Journal of neurotrauma
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Journal of neurotrauma · Feb 2013
The dual cyclooxygenase/5-lipoxygenase inhibitor licofelone attenuates p-glycoprotein-mediated drug resistance in the injured spinal cord.
There are currently no proven effective treatments that can improve recovery of function in spinal cord injury (SCI) patients. Many therapeutic compounds have shown promise in pre-clinical studies, but clinical trials have been largely unsuccessful. P-glycoprotein (Pgp, Abcb1b) is a drug efflux transporter of the blood-spinal cord barrier that limits spinal cord penetration of blood-borne xenobiotics. ⋯ Because inflammation can drive Pgp upregulation, we evaluated the ability of the new generation dual anti-inflammatory drug licofelone to promote spinal cord delivery of riluzole following SCI. We found that licofelone both reduced Pgp expression and enhanced riluzole bioavailability within the lesion site at 72 h post-SCI. This work highlights Pgp-mediated drug resistance as an important obstacle to therapeutic drug delivery for SCI, and suggests licofelone as a novel combinatorial treatment strategy to enhance therapeutic drug delivery to the injured spinal cord.
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Journal of neurotrauma · Feb 2013
Dynamic motor compensations with permanent, focal loss of forelimb force after cervical spinal cord injury.
Incomplete cervical lesion is the most common type of human spinal cord injury (SCI) and causes permanent paresis of arm muscles, a phenomenon still incompletely understood in physiopathological and neuroanatomical terms. We performed spinal cord hemisection in adult rats at the caudal part of the segment C6, just rostral to the bulk of triceps brachii motoneurons, and analyzed the forces and kinematics of locomotion up to 4 months postlesion to determine the nature of motor function loss and recovery. A dramatic (50%), immediate and permanent loss of extensor force occurred in the forelimb but not in the hind limb of the injured side, accompanied by elbow and wrist kinematic impairments and early adaptations of whole-body movements that initially compensated the balance but changed continuously over the follow-up period to allow effective locomotion. ⋯ Ipsilateral foreleg deficits resulted mainly from interruption of axons that innervate the spinal cord segments caudal to the lesion, because chronic loss (about 35%) of synapses was detected at C7 while only 14% of triceps braquii motoneurons died, as assessed by synaptophysin immunohistochemistry and retrograde neural tracing, respectively. We also found a large pool of propriospinal neurons projecting from C2-C5 to C7 in normal rats, with topographical features similar to the propriospinal premotoneuronal system of cats and primates. Thus, concurrent axotomy at C6 of brain descending axons and cervical propriospinal axons likely hampered spontaneous recovery of the focal neurological impairments.
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Journal of neurotrauma · Feb 2013
Segmental spinal root avulsion in the adult rat: a model to study avulsion injury pain.
Road traffic accidents are the most common cause of avulsion injury, in which spinal roots are torn from the spinal cord. Patients suffer from a loss of sensorimotor function, intractable spontaneous pain, and border-zone hypersensitivity. The neuropathic pains are particularly difficult to treat because the lack of a well-established animal model of avulsion injury prevents identifying the underlying mechanisms and hinders the development of efficacious drugs. ⋯ Immunohistochemistry of the spinal cord revealed a localized glial response, phagocyte infiltration, and neuronal loss within the ipsilateral avulsed segment. A comparable response from glia and phagocytes was also found in the intact L4 spinal cord, supporting the role for central mechanisms within the L4-5 spinal cord in contributing to the generation of the pain-related behavior. The SRA model provides a platform to investigate possible new pharmacological treatments for avulsion injuries.
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Spinal cord injury (SCI) researchers have predominately utilized rodents and mice for in vivo SCI modeling and experimentation. From these small animal models have come many insights into the biology of SCI, and a growing number of novel treatments that promote behavioral recovery. It has, however, been difficult to demonstrate the efficacy of such treatments in human clinical trials. ⋯ Histological analysis of the spinal cords 12 weeks post-injury revealed that animals with the more biomechanically severe injuries had less spared white matter and gray matter and less neurofilament immunoreactivity. Additionally, the PTIBS scores correlated strongly with the extent of tissue sparing through the epicenter of injury. This large animal model of SCI may represent a useful intermediary in the testing of novel pharmacological treatments and cell transplantation strategies.