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Electrophysiological and neurological characterization of a thoracic 9 model of spinal cord injury-induced muscle spasticity and the therapeutic anti-spastic effect following spinal GAD65 gene delivery in the rat

  • Author(s): Corleto, Jose Alfredo
  • Advisor(s): Marsala, Martin
  • et al.
Abstract

Spinal cord injury is a problem that carries with it many implications including changes in motor circuit action that then lead to development of muscle spasticity, hyperreflexia, and loss of inhibitory response stemming from injury. These changes contribute to muscle spasms elicited by casual stimulation of afferent fibers that then lead to changes in muscle action and to a decrease in the quality of life. Here, we developed a thoracic 9 spinal cord transection injury model in Sprague-Dawley rats to study the changes in motor circuitry in these paraplegic rats. For the first part of my thesis work, we used electrophysiology in this SCI model to study the development of gastrocnemius muscle spasticity, and also the presence of electrical stimulation- and tactile-evoked hyperreflexia at chronic phase following injury. The second part of my thesis focused on the use of clinical pharmacology (Baclofen, GABAb agonist and Tizanidine, α2 adrenergic agonist) and non-used avenues (NGX424, ampa/kainate antagonist) to look at the amelioration of spasticity and spinal hyper-reflexia. The third part of my thesis was aimed at using experimental gene therapy and to test the effect of spinal GAD65 gene upregulation (as achieved by spinal IT or SP AAV9-GAD65 delivery) on chronic spasticity.

Our results are sequentially organized as follows:

1) Characterization of time-dependent appearance of muscle spasticity and spinal hyper-reflexia after spinal Th9 transection in rat as defined by i) ankle-rotation evoked increase in muscle resistance, ii) tactile stimulus-evoked EMG response, and iii) electrical stimulus (H-reflex) defined muscle hyper-reflexia.

2) Characterization of anti-spastic potency of clinically validated anti-spastic agents in rat Th 9 spinal transection-induced chronic spasticity model.

3) Effect of spinal GAD65 gene upregulation in combination with systemic tiagabine (GABA uptake inhibitor) treatment on chronic muscle spasticity.

In conclusion, my work has demonstrated that our T9 TSCT model can recapitulate several pathologic neurological phenotypes (muscle spasticity, spinal hyper-reflexia) seen in human patients suffering from chronic spinal cord injury. Chronic muscle spasticity measured in the rat model is effectively suppressed by clinically validated anti-spastic agents, which suggests that this model represents an appropriate avenue for development of new anti-spastic therapies.

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