A conus medullaris syndrome results from trauma to the sacral portion of the spinal cord and associated lumbosacral roots. Such injuries cause paralysis and sensory impairment of the lower extremities, pain, as well as bladder, bowel, and sexual dysfunctions. No successful treatments are presently available for patients with these injuries. We have developed a clinically relevant model for the study of conus medullaris/ cauda equina injury and repair in the rat. In this model, lumbosacral ventral roots are avulsed from the surface of the spinal cord and subsequently surgically implanted into the conus medullaris. During the initial research period, we demonstrated that this ventral root implantation strategy is neuroprotective, promotes axonal regeneration, and results in functional reinnervation of the lower urinary tract. The renewal of this project has three new aims: 1) to determine cell death mechanisms of autonomic and motor neurons after a lumbosacral ventral root avulsion (VRA) injury;2) to determine potential neuroprotective effects of minocycline and complement inhibition;3) determine whether minocycline and/or complement inhibition may augment functional reinnervation of the lower urinary tract after a lumbosacral VRA injury followed by acute and delayed surgical implantations of avulsed roots into the conus medullaris. We will use a combined therapeutic strategy approach to study neuronal death mechanisms, neuroprotection, and functional reinnervation of the lower urinary tract after lumbosacral VRA injury and repair. We will perform surgical root avulsions and implantations, pharmacological treatment, immunohistochemistry, electron microscopy, retrograde tracing techniques, stereology, and functional urodynamic studies of the lower urinary tract. Our proposed studies will provide a better understanding of death mechanisms for autonomic and motor neuron death in the spinal cord after proximal cauda equina injuries. We will also investigate new pharmacological strategies to protect these neurons against motor root injury-induced cell death in combination with root implantation to augment the function of the lower urinary tract. We believe that our proposal has translational research potential for the development of new treatments for patients with conus medullaris/cauda equina injuries.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS042719-06S1
Application #
7870679
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Kleitman, Naomi
Project Start
2001-12-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
6
Fiscal Year
2009
Total Cost
$77,000
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Moheban, Adam A; Chang, Huiyi H; Havton, Leif A (2016) The Suitability of Propofol Compared with Urethane for Anesthesia during Urodynamic Studies in Rats. J Am Assoc Lab Anim Sci 55:89-94
Chang, Huiyi H; Havton, Leif A (2013) Serotonergic 5-HT(1A) receptor agonist (8-OH-DPAT) ameliorates impaired micturition reflexes in a chronic ventral root avulsion model of incomplete cauda equina/conus medullaris injury. Exp Neurol 239:210-7
Chang, Huiyi H; Havton, Leif A (2012) Systemic administration of fluorogold for anatomical pre-labeling of autonomic and motor neurons in the rat spinal cord compromises urodynamic recordings in acute but not long-term studies. Neurourol Urodyn 31:162-7
Wu, L; Chang, H H; Havton, L A (2012) The soma and proximal dendrites of sympathetic preganglionic neurons innervating the major pelvic ganglion in female rats receive predominantly inhibitory inputs. Neuroscience 217:32-45
Wu, Lisa; Wu, Jun; Chang, Huiyi H et al. (2012) Selective plasticity of primary afferent innervation to the dorsal horn and autonomic nuclei following lumbosacral ventral root avulsion and reimplantation in long term studies. Exp Neurol 233:758-66
Havton, Leif A (2012) A lumbosacral ventral root avulsion injury and repair model for studies of neuropathic pain in rats. Methods Mol Biol 851:185-93
Chang, Huiyi H; Havton, Leif A (2012) Modulation of the visceromotor reflex by a lumbosacral ventral root avulsion injury and repair in rats. Am J Physiol Renal Physiol 303:F641-7
Chang, H-Y; Havton, L A (2010) Anatomical tracer injections into the lower urinary tract may compromise cystometry and external urethral sphincter electromyography in female rats. Neuroscience 166:212-9
Persson, Stefan; Havton, Leif A (2009) Retrogradely transported fluorogold accumulates in lysosomes of neurons and is detectable ultrastructurally using post-embedding immuno-gold methods. J Neurosci Methods 184:42-7
Havton, Leif A; Carlstedt, Thomas (2009) Repair and rehabilitation of plexus and root avulsions in animal models and patients. Curr Opin Neurol 22:570-4

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