Abstract
Spinal cord injury (SCI) leads to dramatic impairments of motor, sensory, and autonomic functions of affected individuals. Following the primary injury, there is an increased release of glutamate that leads to excitotoxicity and further neuronal death. Therefore, modulating glutamate excitotoxicity seems to be a promising target to promote neuroprotection during the acute phase of the injury. In this study, we evaluated the therapeutic effect of a FDA approved antiepileptic drug (levetiracetam-LEV), known for binding to the synaptic vesicle protein SV2A in the brain and spinal cord. LEV therapy was tested in two models of SCI—one affecting the cervical and other the thoracic level of the spinal cord. The treatment was effective on both SCI models. Treated animals presented significant improvements on gross and fine motor functions. The histological assessment revealed a significant decrease of cavity size, as well as higher neuronal and oligodendrocyte survival on treated animals. Molecular analysis revealed that LEV acts by stabilizing the astrocytes allowing an effective uptake of the excess glutamate from the extracellular space. Overall, our results demonstrate that Levetiracetam may be a promising drug for acute management of SCI.
Highlights
Spinal cord injury (SCI) leads to severe neurological deficits with a strong impact on the physiologic, psychological and social behavior of SCI individuals
LEVtreated rats presented at week 8 a mean BBB score of 10.5 ± 3.3, corresponding to the ability to support their own body weight and to perform occasional plantar steps, while saline-treated group presented a mean BBB score of 6.5 ± 3.5, which is translated into extensive movement of two joints and a slight movement of the third
Excitotoxicity initiates a cascade of events that culminates with the activation of calcium-related proteases, nitric oxide synthase stimulation, production of free radicals, lipid peroxidation, enzymes inactivation of glyceraldehyde-3-phosphate dehydrogenase, and other oxidative processes[14,15]
Summary
Spinal cord injury (SCI) leads to severe neurological deficits with a strong impact on the physiologic, psychological and social behavior of SCI individuals. After the initial trauma that lacerates, compresses or contuses the spinal cord, a cascade of events is initiated, contributing to further tissue damage[1]. Within minutes following a SCI, the extracellular excitatory amino acid concentrations increase to neurotoxic levels, leading to excitotoxicity and neuronal cell death[2]. Modulating the excitatory amino acid levels after trauma may be a valuable strategy to reduce acute neurotoxicity and protect the spinal cord. In this work we explored the therapeutic action of a new antiepileptic drug —Levetiracetam (LEV)—known for binding to the synaptic vesicle protein SV2A in the brain and spinal cord and inhibiting presynaptic neurotransmitter release[3,4,5,6,7]
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