Upregulation of B50/GAP-43 protein mRNA in rat dorsal root ganglia during cisplatin intoxication.
Expression of the growth-associated protein B50 (GAP-43) mRNA in dorsal root ganglia (DRG) of rats was studied by in situ hybridization. In response to treatment with the neurotoxic agent cisplatin, B50 mRNA expression was significantly enhanced following a cumulative cisplatin dose of 14 mg/kg. In the untreated age-matched control animals, only half of the ganglion cells exhibited expression of B50 mRNA (mean hybridization signal, 10 times background), whereas at a cumulative cisplatin dose of 14 mg cisplatin every neuron exhibited well above background expression (mean hybridization signal, 34 times background). Cotreatment with a neuroprotective ACTH4-9 analog known to prevent cisplatin neuropathy in rats did not affect the overall expression of B50 mRNA. However, in the subpopulation of large sensory neurons, B50 mRNA content was significantly higher in the group cotreated with the ACTH4-9 analog as compared with the saline-cotreated group after 14 mg/kg of cisplatin. We conclude that in analogy with the well-known upregulation of B50 mRNA following mechanical nerve lesions, treatment with the neurotoxic drug cisplatin also leads to an increase in B50 mRNA expression. This observation lends strength to the hypothesis that in neuropathies an imbalance between regenerative and degenerative mechanisms exists. The ability of the larger sensory neurons to retain an increased B50 mRNA expression better after cotreatment with the peptide than without may be related to stimulation of regenerative processes by this ACTH4-9 analog.
Hamers
F P
FP
Rudolf Magnus Institute, Department of Medical Pharmacology, Utrecht University, The Netherlands.
Plantinga
L C
LC
Verhaagen
J
J
Neijt
J P
JP
Gispen
W H
WH
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D002945:Cisplatin / Q000633:toxicity*; D019922:GAP-43 Protein; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D017403:In Situ Hybridization; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D009416:Nerve Regeneration / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D016900:Neurofilament Proteins / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009475:Neurons, Afferent / Q000378:metabolism; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic / Q000187:drug effects*
D019922:GAP-43 Protein; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D009498:Neurotoxins; D010446:Peptide Fragments; D012333:RNA, Messenger; C028024:ACTH (4-9); D000324:Adrenocorticotropic Hormone; D002945:Cisplatin