Using a rat spinal ischemia model, we have shown that specific periods of transient spinal ischemia lead to a selective degeneration of small and medium-sized inhibitory neurons in lumbosacral segments and the development of prominent and permanent spasticity and rigidity. Similar development of spasticity and rigidity in patients undergoing thoracoabdominal aortic aneurysm repair or after traumatic spinal injury had been described. While the clinical signs of spasticity and rigidity can be effectively controlled by systemic or spinal treatment with several pharmacological agents including baclofen (GABA B receptor agonist) or tizadinine (alpha2 agonist), significant side effects and complications associated with chronic intrathecal cannulations calls for the development of new and more effective therapies. In recent years, significant attention has been focused on a potential use of adeno-or lenti-viral vectors with the goal to upregulate therapeutic genes in specific areas of the brain or spinal cord. These initial studies clearly show that intrastriatal injections of adeno-associated virus encoding GAD65 gene is effective in suppressing parkinsonian dyskinesias and is associated with an increase in local GABA release. In the present studies, using an established rat model of ischemic spasticity and rigidity, we will examine a possible therapeutic potential of spinal lentivirus-mediated GAD65 gene delivery in order to produce local upregulation of GABA synthesis and ameliorate spasticity and rigidity. The effect of local GAD65 gene upregulation in animals with developed spasticity and rigidity will be accomplished and assessed by i) direct spinal parenchymal lentivirus delivery or spinal grafting of rat neuronal precursors genetically modified to produce GABA, ii) electrophysiological/functional indices of spasticity and rigidity, iii) corresponding spinal parenchyma! GABA release, and, iv) histological analysis of transgene expression. From a practical standpoint, these studies will systematically address issues which we believe have both basic and clinical importance. Thus the ability to selectively increase GABA synthesis in previously ischemic, GABA neuron-depleted segments, may prove to be of particular significance in developing novel therapeutic modalities for managing chronic spasticity and rigidity in patients after ischemic or traumatic spinal injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Hicks, Ramona R
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University of California San Diego
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