Abstract
BackgroundLoss of GABA-mediated pre-synaptic inhibition after spinal injury plays a key role in the progressive increase in spinal reflexes and the appearance of spasticity. Clinical studies show that the use of baclofen (GABAB receptor agonist), while effective in modulating spasticity is associated with major side effects such as general sedation and progressive tolerance development. The goal of the present study was to assess if a combined therapy composed of spinal segment-specific upregulation of GAD65 (glutamate decarboxylase) gene once combined with systemic treatment with tiagabine (GABA uptake inhibitor) will lead to an antispasticity effect and whether such an effect will only be present in GAD65 gene over-expressing spinal segments.Methods/Principal FindingsAdult Sprague-Dawley (SD) rats were exposed to transient spinal ischemia (10 min) to induce muscle spasticity. Animals then received lumbar injection of HIV1-CMV-GAD65 lentivirus (LVs) targeting ventral α-motoneuronal pools. At 2–3 weeks after lentivirus delivery animals were treated systemically with tiagabine (4, 10, 20 or 40 mg/kg or vehicle) and the degree of spasticity response measured. In a separate experiment the expression of GAD65 gene after spinal parenchymal delivery of GAD65-lentivirus in naive minipigs was studied. Spastic SD rats receiving spinal injections of the GAD65 gene and treated with systemic tiagabine showed potent and tiagabine-dose-dependent alleviation of spasticity. Neither treatment alone (i.e., GAD65-LVs injection only or tiagabine treatment only) had any significant antispasticity effect nor had any detectable side effect. Measured antispasticity effect correlated with increase in spinal parenchymal GABA synthesis and was restricted to spinal segments overexpressing GAD65 gene.Conclusions/SignificanceThese data show that treatment with orally bioavailable GABA-mimetic drugs if combined with spinal-segment-specific GAD65 gene overexpression can represent a novel and highly effective anti-spasticity treatment which is associated with minimal side effects and is restricted to GAD65-gene over-expressing spinal segments.
Highlights
Spinal cord injury may lead to the development of clinically-defined spasticity and rigidity [1,2]
In addition to the role of decreased inhibition, several other potential mechanisms have been shown to contribute to the development of spasticity after spinal trauma, including: i) progressive increase in a-motoneuronal 5-HT2C receptor activity which became spontaneously active in the absence of brain-derived serotonin [14], or ii) the down regulation of the potassium-chloride co-transporter KCC2 in motoneurons and resulting switch to GABA-mediated depolarization [3]
We analyzed the presence of GABA B R1 and R2 receptors on lumbar a-motoneurons using immunofluorescence staining in control animals and animals at 3 months after induction of ischemic spasticity (n = 3)
Summary
Spinal cord injury (traumatic or ischemic) may lead to the development of clinically-defined spasticity and rigidity [1,2]. In addition to the role of decreased inhibition, several other potential mechanisms have been shown to contribute to the development of spasticity after spinal trauma, including: i) progressive increase in a-motoneuronal 5-HT2C receptor activity which became spontaneously active in the absence of brain-derived serotonin [14], or ii) the down regulation of the potassium-chloride co-transporter KCC2 in motoneurons and resulting switch to GABA-mediated depolarization [3]. These data indicate that the mechanism leading to the development of spasticity after spinal injury (traumatic or ischemic) is complex and can vary depending on the model used as well as the age of experimental animals when the injury is induced. The goal of the present study was to assess if a combined therapy composed of spinal segmentspecific upregulation of GAD65 (glutamate decarboxylase) gene once combined with systemic treatment with tiagabine (GABA uptake inhibitor) will lead to an antispasticity effect and whether such an effect will only be present in GAD65 gene over-expressing spinal segments
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