Pharmacological blockage of serotonin biosynthesis and circadian changes in oxaliplatin toxicity in rats.
This study investigates if the serotoninergic system plays a role in chronotoxic effects of the anticancer agent oxaliplatin (l-OHP). Four groups of female rats (120 in total) synchronized with light-dark (12 h:12 h) were treated with: (i) saline, (ii) para-chlorophenylalanine (pCPA, an inhibitor of serotonin biosynthesis: 300 mg/kg/d, i.p. for two consecutive days), (iii) l-OHP (23 mg/kg, i.v.) at three different dosing times, or (iv) both pCPA and l-OHP. The results show pCPA (ii) obliterates the circadian rhythm in plasma ACTH but not in corticosterone or leukocytes, and (iii) l-OHP exerts circadian time-dependent toxic effects (body weight loss, leukopenia, and intestinal lesions) with greatest toxicity coinciding with treatment at the end of the nocturnal activity span (P < 0.05). In rats whose serotonin biosynthesis was blocked (iv), the circadian rhythms in the toxic effects of l-OHP and in ACTH were obliterated, while the rhythms in corticosterone and leukocytes persisted.
Boughattas
Naceur A
NA
Laboratoire de Pharmacologie, Faculté de Médecine, 5019 Monastir, Tunisie. naboughattas@yahoo.fr
Ben Attia
Mossadok
M
Ixart
Guy
G
Lemaigre
Guy
G
Mechkouri
Mohamed
M
Reinberg
Alain
A
D000324:Adrenocorticotropic Hormone / Q000097:blood; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001683:Biological Clocks / Q000502:physiology; D001835:Body Weight; D002940:Circadian Rhythm / Q000502:physiology*; D003345:Corticosterone / Q000097:blood; D004068:Digestive System Physiological Phenomena; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D010134:Fenclonine / Q000378:metabolism; D007107:Immune System / Q000502:physiology; D007962:Leukocytes / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D017440:Photoperiod; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000096:biosynthesis*; D012702:Serotonin Antagonists / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009944:Organoplatinum Compounds; D012702:Serotonin Antagonists; D000077150:Oxaliplatin; D012701:Serotonin; D000324:Adrenocorticotropic Hormone; D010134:Fenclonine; D003345:Corticosterone