Levetiracetam treatment leads to functional recovery after thoracic or cervical injuries of the spinal cord

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.

Synaptic Vesicle Glycoprotein 2A Is Affected in the Central Nervous System of Mice with Huntington Disease and in the Brain of a Human with Huntington Disease Postmortem

“…Next, based on the clinical evidence of mHTT pathology in the spinal cord (25), we explored 11 C-UCB-J binding in the cervical spinal cord of symptomatic heterozygous mice and observed a decline in SV2A density with a similar magnitude to the brain. Altogether these observations support the exploration of SV2A PET imaging as synaptic integrity marker in spinal cord-related disorders, for instance, amyotrophic lateral sclerosis as well as spinal cord injury (SCI), currently being investigated in our group and supported by the recent evidence that levetiracetam treatment leads to functional recovery in SCI models (34).…”

Reactive Astrocytes in Central Nervous System Injury: Subgroup and Potential Therapy

“…A sharp increase in extracellular glutamate levels has been detected in both CNS injury models and human patients, and this increase represents the cumulative effect of several pathological events that lead to the overstimulation of glutamate receptors and the occurrence of large cation fluxes (Lima et al, 2021 ). Glutamate excitotoxicity plays an important role in the development of secondary CNS injury.…”

“…A better understanding of the changes occurring in mitochondrial morphology and function after CNS insult may yield novel strategies for the treatment of CNS injuries. Baicalin and LEC were shown to stabilize astrocytes after injury and increase their glutamate uptake, effects that can reduce excitotoxicity and protect both neurons and oligodendrocytes (Song X. et al, 2020 ; Lima et al, 2021 ). Agathisflavone and ganglioside GM1 promoted the neuroprotective effect of astrocytes (de Amorim et al, 2020 ; Finsterwald et al, 2021 ).…”

Acute baclofen administration promotes functional recovery after spinal cord injury

“…Motor neuron quantification was performed as previously described [19], every 200 µm both rostrally and caudally from the lesion epicenter, -2000 µm rostrally to the lesion site and 2000 µm caudally to the lesion site. Spinal cord transversal cross-sections were stained with the primary antibody anti-NeuN (1:200; Millipore, Darmstadt, German) and the secondary anti-body Alexa FluorTM 594 goat anti-mouse IgG (1:1000; Invitrogen, Paisley, UK).…”

“…To assess if Baclofen administration could lead to -motor neurons preservation after SCI, we performed an immunostaining with anti-NeuN antibody for the four experimental groups (Figure 3A). The -motor neurons were quantified in the ventral horn of the spinal cord, 2 mm rostrally and 2 mm caudally to the lesion site, nine weeks after the injury, as previously described [19] (Figure 3B). The quantification of -motor neurons revealed that there were no differences between the experimental groups (Figure 3B).…”