Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells.
Paclitaxel-induced peripheral neuropathy (PN) can be a significant problem for patients receiving chemotherapeutic regimens for the treatment of breast, ovarian, and lung cancer as PN can influence the quality of life and survivorship in these patients. To begin to understand the cellular changes that occur within the peripheral and central nervous system as PN develops, we intravenously infused rats with clinically relevant doses of paclitaxel. Ten days later, behavioral changes indicative of PN became evident that included mechanical allodynia, cold hyperalgesia, and deficits in ambulation/coordination. These behaviors were accompanied by increased expression of activating transcription factor 3 (ATF3; a marker of cellular injury) in a population of large>medium>small diameter sensory neurons, a population of satellite cells in the lumbar dorsal root ganglia (DRG) and in myelinating Schwann cells in the sciatic nerve. In addition, there was an increase in the expression of glial fibrillary acidic protein (GFAP) in DRG satellite cells and an increase in the number of CD68 positive activated macrophages within the DRG and peripheral nerve. Within lamina III-IV of the lumbar spinal cord, there was an increase in OX42 positive microglia. These data suggest that intravenous infusion of paclitaxel induces a peripheral neuropathy characterized by injury of neuronal and non-neuronal cells in the peripheral nervous system, macrophage activation in both the DRG and peripheral nerve, and microglial activation within the spinal cord. An understanding of the factors involved in the development and maintenance of PN may lead to mechanism based therapies that prevent/treat PN and thus improve the survival and quality of life of patients receiving chemotherapy.
Peters
Christopher M
CM
Departments of Diagnostic and Biological Sciences, Neuroscience, Psychiatry, Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Jimenez-Andrade
Juan Miguel
JM
Jonas
Beth M
BM
Sevcik
Molly A
MA
Koewler
Nathan J
NJ
Ghilardi
Joseph R
JR
Wong
Gilbert Y
GY
Mantyh
Patrick W
PW
D051700:Activating Transcription Factor 3 / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000187:drug effects / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D039481:CD11b Antigen; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000187:drug effects / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D007275:Injections, Intravenous; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000633:toxicity*; D010525:Peripheral Nerves / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D027161:Satellite Cells, Perineuronal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000097382:CD68 Molecule
D051700:Activating Transcription Factor 3; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000972:Antineoplastic Agents, Phytogenic; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D017239:Paclitaxel; C497108:Atf3 protein, rat; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C509295:ITGAM protein, human