A 5-HT3 receptor antagonist fails to prevent cisplatin-induced toxicity in immature rat spinal cord.
The use of high doses of cisplatin in treating cancers has been limited by two major adverse effects--emesis and peripheral neuropathies. The emesis has become largely controlled by the introduction of a new class of drugs--the 5-HT3 receptor antagonists. The current study was undertaken to determine if these drugs would also prevent cisplatin-induced neuropathy. We have used a developing rat as an animal model and determined the effects of cisplatin on morphology (loss of spinal cord calcitonin gene-related peptide (CGRP)-containing neurons) and behavior (gait abnormalities and pain perception). Rat pups from the age of 5 days were treated twice weekly for 4 weeks with cisplatin (1 mg/kg), the 5-HT3 antagonist MDL 72222 (3 mg/kg) or both. The animals were tested for pain perception (using tail-flick latencies) at 17 and 21 days of age and for a gait abnormality at 24 days of age. At 34 days of age, the animals were perfused and the lumbar region of the spinal cords stained immunocytochemically for CGRP. Our results show that cisplatin treatment resulted in a dramatic loss of CGRP neurons in the dorsal horn of the spinal cord and a corresponding increase in the animals' threshold for pain. In addition, the animals showed a pronounced gait abnormality, characterized by 'toeing-in'. Treatment with MDL 72222 not only failed to protect against the loss of CGRP neurons but also worsened the gait abnormalities seen after cisplatin treatment alone. These studies confirm and extend the list of morphological and functional adverse effects of cisplatin treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Whitaker-Azmitia
P M
PM
Department of Psychiatry and Behavioral Science, State University of New York, Stony Brook 11794-8101, USA.
Raio
M
M
Raio
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D
Borella
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A
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002452:Cell Count; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use / Q000633:toxicity*; D004195:Disease Models, Animal; D005684:Gait / Q000187:drug effects; D007150:Immunohistochemistry; D008297:Male; D009474:Neurons / Q000737:chemistry / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology; D014326:Tropanes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014839:Vomiting / Q000139:chemically induced / Q000188:drug therapy
D012702:Serotonin Antagonists; D014326:Tropanes; D015740:Calcitonin Gene-Related Peptide; C042253:bemesetron; D002945:Cisplatin