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.
| Kimpinski, Kurt; Iodice, Valeria; Sandroni, Paola et al. (2012) Sudomotor dysfunction in autoimmune autonomic ganglionopathy: a follow-up study. Clin Auton Res 22:131-6 |
| Geser, F; Malunda, J A; Hurtig, H I et al. (2011) TDP-43 pathology occurs infrequently in multiple system atrophy. Neuropathol Appl Neurobiol 37:358-65 |
| Figueroa, Juan J; Basford, Jeffrey R; Low, Phillip A (2010) Preventing and treating orthostatic hypotension: As easy as A, B, C. Cleve Clin J Med 77:298-306 |
| Kimpinski, Kurt; Iodice, Valeria; Low, Phillip A (2010) Postural Tachycardia Syndrome associated with peripartum cardiomyopathy. Auton Neurosci 155:130-1 |
| Kimpinski, Kurt; Iodice, Valeria; Sandroni, Paola et al. (2010) Effect of pregnancy on postural tachycardia syndrome. Mayo Clin Proc 85:639-44 |
| Iodice, V; Kimpinski, K; Vernino, S et al. (2009) Efficacy of immunotherapy in seropositive and seronegative putative autoimmune autonomic ganglionopathy. Neurology 72:2002-8 |
| Kimpinski, K; Iodice, V; Sandroni, P et al. (2009) Sudomotor dysfunction in autoimmune autonomic ganglionopathy. Neurology 73:1501-6 |
| Kimpinski, Kurt; Iodice, Valeria; Vernino, Steve et al. (2009) Association of N-type calcium channel autoimmunity in patients with autoimmune autonomic ganglionopathy. Auton Neurosci 150:136-9 |
| Wang, Annabel K; Fealey, Robert D; Gehrking, Tonette L et al. (2008) Patterns of neuropathy and autonomic failure in patients with amyloidosis. Mayo Clin Proc 83:1226-30 |
| Vogel, Elizabeth R; Corfits, Jeanne L; Sandroni, Paola et al. (2008) Effect of position on valsalva maneuver: supine versus 20 degree position. J Clin Neurophysiol 25:313-6 |
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