Indiana University-Purdue University Indianapolis (IUPUI) / Although paclitaxel is a commonly used anti-neoplastic agent for
the treatment of solid tumors, therapy often results in a number of side
effects, the most debilitating of which is peripheral neuropathy. Peripheral
neuropathy is defined as a pathology of peripheral nerves, and, depending
on the type of nerves damaged, the neuropathy can be classified as
sensory, motor, or autonomic neuropathy. In the case of peripheral
neuropathy induced by paclitaxel, the symptoms are experienced in the
extremities and are sensory in nature. Patients undergoing chemotherapy
with paclitaxel often report sensory disturbances such as burning, tingling,
numbness, a diminished sensation to pain and temperature, loss of
vibration sense, loss of proprioception, and loss of deep tendon reflexes.
Electrophysiological abnormalities including decreased sensory nerve
action potential amplitude and conduction confirm damage to large
myelinated fibers. However, the involvement of damage to small diameter
sensory neurons in the etiology of paclitaxel – induced peripheral
neuropathy is still controversial. Therefore, experiments were performed to
determine if paclitaxel alters the function of small diameter sensory
neurons and to examine the mechanisms responsible for the change in
function.
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Sensory neuron mediated vasodilatation in paclitaxel – injected
animals was examined as an indirect measure of calcitonin gene related
peptide (CGRP) release and therefore of sensory neuron function. CGRP
release was also directly measured from central terminals in the spinal
cord. To examine mechanisms of paclitaxel – induced sensory neuron
damage, CGRP release and neurite length was examined in paclitaxel –
treated sensory neurons in culture. The results demonstrate that (1)
paclitaxel decreases the ability of small diameter sensory neurons to
produce an increase in blood flow in the skin; (2) paclitaxel alters the
release of CGRP from the small diameter sensory neurons; (3) paclitaxel
causes the neuronal processes of isolated sensory neurons to
degenerate. This dissertation provides novel information showing that
paclitaxel alters the function of small diameter sensory neurons and thus
provides a better understanding of the mechanisms mediating the sensory
disturbances characteristic of peripheral neuropathy resulting from
chemotherapy with paclitaxel.
| Identifer | oai:union.ndltd.org:IUPUI/oai:scholarworks.iupui.edu:1805/2606 |
| Date | 08 July 2011 |
| Creators | Gracias, Neilia |
| Contributors | Vasko, Michael R., Brustovetsky, Nickolay, Hingtgen, Cynthia M., 1966-, Hudmon, Andrew, Kelley, Mark Richard, 1957- |
| Source Sets | Indiana University-Purdue University Indianapolis |
| Detected Language | English |
| Type | Thesis |
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