A GHRH szerepe az alvásszabályozásban = The role of GHRH in sleep regulation

Kísérleteink célja a szomatotrop rendszer alvásszabályozásban betöltött szerepének vizsgálata volt. A spontán törpe patkányokra növekedési hormon (GH)-hiány és fokozott GHRH-hatás jellemző, melynek oka a GH-gén mutációja. Alvásvizsgálataink megerősítik azt az elképzelést, hogy a NREM-alvás szabályozásában a GHRH-nak, míg a REM-alvás, és a NREM-alvás alatti EEG lassú hullámú aktivitás mediálásában a GH-nak van szerepe. A ghrelin a szomatotrop rendszer új tagja. Kísérleteink szerint a ghrelin gátolja mind a NREM-, mind a REM-alvást, ami azt mutatja, hogy a ghrelinnek szerepe lehet az alvás szabályozásában. Meghatároztuk a plazma és a hypothalamus ghrelintartalmának, valamint a plazma leptinszintjének napszaki ritmusát és ezt összevetettük az alvás-ébrenlét és a táplálékfelvétel ritmusával. Kimutattuk, hogy míg szoros összefüggés van ezen hormonok és a táplálékfelvétel között, addig nincs közvetlen kapcsolat a ghrelin, valamint a leptin napszaki változása és az alvás-ébrenlét ritmusa között. Ugyanakkor alvásmegvonás hatására a ghrelinszintben bekövetkező változások a hypothalamikus ghrelin alvásszabályozásban betöltött szerepére utalhatnak. Tanulmányoztuk a mediobazális hypothalamus (MBH) és a preoptikus régió kapcsolatainak az alvásszabályozásban betöltött szerepét. Az MBH elülső és oldalsó kapcsolatainak elválasztásához Halász-késes technikát alkalmaztunk. Az eredmények arra utalnak, hogy ezeknek a projekcióknak fontos szerep jut az alvásszabályozásban. | The aim of this grant was to ivestigate the role of the somatotropic axis in sleep regulation. Spontaneous dwarf rats display growth hormone (GH)-deficiency associated with increased GH-releasing hormone (GHRH)-ergic activity due to a mutation in the GH gene. The results of the sleep-studies with this strain of rats support the ideas that GHRH is involved in NREM sleep regulation and that GH is involved in the regulation of REM sleep and in EEG slow wave activity regulation during NREMS. Ghrelin is a new member of the somatotropic system. Our data show that ghrelin suppress NREM sleep and REM sleep supporting the notion that ghrelin has a role in sleep regulation. We determined the relationships among plasma ghrelin and leptin concentrations and hypothalamic ghrelin contents, and sleep, and feeding in rats. While a strong relationship may exist between these hormones and feeding, the ghrelin and leptin rhythms failed to exhibit obvious direct connections to the diurnal sleep-wake rhythm. However, the variations in hypothalamic ghrelin concentrations might be associated with sleep-wake activity. We investigated the physiological connections of the medial basal hypothalamus (MBH) and the anterior hypothalamus/preoptic area in sleep regulation. We have utilized Halasz knife technique to isolate anterior and lateral connections of the MBH. The results indicate that these projections are important in the regulation of NREM sleep and the circadian rhythm of the REM sleep

The interaction of Urocortin II and Urocortin III with amygdalar and hypothalamic cotricotropin-releasing factor (CRF) - reflections on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis

Electroosmotic pumps employing silica frits synthesized from potassium silicate as a stationary phase show strong electroosmotic flow velocity and resistance to pressure-driven flow. We characterize these pumps and measure an electroosmotic mobility of 2.5x10(-8) m(2)/V s and hydrodynamic resistance per unit length of 70 x10(17) Pa s/m(4) with a standard deviation of less than 2% even when varying the amount of water used in the potassium silicate mixture. Furthermore, we demonstrate the simple integration of these pumps into a proofof- concept PDMS lab-on-a-chip device fabricated from a 3D-printed template.Funding Agencies|Vetenskapsradet [2007-3983, 2008-7537, 2011-6404]</p

Steroidal Ferrocenes as Potential Enzyme Inhibitors of the Estrogen Biosynthesis

The potential inhibitory efect of diverse triazolyl-ferrocene steroids on key enzymes of the estrogen biosynthesis was investigated. Test compounds were synthesized via copper-catalyzed cycloaddition of steroidal azides and ferrocenylalkynes using our efcient methodology published previously. Inhibition of human aromatase, steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) activities was investigated with in vitro radiosubstrate incubations. Some of the test compounds were found to be potent inhibitors of the STS. A compound bearing ferrocenyl side chain on the C-2 displayed a reversible inhibition, whereas C-16 and C-17 derivatives displayed competitive irreversible binding mechanism toward the enzyme. 17α-Triazolyl-ferrocene derivatives of 17β-estradiol exerted outstanding inhibitory efect and experiments demonstrated a key role of the ferrocenyl moiety in the enhanced binding afnity. Submicromolar IC50 and Ki parameters enroll these compounds to the group of the most efective STS inhibitors published so far. STS inhibitory potential of the steroidal ferrocenes may lead to the development of novel compounds able to suppress in situ biosynthesis of 17β-estradiol in target tissues

Determination of 17α-hydroxylase-C_17,20-lyase (P450_17α) enzyme activities and their inhibition by selected steroidal picolyl and picolinylidene compounds

17α-hydroxylase-C17,20-lyase (P45017α) is a key regulator enzyme of the steroid hormone biosynthesis in both the adrenals and the testes. Inhibition of this enzyme can block androgen synthesis in an early step, and may thereby be useful in the treatment of several androgen-dependent diseases. We developed radio-substrate in vitro incubation methods for the determination of the distinct 17α-hydroxylase and C17,20-lyase activities of the enzyme using rat testicular homogenate as enzyme source. With this method we have studied the inhibiting activity of selected steroidal picolyl and picolinylidene compounds. Tests revealed a substantial inhibitory action of the 17-picolinyliden-androst-4-en-3-one compound