Chemotherapy-induced anorexia is accompanied by activation of brain pathways signaling dehydration.
OBJECTIVE
Cancer chemotherapy is accompanied by anorexia and mucositis. To clarify the mechanisms of chemotherapy-induced anorexia, we studied the expression of c-fos and appetite-regulating neuropeptidergic and inflammatory mediators in the hypothalamus of rats treated with methotrexate (MTX).


METHODS
Sprague-Dawley rats received MTX (2.5mg/kg, subcutaneously) on three consecutive days and were compared with ad libitum- and pair-fed control rats five days after the first injection.


RESULTS
MTX administration inhibited food and water intake and induced lean and fat mass losses. MTX also induced mucositis and diarrhea without changes in plasma osmolality. Pair-fed rats lost a similar amount of body weight but had no mucositis or diarrhea. Increased number of c-fos positive hypothalamic vasopressin neurosecretory neurons as well as numerous c-fos positive cells in the subfornical organ and in the organum vasculosum of the lamina terminalis were found in MTX-treated as compared to control or pair-fed rats. In both MTX and pair-fed rats, a decrease of hypothalamic proopiomelanocortin mRNA expression and low plasma levels of interleukin-1β (IL-1β) were found reflecting probably the energy deficit. No significant changes of IL-1β mRNA expression and intensity of microglial staining in the hypothalamus were found in MTX-treated rats.


CONCLUSIONS
The pattern of c-fos expression in the hypothalamus during MTX treatment is similar to that seen with systemic dehydration, which is known to cause anorexia. No evidence of inflammatory origin of anorexia was found, suggesting that chemotherapy accompanied by mucositis and diarrhea may cause anorexia associated with systemic dehydration.
Sinno
Maria Hamze
MH
Digestive System & Nutrition Laboratory (ADEN EA4311), Rouen University, IFR23, Rouen 76183, France.
Coquerel
Quentin
Q
Boukhettala
Nabile
N
Coëffier
Moïse
M
Gallas
Syrine
S
Terashi
Mutsumi
M
Ibrahim
Ayman
A
Breuillé
Denis
D
Déchelotte
Pierre
P
Fetissov
Sergueï O
SO
D000704:Analysis of Variance; D000818:Animals; D000855:Anorexia / Q000139:chemically induced* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D001066:Appetite / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003681:Dehydration / Q000378:metabolism*; D004326:Drinking / Q000187:drug effects; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D008727:Methotrexate / Q000494:pharmacology*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D053583:Interleukin-1beta; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin; D008727:Methotrexate