete analysis of dose response, time and mode of Ga administration (preinjury or postinjury), and availability of Ga across the blood-brain barrier is needed to further evaluate the efficacy of this compound. Keywords: spinal cord injury; gallium nitrate. , Introduction pathology 2-4 involves this complex cascade of events following SCI which can result in Therapeutic interventions directed at min­ progression of tissue ischemia and perman­ imizing spinal cord damage following an ent destruction of injured neural elements. acute traumatic spinal cord injury (SCI) are Research efforts directed at modulating based upon our understanding of the se­ secondary spinal cord injury have involved quence of events occurring within minutes the use of agents such as calcium channel to hours of the neurologic insult. Disruption blockers,5 antiadrenergic compounds,6 os­ of vascular perfusion and extracellular ionic motic diuretics,7 enzyme therapy, 8 local activity, followed by edema, metabolic de­ anesthetics,9 opiate antagonists,1O ganglio­ rangements, and free radical reactions is sides, II and steroids. 10 The efficacy of high­ concomitant with the initiation of an inflam­ dose steroids following acute traumatic SCI matory process and release of excitatory in humanslO provides strong support for amino acids.1.2 The concept of 'secondary modulating the associated inflammatory process.12 Although secondary inflamma­ Correspondence: Sam C Colachis, MD The Ohio tion appears to play an integral role in the State University, Dodd Hall/Davis Center, 480 West development of further spinal injury,2 the Ninth Avenue, Columbus, Ohio 43210, USA. precise mechanisms have not been fully Paraplegia 32 (1994) 86-92 Gallium nitrate and spinal cord injury 87 elucidated. Despite this, investigators have duce experimental spinal cord injury in postulated a central role of the tissue macro­ order to determine a known starting point phage in the secondary injury observed for injury production, produce a known and following experimentally induced SCI. 2-4 reproducible displacement profile during Such observations give impetus to further the injury, and estimate the force needed to evaluation of this immunologic interaction. compress the spinal cord by the same Gallium (Ga) is a group IlIA transitional amount for each animal. Such force feed­ element with multiple valences which in one back is quite useful in determining the of its salt forms (ie Ga nitrate) can inhibit biomechanical properties of the spinal com­ macrophage and lymphocyte activity under partment during the injury and in prevent­ experimental conditions.13-15 Ga nitrate has ing the impactor probe from contacting shown efficacy in suppression of experi­ adjacent tissue during the impact phase. It mental autoimmune encephalomyelitis,15 as has shown previously that this impact device well as in prevention of adjuvant arthri­ produces predictable incomplete spinal cord tis13 .16 in rats. The use of Ga salts in the injuries of similar severity between animal clinical treatment of Paget's disease may groups. 17-19 inhibit the function of osteoclasts, macro­ phage-like cells derived from bone marrow precursors. 13.1" The present pilot study was Production of SCI lesions designed to determine the efficacy of Ga The animals were anesthetized with an nitrate in modifying SCI and spinal cord intraperitoneal solution of ketamine hydro­ recovery in an experimental SCI model. chloride (SO mg/kg) and xylazine (10 mg/kg). A partial dorsal laminectomy was then performed at TS-9, ensuring minimal disturbance of the dura. The laminectomy Methods site was limited to one vertebral level. which Animals was slightly larger than the tip of the Twelve adult female Sprague-Dawley rats impactor probe (7 mm2). weighing between 250 and 275 g were util­ Following laminectomy, the animals were ized (Harlan Sprague-Dawley. Inc, Indian­ mounted in a spinal frame in which the apolis, IN). All animals were housed in a nearby dorsal processes were rigidly fixed, 1 -2 controlled environment with regularly as described previously. 9 1 A Ling shaker cycled light/dark periods of 12 hours. The (Model V203/S, Ling Dynamics Systems animals were familiarized with their en­ Corp) was used to compress the spinal cord vironment prior to the onset of the project, dorsal surface approximately 1. 1 mm over a and allowed free access to food and water. 23 ms time period. The injury process in­ Approval of the research protocol and volves approximately 11 ms to produce the treatment of the animals throughout the full impact and reach peak compression, duration of the study was in accordance with followed by removal of the impactor probe the doctrines of the Animal Review Com­ from contact with the dural surface of the mittee at The Ohio State University. cord over the remaining 12 ms time period. Muscle and skin wounds were then closed in layers. Following surgery. the animals were placed on a heating pad and allowed to Spinal cord impactor device recover spontaneously. They were given Contusion lesions in the spinal cords of the fluids to maintain hydration and were al­ animals were produced by our Ohio State lowed to eat ad libitum as they recovered. impact device.17 This impact device delivers Bladders were expressed at least three times controlled displacement. force. and ac­ daily until reflexes returned (usually within celeration of the impactor probe, while 2 weeks). Antibiotics were administered allowing feedback of these parameters.17.1� orally (4.0 mg trimethoprim; 20 mg sulfadia­ Two highly sensitive transducers are at­ zine. daily) from 2 days preoperatively until tached to the impactor probe used to pro- reflex bladder function returned. 88 Colachis et al Paraplegia 32 (1994) 86-92 Gallium nitrate injection protocol ment in space. Animals were tested for 5 Rats were randomized into two groups to seconds in each of three positions: head up, receive either Ga nitrate (n = 8) or saline right side up, or left side up. Animals (n = 4). Ga nitrate (Ben Venue Labora­ respond consistently over chronic postinjury tories, Inc, Bedford, Ohio) was a gift from times. The grid walking task21l.2� assessed the the National Cancer Institute (Bethesda, animals' ability to traverse a wire mesh with Maryland). Ga nitrate was administered to widely spaced bars (3.7 cm apart). Animals the rats subcutaneously in the nape of the were required to move for at least 30 neck at 1 hour after spinal cord injury as an seconds on this device in a 3-minute period initial bolus of 30 mg/kg of elemental Ga. while the footfalls of the hind feet through Thereafter, the animals received weekly the wire mesh were counted (in number of subcutaneous injections of Ga nitrate in the footfalls per second). nape of the neck (10 mg/kg of elemental These behavioral tasks have been shown Ga) for the following 2 weeks. The follow in our previous studies of contusion injuries up injections required the use of a restraint to correlate highly with biomechanical in­ cage to ensure that the complete dose was jury descriptors, lesion geometry, and given. The dosing schedule was based upon physiological analysis of the injury pro­ prior experimental studies demonstrating cess.19-2L2� Each has unique predictive value the clinical efficacy of Ga nitrate in rodent during different times after injuryY·1R.21 models of experimental adjuvant arthritis13 and experimental autoimmune encephalo­ myelitis.Is All investigators and laboratory Tissue collection. histology. and personnel involved in this study were immllnocvtochernistrv blinded from knowledge of which animals Six animals (four Ga, two saline treated) received Ga nitrate or saline solution. were sacrificed under deep anesthesia 18 days following SCI. and their spinal cords were removed using the method of De Evaluation of general motor functions Sousa and Horrocks.2) Application of hy­ Each of the animals was conditioned to draulic pressure via syringe to the caudal three different paradigms (ie Tarlov open­ spinal canal forced the intact spinal cord field scoring, inclined plane analysis, and through a cervical opening created by de­ footfalls on an open grid) for several weeks capitation. The spinal cord specimens were prior to receiving a spinal cord injury. All then quickly frozen in liquid nitrogen.
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