Chronic histamine 3 receptor antagonism alleviates depression like conditions in mice via modulation of brain-derived neurotrophic factor and hypothalamus-pituitary adrenal axis.
The last two decades of research has established histamine (HA) as a neurotransmitter. Since H3R antagonists are known to modulate several neurotransmitters besides HA, H3R antagonists have shown potential for the treatment of different central nervous system disorders, including depression. However, molecular mechanisms underlying the beneficial effects of H3R antagonism in depression are not clear, yet. In the present study, we investigated the antidepressant potential of ciproxifan, a selective H3R antagonist, in chronic unpredictable stress (CUS) model of depression in C57BL/6 J mice. We observed that chronic treatment of CUS mice with ciproxifan (3 mg/kg i.p.; for three weeks) alleviates depression-like symptoms such as helplessness measured by forced swim and tail suspension test (FST and TST), anhedonia measured by sucrose preference test (SPT) and social deficit measured in social behavior test. Chronic ciproxifan treatment restored CUS induced BDNF expression in the prefrontal cortex (PFC) and hippocampus. We also observed that ciproxifan modulates CUS induced NUCB2/nesfatin-1 and CRH expression in the hypothalamus and plasma corticosterone. We also determined the direct effect of HA on BDNF expression in neurons by western blotting and immunocytochemistry, and found that HA significantly induced BDNF expression, which was blocked by the H4R selective antagonist, but not by other HA receptor selective antagonists. Furthermore, ciproxifan significantly modulated NMDA glutamate receptor subunits NR2B and NR2A. Thus, these results suggest that increased HA signaling in the brain produces antidepressant-like effects in mice and modulates BDNF expression and HPA-axis.
['Kumar|Ajeet|A|', 'Dogra|Shalini|S|', 'Sona|Chandan|C|', 'Umrao|Deepmala|D|', 'Rashid|Mamunur|M|', 'Singh|Sandeep K|SK|', 'Wahajuddin|Muhammad|M|', 'Yadav|Prem N|PN|']
D000818:Animals D000928:Antidepressive Agents D001522:Behavior, Animal D001921:Brain D019208:Brain-Derived Neurotrophic Factor D003345:Corticosterone D003863:Depression D003866:Depressive Disorder D004195:Disease Models, Animal D006624:Hippocampus D006632:Histamine D006633:Histamine Antagonists D007030:Hypothalamo-Hypophyseal System D007031:Hypothalamus D007093:Imidazoles D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D010913:Pituitary-Adrenal System D018100:Receptors, Histamine H3 D013315:Stress, Psychological
Histamine H3R CUS BDNF Nesfatin-1 and NMDA