EXPERIMENTAL THERAPY OF SPINAL CORD INJURY

  • Young, Wise (PI)
  • YOUNG, WISE (PI)
  • CHESLER, MITCHELL (PI)
  • YOUNG, WISE (PI)
  • CHESLER, MITCHELL (PI)
  • RICE, MARGARET (PI)
  • NICHOLSON, CHARLES (PI)
  • YOUNG, WISE (PI)
  • RICE, MARGARET (PI)
  • NICHOLSON, CHARLES (PI)
  • YOUNG, WISE (PI)

Project Details

Description

We recently discovered the cyclosporin A (CsA), a commonly used
immunosuppressant, is neuroprotective in a rat model of spinal cord injury
(SCI), CsA inhibitors calcineurin, a key intracellular phosphatase in
neurons and lymphocyts. Recent studies have shown that calcineurin induces
and regulates immune and inflammatory responses of cells, as well as
calcium channels, neurotransmitter receptors, and secretion. We
consequently propose to study CsA and other calcineurin inhibitors further.


Our first aim is to determine whether calcineurin inhibition protects the
spinal cord. We will compare the effects of methylprednisolone (MP, the
current standard therapy for human SCI), CsA, CsA+MP, FK506, rapamuycin,
and FK506+rapamycin. FK506 is a macrolide antibiotic which inhibits
calcineurin but by binding to a different protein. Rapamycin is a
macrolide that does not inhibit calcineurin and antagonizes FK506
inhibition of calcineurin. If Cs[unreadable] and FK506 are neuroprotective,
rapamycin is not and antagonizes FK506's neuroprotective effect, the data
would argue strongly that calcineurin plays a major role in SCI.

Our second aim is to establish that GsA and FK506 improves motor recovery
and saves axons in the spinal cord. We will assess locomotor recovery,
count spinal axons, and assess myelination in the rats at 6 weeks after
injury and CsA, MP, CsA+MP, FK506, and FK506+ rapamycin treatment.

Our third aim is to study the effects of calcineurin inhibitors on blood
flow in injured spinal cords. Calcineurin stimulates the nitric oxide
synthase which produces nitric oxide, a potent vasodilating agent. We
propose the nitric oxide causes an initial increase in flow and delays
onset of blood flow loss in SCI.

Our fourth aim is to determine whether serotonin (5-HT) and gamma-amino-
butyrate acid (GABA) contribute to SCI. Both neurotransmitters are
released in injured spinal cords. We recently found that spinal axons have
5-HT and GABA receptors. Calcineurin prevents desensitization of 5-HT
gated calcium channels and CsA may protect spinal axons by turning off 5-HT
receptors. Mianserin, a 5-HT receptor blocker, has been reported to be
neuroprotective in SCI. We will therefore assess the effects of
calcineurin on 5-HT and GABA-induced excitability changes in vitro and in
vivo.

Our fifth aim is to assess the role of glutamate in spinal cord injury.
Glutamate is known to injure neurons and glutamate receptor blockers have
been reported to be neuroprotective in spinal cord injury. Recent studies,
however, report that calcineurin inactivates glutamate channels and also
enhances glutamate release. Calcineurin inhibitors therefore may
paradoxically enhance glutamate-induced neurotoxicity in SCI. To resolve
this issue, we will examine glutamate sensitivity in spinal cords and
determine the effects of calcincurin inhibitors on glutamate-mediated
axonal changes, in vitro and in vivo.
StatusFinished
Effective start/end date1/1/015/31/03

ASJC

  • Clinical Neurology
  • Neurology
  • Pathophysiology
  • Medicine(all)
  • Geometry and Topology
  • Epidemiology
  • Pathology and Forensic Medicine