Repair of Bladder Function after Cauda Equina Injury

Summary

Principal Investigator: LEIF HAVTON
Abstract: 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.
Funding Period: ----------------2001 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Differential effects of urethane and isoflurane on external urethral sphincter electromyography and cystometry in rats
    Hui Yi Chang
    Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E Young Drive South, Los Angeles, CA 90095, USA
    Am J Physiol Renal Physiol 295:F1248-53. 2008
  2. pmc 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
    Huiyi H Chang
    Department of Anesthesiology and Perioperative Care, UC Irvine, Irvine, CA 92697, USA
    Exp Neurol 239:210-7. 2013
  3. pmc Modulation of the visceromotor reflex by a lumbosacral ventral root avulsion injury and repair in rats
    Huiyi H Chang
    Dept of Anesthesiology and Perioperative Care, Reeve Irvine Research Center, Univ of California at Irvine School of Medicine, 837 Health Science Road, Irvine, CA 92697, USA
    Am J Physiol Renal Physiol 303:F641-7. 2012
  4. pmc The soma and proximal dendrites of sympathetic preganglionic neurons innervating the major pelvic ganglion in female rats receive predominantly inhibitory inputs
    L Wu
    Interdepartmental Program for Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Neuroscience 217:32-45. 2012
  5. pmc Differential synaptic inputs to the cell body and proximal dendrites of preganglionic parasympathetic neurons in the rat conus medullaris
    S Persson
    Department of Neurology, David Geffen School of Medicine at UCLA, Neuroscience Research Building, 635 Charles E Young Drive South, Los Angeles, CA 90095, USA
    Neuroscience 157:656-65. 2008
  6. pmc Surgical implantation of avulsed lumbosacral ventral roots promotes restoration of bladder morphology in rats
    Hui Yi Chang
    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Exp Neurol 214:117-24. 2008
  7. ncbi Novel repair strategies to restore bladder function following cauda equina/conus medullaris injuries
    Thao X Hoang
    Department of Neurology, David Geffen School of Medicine at University of California Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095 1769, USA
    Prog Brain Res 152:195-204. 2006
  8. pmc Re-established micturition reflexes show differential activation patterns after lumbosacral ventral root avulsion injury and repair in rats
    Hui Yi Chang
    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Exp Neurol 212:291-7. 2008
  9. pmc Minocycline protects motor but not autonomic neurons after cauda equina injury
    Thao X Hoang
    Department of Neurology, David Geffen School of Medicine at UCLA, Neuroscience Research Building, 635 Charles E Young Drive South, Los Angeles, CA 90095 7334, USA
    Exp Brain Res 189:71-7. 2008
  10. pmc Reimplantation of avulsed lumbosacral ventral roots in the rat ameliorates injury-induced degeneration of primary afferent axon collaterals in the spinal dorsal columns
    A J Bigbee
    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 7334, USA
    Neuroscience 152:338-45. 2008

Scientific Experts

  • LEIF HAVTON
  • Thao X Hoang
  • Huiyi H Chang
  • Hui Yi Chang
  • A J Bigbee
  • T X Hoang
  • Marcus Ohlsson
  • Jun Wu
  • Mahnaz Akhavan
  • L Wu
  • Lisa Wu
  • H Y Chang
  • Stefan Persson
  • S Persson
  • H H Chang
  • B H Dobkin
  • Victor Pikov
  • J H Nieto
  • N J K Tillakaratne

Detail Information

Publications23

  1. pmc Differential effects of urethane and isoflurane on external urethral sphincter electromyography and cystometry in rats
    Hui Yi Chang
    Department of Neurology, David Geffen School of Medicine at UCLA, 635 Charles E Young Drive South, Los Angeles, CA 90095, USA
    Am J Physiol Renal Physiol 295:F1248-53. 2008
    ..We suggest that these anesthetic properties be taken into consideration during the experimental design and interpretation of urodynamic recordings in rodent models...
  2. pmc 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
    Huiyi H Chang
    Department of Anesthesiology and Perioperative Care, UC Irvine, Irvine, CA 92697, USA
    Exp Neurol 239:210-7. 2013
    ..We conclude that serotonergic modulation of the 5-HT(1A) receptor may represent a new strategy to improve lower urinary tract function after incomplete cauda equina/conus medullaris injuries in experimental studies...
  3. pmc Modulation of the visceromotor reflex by a lumbosacral ventral root avulsion injury and repair in rats
    Huiyi H Chang
    Dept of Anesthesiology and Perioperative Care, Reeve Irvine Research Center, Univ of California at Irvine School of Medicine, 837 Health Science Road, Irvine, CA 92697, USA
    Am J Physiol Renal Physiol 303:F641-7. 2012
    ..An acute root replantation decreased the VMR induced by VRA injury and provides earlier sensory recovery...
  4. pmc The soma and proximal dendrites of sympathetic preganglionic neurons innervating the major pelvic ganglion in female rats receive predominantly inhibitory inputs
    L Wu
    Interdepartmental Program for Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Neuroscience 217:32-45. 2012
    ..Boutons with dense-core vesicles were rare. Our results demonstrate that SPNs of the DCN and IML of female rats are similar morphologically, and that synaptic input on these cells, though sparse, is predominantly inhibitory...
  5. pmc Differential synaptic inputs to the cell body and proximal dendrites of preganglionic parasympathetic neurons in the rat conus medullaris
    S Persson
    Department of Neurology, David Geffen School of Medicine at UCLA, Neuroscience Research Building, 635 Charles E Young Drive South, Los Angeles, CA 90095, USA
    Neuroscience 157:656-65. 2008
    ..Our studies suggest that the synaptic input to PPNs originates from multiple distinct sources and is differentially distributed and integrated over the cell membrane surface...
  6. pmc Surgical implantation of avulsed lumbosacral ventral roots promotes restoration of bladder morphology in rats
    Hui Yi Chang
    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Exp Neurol 214:117-24. 2008
    ..Our results support the notion that surgical implantation of severed ventral roots into the spinal cord may promote the recovery of a normal morphological phenotype in peripheral end organs...
  7. ncbi Novel repair strategies to restore bladder function following cauda equina/conus medullaris injuries
    Thao X Hoang
    Department of Neurology, David Geffen School of Medicine at University of California Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095 1769, USA
    Prog Brain Res 152:195-204. 2006
    ..A brief discussion on a variety of outcome measures that may be suitable to evaluate the function of the lower urinary tract in rodent neural repair models is also provided...
  8. pmc Re-established micturition reflexes show differential activation patterns after lumbosacral ventral root avulsion injury and repair in rats
    Hui Yi Chang
    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Exp Neurol 212:291-7. 2008
    ..Our future studies will aim to increase successful axonal regeneration in attempts to augment the recovery of the LUT after cauda equina injury and repair...
  9. pmc Minocycline protects motor but not autonomic neurons after cauda equina injury
    Thao X Hoang
    Department of Neurology, David Geffen School of Medicine at UCLA, Neuroscience Research Building, 635 Charles E Young Drive South, Los Angeles, CA 90095 7334, USA
    Exp Brain Res 189:71-7. 2008
    ..Our findings suggest that minocycline may protect degenerating motoneurons and expand the therapeutic window of opportunity for surgical repair of proximal root lesions affecting spinal motoneurons...
  10. pmc Reimplantation of avulsed lumbosacral ventral roots in the rat ameliorates injury-induced degeneration of primary afferent axon collaterals in the spinal dorsal columns
    A J Bigbee
    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 7334, USA
    Neuroscience 152:338-45. 2008
    ..These data further support the therapeutic potential for reimplantation of avulsed ventral roots following trauma to the cauda equina/conus medullaris...
  11. pmc At-level neuropathic pain is induced by lumbosacral ventral root avulsion injury and ameliorated by root reimplantation into the spinal cord
    A J Bigbee
    Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095 1769, USA
    Exp Neurol 204:273-82. 2007
    ..We believe that our findings are of translational research interest, as root implantation surgery is emerging as a potentially useful strategy for the repair of cauda equina/conus medullaris injuries...
  12. ncbi Functional reinnervation of the rat lower urinary tract after cauda equina injury and repair
    Thao X Hoang
    Department of Neurology and Brain Research Institute, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095, USA
    J Neurosci 26:8672-9. 2006
    ....
  13. ncbi Acute implantation of an avulsed lumbosacral ventral root into the rat conus medullaris promotes neuroprotection and graft reinnervation by autonomic and motor neurons
    T X Hoang
    Department of Neurology and Brain Research Institute, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095 1769, USA
    Neuroscience 138:1149-60. 2006
    ....
  14. ncbi Glial reactions in a rodent cauda equina injury and repair model
    Marcus Ohlsson
    Department of Neurology and Brain Research Institute, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095 1769, USA
    Exp Brain Res 170:52-60. 2006
    ....
  15. ncbi Complement activation after lumbosacral ventral root avulsion injury
    Marcus Ohlsson
    Department of Neurology and Brain Research Institute, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095 1769, USA
    Neurosci Lett 394:179-83. 2006
    ..We speculate that inhibition of MAC may constitute a potential neuroprotective strategy following cauda equina injuries...
  16. ncbi A single re-implanted ventral root exerts neurotropic effects over multiple spinal cord segments in the adult rat
    Thao X Hoang
    Department of Neurology and Brain Research Institute, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095 1769, USA
    Exp Brain Res 169:208-17. 2006
    ....
  17. ncbi Improved detection of fluorogold-labeled neurons in long-term studies
    Mahnaz Akhavan
    Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, CA 90095 1769, USA
    J Neurosci Methods 152:156-62. 2006
    ..We conclude that FG-labeling is a useful tool to determine neuronal counts in long-term studies, but should be used cautiously for neuronal size measurements...
  18. pmc Retrogradely transported fluorogold accumulates in lysosomes of neurons and is detectable ultrastructurally using post-embedding immuno-gold methods
    Stefan Persson
    Department of Neurology, David Geffen School of Medicine at UCLA, Neuroscience Research Building, 635 Charles E Young Drive South, Los Angeles, CA 90095, United States
    J Neurosci Methods 184:42-7. 2009
    ..g., neuro-transmitter studies in the electron microscope. We suggest that the described method for sensitive detection of FG in the spinal cord may also have broad applicability to other areas of the central nervous system...
  19. doi Repair and rehabilitation of plexus and root avulsions in animal models and patients
    Leif A Havton
    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
    Curr Opin Neurol 22:570-4. 2009
    ....
  20. pmc Anatomical tracer injections into the lower urinary tract may compromise cystometry and external urethral sphincter electromyography in female rats
    H Y Chang
    Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Neuroscience 166:212-9. 2010
    ....
  21. pmc 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
    Huiyi H Chang
    Department of Anesthesiology and Perioperative Care, University of California at Irvine School of Medicine, Irvine, California 92697, USA
    Neurourol Urodyn 31:162-7. 2012
    ..The use of anatomical tracer injections into peripheral tissues for retrograde labeling of spinal cord neurons may compromise physiological experiments in combined functional and morphological studies...
  22. doi Selective plasticity of primary afferent innervation to the dorsal horn and autonomic nuclei following lumbosacral ventral root avulsion and reimplantation in long term studies
    Lisa Wu
    Interdepartmental Program for Neuroscience, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
    Exp Neurol 233:758-66. 2012
    ..We conclude that even remote, efferent root injuries and repair procedures can have an effect on remote and non-lesioned sensory systems sharing common peripheral ganglia...
  23. doi A lumbosacral ventral root avulsion injury and repair model for studies of neuropathic pain in rats
    Leif A Havton
    Department of Anesthesiology, School of Medicine, University of California Irvine, Irvine, CA, USA
    Methods Mol Biol 851:185-93. 2012
    ..Interestingly, an acute replantation of the avulsed ventral roots into the spinal cord results in amelioration of the neuropathic pain. A detailed description of this injury and repair model is provided...