And my head doesn't hurt
Migraine Medication helped Mice cope with obesity
Oleg Lischuk, N+1
An international team of researchers has found that a drug used to treat migraines reduces appetite and promotes weight loss in mice with alimentary obesity. As it turned out, a similar effect is associated with the effect on serotonin 5-HT 1B receptors in the arcuate (arcuate) nucleus of the hypothalamus. The work report is published in the Journal of Experimental Medicine (Li et al., Delineating a serotonin 1B receptor circuit for appetite suppression in mice).
Overweight is one of the main problems of world health, which affects about two billion inhabitants of the Earth, including children and adolescents, more than from malnutrition. It serves as a key risk factor for the development of cardiovascular diseases, type 2 diabetes mellitus, deforming osteoarthritis and other diseases, and also complicates the course of a wide range of diseases. The main reason for this problem lies in the increased consumption of calories with food (alimentary obesity).
Some drugs acting on serotoninegic transmission in the brain, for example, 5-HT 1C-receptor agonists lorcaserin and fenfluramine, have proven effective in reducing appetite and, consequently, body weight. However, the exact mechanism of such anorexigenic action has not been established, in addition, their use is now prohibited or restricted due to severe side effects.
Because of this, a group of researchers from the USA, Great Britain and South Korea led by Chen Liu from the Southwest Medical Center of the University of Texas decided to investigate the anorexigenic potential of the so-called triptans (agonists of serotonin 5-HT 1B/1D receptors), which are widely used to treat migraine attacks.
At the first stage of the experiments, six different triptans (zolmitriptan, almotriptan, risatriptan, naratriptan, eletriptan and frovatriptan) were injected into hungry mice and their food intake was compared with the control group. It turned out that four of these drugs significantly reduce appetite, and this effect is most pronounced in frovatriptan (it differs from other representatives of the group by its high affinity for 5-HT 1B receptors and longer duration of action). In knockout mice with the gene of this Htr1b receptor switched off, the anorexigenic effect of triptans was absent, so it was associated specifically with 5-HT 1B.
After that, obese mice (due to a high-calorie diet with a high fat content) were injected with 10 milligrams of frovatriptan per kilogram of body weight per day for 24 days. The weight of the animals decreased by 3.58 ± 1.6 percent, while when taking a placebo, it increased by 5.83 ± 2.04 percent. Also, the administration of the drug reduced the volume of fat, but not muscle tissue and improved the results of the glucose tolerance test. Experiments with a highly selective agonist of 5-HT 1B receptors CP-94253 have shown that the anorexigenic effect when exposed to them does not depend on the activation of 5-HT 1C.
The key role of the melanocortin-activated glutamatergic nerve pathway ARC→PVH in regulating the effects of leptin and ghrelin, eating behavior and energy metabolism has been shown before. Taking this into account, the researchers, using optogenetic activation of neurons in knockout mice with different sets of switched-off genes, confirmed a clear effect on appetite and body weight of the ARC projection on PVH (but not on the paraventricular nucleus of the thalamus, lateral hypothalamic region and the nucleus of the terminal strip bed, as previously suspected) and found out that its activity is controlled by 5-HT 1B are the receptors of AgRP neurons, on which frovatriptan acts.
Considering that this drug has already been registered and is used in humans, and also belongs to the latest generation of triptans, which do not affect pulse and blood pressure and are relatively safe in cardiovascular diseases, its use for the treatment of obesity has significant prospects. Also, according to the researchers, more specific agonists of 5-HT 1B receptors, such as the above-mentioned CP-94253 and others, deserve serious attention.
Serotonin is one of the main mediators of the central and peripheral nervous system, regulating many physiological and mental processes. An example of the variety of its effects is an experiment conducted at the American Tufts University, when with the help of zolmitriptan it was possible to partially restore vision in tadpoles with an eye transplanted into the tail. The study of the serotonin 5-HT 2B receptor at one time helped to understand the nature of the unusual power of the psychedelic LSD, the effects of which are manifested in doses of less than 100 micrograms. In 2018, with the participation of Russian scientists, the structure of 5-HT 2C was established — the third after 5-HT 1B and 5-HT 2B from the family of serotonin receptors.
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