Project: Research project

Project Details


Nerve microvasculature is physiologically unique, being a poorly
autoregulating, nutritive-capacitance system of large capillaries
that is relatively resistant to ischemia. Yet angiopathic
neuropathies occur, are relatively common and are difficult to
treat. Nerve ischemia may also occur in disorders such as
diabetic , edematous and entrapment neuropathies. The broad
aim of this continuation proposal is an intensified focus on the
physiology of nerve ischemia. The specific aims, rationale, and
methods proposed are: First, a 3-dimensional reconstruction of
nerve blood flow (NBF) in ischemic models of neuropathy and in
response to sympathetic stimulation and denervation. Studies to
date on the physiology of nerve ischemia have been
unidimensional, focusing on nerve trunk and neglecting the much
more metabolically active cell body and at-risk distal axon. By
using combined microelectrode-H2-polarography and 14C-
iodoantipyrine autoradiography, it should be possible to determine
flow simultaneously at the cell body (dorsal root and sympathetic
ganglia) and the nerve fiber levels. Second, an evaluation of the
molecular mechanisms of nerve ischemic and reperfusion injury on
which information is totally lacking. The hypothesis that nerve is
damaged during ischemia and reperfusion due to an interplay of
oxygen free radicals (OFR) and eicosanoids will be tested. NBF,
computerized videoangiology, blood-nerve barrier (BNB; to 14C-
sucrose) and nerve electrophysiologic indices will be supplemented
by estimations of nerve cholesterol, arachidonic acid, fatty acid
profile, malondialdehyde (MDA) and superoxide dismutase (SOD)
as indices of OFR damage and the biosynthesis by nerve in situ
and in vitro of thromboxane B2 and 6-keto-PFG1 alpha will be
used as indices of nerve eiscosanoids and nerve catecholamines
will be measured. These studies will be done during ischemia and
following reperfusion. Third, an evaluation of mechanisms to
ameliorate the effects of ischemia and reperfusion. Calcium
channel blockers, vasodilator eiscosanoids, corticosteroids,
pentoxifylline and ketanserin may ameliorate microvascular
ischemia in other tissues, but their mechanisms and effectiveness
in peripheral nerve is unknown. Since the time-course of ischemic
fiber damage is very slow, occurring over many hours, nerve
comprises a system particularly suited for intervention therapy
should it become available. Finally, nerve catecholamines,
eicosanoids, MDA and SOD will be measured in sural nerve
biopsied for reasons unrelated to this proposal to apply some of
these techniques and strategies to humans.
Effective start/end date7/1/856/30/06


  • Medicine(all)
  • Neuroscience(all)