Influence of a selective histamine H3 receptor antagonist on hypothalamic neural activity, food intake and body weight.
OBJECTIVE
This study was conducted to elucidate whether antagonistic targeting of the histamine H3 receptor increases hypothalamic histamine levels, in parallel with decreases in food intake and body weight.


METHODS
The competitive antagonist potency of a recently synthesized histamine H3 receptor antagonist, NNC 38-1049, was studied in intact HEK293 cells expressing human or rat histamine H3 receptor, in which NNC 38-1049 was allowed to antagonize the effect of the H3 receptor agonist R-alpha-methylhistamine on isoprenaline-induced accumulation of cAMP. The affinity of NNC 38-1049 for a number of variants of the histamine receptor was also determined. Following single dosing of normal rats with NNC 38-1049, hypothalamic histamine levels were assessed by means of microdialysis. Plasma and brain levels of NNC 38-1049 and acute effects on food intake and energy expenditure were followed after oral doses of 3-60 mg/kg. Potential side effects were examined with rat models of behaviour satiety sequence (BSS), pica behaviour and conditioned taste aversion (CTA). Intakes of food and water together with body weight were recorded for 15 days during daily dosing of dietary obese rats.


RESULTS
NNC 38-1049 was found to be a highly specific and competitive antagonist towards both human and rat histamine H3 receptors, and measurable amounts of NNC 38-1049 were found in the plasma of rats following single oral doses of 3-60 mg/kg and in the brain after 15-60 mg/kg. Following single intraperitoneal injections of NNC 38-1049 (20 mg/kg), significant increases in extracellular histamine concentrations were observed. The same dose did not change BSS or pica behaviour acutely, nor did it induce CTA following repeated administration for 7 days. Reductions in food intake were seen very soon after administration, and occurred in a dose-dependent fashion. Energy expenditure was unchanged, but the respiratory quotient (RQ) tended to decrease at higher doses, indicating an increase in lipid oxidation. Twice daily administration of 20 mg/kg of NNC 38-1049 in old and dietary obese rats resulted in sustained reduction of food intake throughout a 2-week study, and was associated with a highly significant (P<0.01) decrease in body weight compared with controls (-18.4+/-3.4 vs +0.4+/-2.7 g). The same dose of NNC 38-1049 produced an acute decrease of water intake, but 24 h intakes were not significantly changed.


CONCLUSIONS
The results of this study strongly support the idea that an increase in the hypothalamic concentration of histamine produces a specific reduction of food intake and that this effect can be translated into a decrease in body weight.
Malmlöf
K
K
Department of Pharmacology Research, Novo Nordisk A/S, Måløv, Denmark. kmal@novonordisk.com
Zaragoza
F
F
Golozoubova
V
V
Refsgaard
H H F
HH
Cremers
T
T
Raun
K
K
Wulff
B S
BS
Johansen
P B
PB
Westerink
B
B
Rimvall
K
K
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004326:Drinking / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000097:blood / Q000187:drug effects*
D006633:Histamine Antagonists; C510817:NNC 38-1049; D010879:Piperazines; D018100:Receptors, Histamine H3