A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding
Persistent neurotoxic side effects of oxaliplatin (OX) chemotherapy, including sensory ataxia, limit the efficacy of treatment and significantly diminish patient quality of life. The common explanation for neurotoxicity is neuropathy, however the degree of neuropathy varies greatly among patients an...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-11-01
|
| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996116301620 |
| _version_ | 1818870017940258816 |
|---|---|
| author | Jacob A. Vincent Krystyna B. Wieczerzak Hanna M. Gabriel Paul Nardelli Mark M. Rich Timothy C. Cope |
| author_facet | Jacob A. Vincent Krystyna B. Wieczerzak Hanna M. Gabriel Paul Nardelli Mark M. Rich Timothy C. Cope |
| author_sort | Jacob A. Vincent |
| collection | DOAJ |
| description | Persistent neurotoxic side effects of oxaliplatin (OX) chemotherapy, including sensory ataxia, limit the efficacy of treatment and significantly diminish patient quality of life. The common explanation for neurotoxicity is neuropathy, however the degree of neuropathy varies greatly among patients and appears insufficient in some cases to fully account for disability. We recently identified an additional mechanism that might contribute to sensory ataxia following OX treatment. In the present study, we tested whether that mechanism, selective modification of sensory signaling by muscle proprioceptors might result in behavioral deficits in rats. OX was administered once per week for seven weeks (cumulative dose i.p. 70 mg/kg) to adult female Wistar rats. Throughout and for three weeks following treatment, behavioral analysis was performed daily on OX and sham control rats. Compared to controls, OX rats demonstrated errors in placing their hind feet securely and/or correctly during a horizontal ladder rung task. These behavioral deficits occurred together with modification of proprioceptor signaling that eliminated sensory encoding of static muscle position while having little effect on encoding of dynamic changes in muscle length. Selective inability to sustain repetitive firing in response to static muscle stretch led us to hypothesize that OX treatment impairs specific ionic currents, possibly the persistent inward Na currents (NaPIC) that are known to support repetitive firing during static stimulation in several neuron types, including the class of large diameter dorsal root ganglion cells that includes muscle proprioceptors. We tested this hypothesis by determining whether the chronic effects of OX on the firing behavior of muscle proprioceptors in vivo were mimicked by acute injection of NaPIC antagonists. Both riluzole and phenytoin, each having multiple drug actions but having only antagonist action on NaPIC in common, reproduced selective modification of proprioceptor signaling observed in OX rats. Taken together, these findings lead us to propose that OX chemotherapy contributes to movement disability by modifying sensory encoding, possibly via a chronic neurotoxic effect on NaPIC in the sensory terminals of muscle proprioceptors. |
| first_indexed | 2024-12-19T12:00:20Z |
| format | Article |
| id | doaj.art-09fb9bc0271c4929a0d6dfed8fa2f0ec |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-19T12:00:20Z |
| publishDate | 2016-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-09fb9bc0271c4929a0d6dfed8fa2f0ec2022-12-21T20:22:31ZengElsevierNeurobiology of Disease1095-953X2016-11-01955465A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encodingJacob A. Vincent0Krystyna B. Wieczerzak1Hanna M. Gabriel2Paul Nardelli3Mark M. Rich4Timothy C. Cope5Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH 45435, United StatesDepartment of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH 45435, United StatesDepartment of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH 45435, United StatesDepartment of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH 45435, United States; School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30318, United StatesDepartment of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH 45435, United StatesDepartment of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH 45435, United States; School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30318, United States; Corresponding author at: School of Biological Sciences and Department of Biomedical Engineering, Georgia Institute of Technology, 555 14th St. NW., Atlanta, GA 30318, United States.Persistent neurotoxic side effects of oxaliplatin (OX) chemotherapy, including sensory ataxia, limit the efficacy of treatment and significantly diminish patient quality of life. The common explanation for neurotoxicity is neuropathy, however the degree of neuropathy varies greatly among patients and appears insufficient in some cases to fully account for disability. We recently identified an additional mechanism that might contribute to sensory ataxia following OX treatment. In the present study, we tested whether that mechanism, selective modification of sensory signaling by muscle proprioceptors might result in behavioral deficits in rats. OX was administered once per week for seven weeks (cumulative dose i.p. 70 mg/kg) to adult female Wistar rats. Throughout and for three weeks following treatment, behavioral analysis was performed daily on OX and sham control rats. Compared to controls, OX rats demonstrated errors in placing their hind feet securely and/or correctly during a horizontal ladder rung task. These behavioral deficits occurred together with modification of proprioceptor signaling that eliminated sensory encoding of static muscle position while having little effect on encoding of dynamic changes in muscle length. Selective inability to sustain repetitive firing in response to static muscle stretch led us to hypothesize that OX treatment impairs specific ionic currents, possibly the persistent inward Na currents (NaPIC) that are known to support repetitive firing during static stimulation in several neuron types, including the class of large diameter dorsal root ganglion cells that includes muscle proprioceptors. We tested this hypothesis by determining whether the chronic effects of OX on the firing behavior of muscle proprioceptors in vivo were mimicked by acute injection of NaPIC antagonists. Both riluzole and phenytoin, each having multiple drug actions but having only antagonist action on NaPIC in common, reproduced selective modification of proprioceptor signaling observed in OX rats. Taken together, these findings lead us to propose that OX chemotherapy contributes to movement disability by modifying sensory encoding, possibly via a chronic neurotoxic effect on NaPIC in the sensory terminals of muscle proprioceptors.http://www.sciencedirect.com/science/article/pii/S0969996116301620ChemotherapySensorimotor deficitsNeurotoxicitymuscle proprioceptorsNeuropathy |
| spellingShingle | Jacob A. Vincent Krystyna B. Wieczerzak Hanna M. Gabriel Paul Nardelli Mark M. Rich Timothy C. Cope A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding Neurobiology of Disease Chemotherapy Sensorimotor deficits Neurotoxicity muscle proprioceptors Neuropathy |
| title | A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding |
| title_full | A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding |
| title_fullStr | A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding |
| title_full_unstemmed | A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding |
| title_short | A novel path to chronic proprioceptive disability with oxaliplatin: Distortion of sensory encoding |
| title_sort | novel path to chronic proprioceptive disability with oxaliplatin distortion of sensory encoding |
| topic | Chemotherapy Sensorimotor deficits Neurotoxicity muscle proprioceptors Neuropathy |
| url | http://www.sciencedirect.com/science/article/pii/S0969996116301620 |
| work_keys_str_mv | AT jacobavincent anovelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding AT krystynabwieczerzak anovelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding AT hannamgabriel anovelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding AT paulnardelli anovelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding AT markmrich anovelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding AT timothyccope anovelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding AT jacobavincent novelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding AT krystynabwieczerzak novelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding AT hannamgabriel novelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding AT paulnardelli novelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding AT markmrich novelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding AT timothyccope novelpathtochronicproprioceptivedisabilitywithoxaliplatindistortionofsensoryencoding |