Mosebetsi oa Orexin-1 Mekhoa ea ho Sebelisa Lijo ka Kelello ka Mohlala oa ho ja Litlhapi ka Makhoche a Basali (2012)

Neuropsychopharmacology. 2012 Aug; 37 (9): 1999-2011.

PMCID: PMC3398727

Sehlooho sena se bile teng e boletsoeng ke lihlooho tse ling ho PMC.

Eya ho:

inahaneloang

Li-Orexins (OX) le li-receptor tsa tsona (OXR) li fetolela ho fepa, ho tsosa, khatello ea maikutlo le ts'ebeliso e mpe ea lithethefatsi. Litsamaiso tsa Neural tse khothatsang le ho tiisa tšebeliso e mpe ea lithethefatsi le tsona li ka etsa hore ho batloe lijo le ho li ja ka matla. Ka hona, litlamorao tsa GSK1059865 (5-bromo-N- [(2S,5S) -1- (3-fluoro-2-methoxybenzoyl) -5-methylpiperidin-2-yl] methyl-pyridin-2-amine), OX ea khethiloeng1R mohanyetsi, JNJ-10397049 (N- (2,4-dibromophenyl) -N′ - [(4S,5S) -2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl] urea), OX ea khethang2R antagonist, 'me SB-649868 (N- [((2.)S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide), a dual OX1/ OX2R antagonist e ile ea hlahlojoa ka mokhoa oa ho itlopa joala ho ja (BE) mefuteng ea likhoto tsa basali. BE ea lijo tse matlafatsoang haholo (HPF) e ile ea tsosoa ke mekhahlelo e meraro ea thibelo ea lijo e lateloang ke khatello ea maikutlo, e phahamisoa ke ho pepesetsa likhoto ho HPF, empa li ba thibela ho fihlella bakeng sa 15 min. Liteko tsa Pharmacokinetic tsa metsoako eohle li fumanoe tlasa maemo a tšoanang a liteko a sebelisoang litekong tsa boits'oaro. Topiramate e ne e sebelisoa e le sebopeho sa litšupiso ha e khetha ka mokhoa o ikhethileng BE ho litšoelesa le batho. Meketjana e amanang le litheko ea litlamorao tse susumetsang boroko ba bahanyetsi ba OXR e lekantsoe ho sebelisoa polysomnography litekong tse tšoanang. SB-649868 le GSK1059865, empa eseng JNJ-10397049, e ile ea theoloa ka boikhethelo bakeng sa HPF ntle le ho ama lijo tse tloaelehileng, litekong tse sa kang tsa tsosa boroko. Liphetho tsena li bonts'a, ka lekhetlo la pele, karolo e kholo ea OX1Mechine ea R ho B, e fana ka tlhahiso ea hore khethollo e khethollo ho OX1R e ka emela mofuta o mocha oa kalafo ea meriana bakeng sa BE le mathata a mang a ho ja ka karolo e qobelloang.

Keywords: orexin-1 mohanyetsi oa li-receptor antagonist, orexin-2 receptor antagonist, ho itlopa joala, likhoto tsa basali, tšebeliso ea lijo e qobelloang

SELELEKELA

Likarolo tsa ho itlopa lijo tse nang le phepo e ngata (BE) bathong li tšoauoa ka tšebeliso e sa qobelloeng ea hae ea lijo tse ngata tse sa tloaelehang ka nako e khuts'oane. Leha li sa lapa, lithuto li ja ka potlako ho feta tse tloaelehileng ho fihlela li ikutloa li sa thaba. Joalokaha ho hlalositsoe ke DMS-IV-TR (Mokhatlo oa Mahlale oa Amerika, 2000), liketsahalo tsena li tsamaisana le maikutlo a ho lahleheloa ke taolo holim'a lijo, hape li hokahanngoa le maikutlo a khatello ea maikutlo, ho teneha, khatello ea maikutlo, ho ba le molato oa ho ja ho feta tekano, le ho ja u le mong ka lebaka la lihlong.

BE e emela karolo e bohareng ea bulimia mothosa, moo li-episode tsa BE li lateloang ke boits'oaro bo reretsoeng ho qoba ho phahamisa boima ba mmele, joalo ka ho hlatsa. Likarolo tse matla tsa phepelo ea Be e matla ebile e phehella e supa liketsahalo tse tloaelehileng le tsona li hlaha lithutong tse nang le bothata ba ho ja ho itlopa lijo (BED) (Walsh le Devlin, 1998). BED e tšoauoa ke likarolo tse pheta-phetoang tsa BE ha ho e-na le boits'oaro bo khothalletsang ho qoba ho nona. Litekanyetso tsa tlhahlobo ea BED ho DSM-IV-TR li bonts'a hore likarolo tsa BE li lokela ho hlaha bonyane matsatsi a 2 ka beke bakeng sa likhoeli tsa 6. BED e amahanngoa le co-morbidity ea bohlokoa ea bongaka le kelelloJavaras et al a, 2008; Grucza et al a, 2007; Fassino et al a, 2003). Ho nahanoa hore BE e hlokofatsa hoo e ka bang 5% ea batho ba baholo ba US ka nako e ngoe nakong ea bophelo ba bona (Flots Mathes et al a, 2009) mme e thusa ho mpefatsa ho tepella le mafu a amanang le ona (Hudson et al a, 2007; Heath, 1998; Etsa qeto et al a, 2000; Yanovski, 2003).

Meriana ea hajoale, joalo ka topiramate (McElroy et al a, 2007; McElroy et al a, 2009) kapa sibutramine (Appolinario et al a, 2000; Wilfley et al a, 2008), ho tlalehiloe ho fokotsa BE lithutong tsa kliniki. Leha ho le joalo, tsamaiso ea bona e amahanngoa le litlamorao tse fapaneng tse fapaneng, tse hlahisang mathata a tebileng nakong ea kalafo e sa foleng (McElroy et al a, 2009; Carter et al a, 2003; Yager, 2008). Haholo-holo, sibutramine e sa tsoa tlosoa 'marakeng oa Europe, ha topiramate e tsebahala ka thepa ea eona e hlokisang botsitso. Mekhoa ea phekolo e ncha ea bulimia mothosa le BED ntle le litlamorao tse matla e hlokahala haholo.

Ho 1998, lihlopha tse peli ka botsona li ile tsa supa sehlopha se secha sa li-neuropeptides tse tsoang ho hypothalamic nuclei (Sakurai et al a, 1998; de Lecea et al a, 1998). Li-peptide tsena, tse bitsoang orexin-A (OXA) le orexin-B (OXB) (hape li supa hypocretin 1 le hypocretin 2), li hlahisoa ho tsoa ts'ebetsong ea proteinolytic ea peptide ea pro-OX mme e tlama ho GPCRs tse peli, e leng OX- Li-receptors tsa 1 le OX-2 (OX1R le OX2R) (e boetse e bontšoa e le HcrtR1 le HcrtR2). OX1R e kopantsoe le Gq / 11, athe lithuto tse sebelisang lisele tsa neuronal li fana ka maikutlo a hore OX2R e kopantsoe le liprotheine tsa Gq, Gs le Gi. Ts'ebetsong ea methapo ea kutlo, OX1R le OX2R bonts'a ho lekana, empa mekhoa e arohaneng haholo ebile e tlatsanaSakurai, 2007). Libaka tsa boko tse kang infralimbic cortex, hippocampus, le locus coeruleus li bonts'a polelo e phahameng ea OX1R, athe OX2R ke eona feela "li-receptor" tse hlahisoang ho "arcuate nucleus", "tuberomammillary nucleus" le "dorsomedial and lateral hypothalamus" (LH). Li-receptor ka bobeli li teng sebakeng sa "cortex" ea pele, amygdala, mookotaba oa stria terminalis, paraventricular thalamic nucleus, dorsal raphe, sebaka sa "subral tegmental" (VTA), le "laterodorsal tegmental nucleus-peduncolo pontine"Lu et al a, 2000; Marcus et al a, 2001; Khoele et al a, 1998). Liphumano tsena li fana ka maikutlo a hore li-OX le li-receptor tsa tsona li kanna tsa bapala karolo e pharaletseng ea taolo tsamaisong ea methapo e bohareng.

Physiology ea boemo ba ho tsoha / ho robala ke e 'ngoe ea likarolo tseo karolo ea li-OX e ithutoang haholo ho tsona. Ka sebele, ho ferekana ha ho bonts'a OX ho litoeba tsa pele tsa ho ea li-OX ho hlahisitse mokhoa oa tlhaho o nang le litšobotsi tse ts'oanang le tsa bakuli ba nang le lefu la kelello, bokuli bo sa foleng bo khetholloang ke boroko bo feteletseng bo ka amahanngoang le ho holofala haholo boroko, lipono tse matla le ho se tsitse. (Chemelli et al a, 1999). Ho robala ka ho feteletseng ho bonahala e le sesupo sa ho sitoa ho boloka tsoho e telele.

Ho feta moo, mohanyetsi oa nako e tšoanang oa bobeli ba OX1R le OX2R kapa thibelo e thibelang OX2R e hlahisa ho kenyelletsoa ha phello e matla ea hypnotic (Brisbare-Roch et al a, 2007; Dugovic et al a, 2009; Di Fabio et al a, 2011).

Lintlha ka har'a lingoliloeng li boetse li tšehetsa karolo ea Sisteme ea OX ho fepheng boitšoaro, taolong ea lijo tse hloloheloang lapeng le moputso. Ntle le ho bonts'a mofuta oa "narcolepsy phenotype"Willie et al a, 2001). Ho kenella ha OXA ho kenella ka morao ho likhoto, nakong ea khanya ea pele, ho kenyelitse keketseho e amanang le lethal dose ea lijo tse amanang le likhoto (Sakurai et al a, 1998), e neng e thibetsoe ke kalafo ea pele le OX1R mohanyetsi SB-334867 (Haynes et al a, 2000; Rodgers et al a, 2001). Karolo ea li-OXs ho ja lijo tse thehiloeng ho moputso e ngotsoe ke sengoloa sa pampiri ea Perello et al a (2010), e bonts'ang hore keketseho ea boleng bo putsa ba ho ja lijo tse nang le mafura a mangata tse tlisoang ke ghrelin e its'etleha ho OX; ho feta moo, SB-334867 e tlalehiloe ho thibela boitaolo ba lijo tse phahameng haholo (Nair et al a, 2008). Ts'ebetso ea OX1R ke karolo e hlokahalang ea karabo e matlafatsoang ke lijo, khothatso, kapa bobeli ba tsona (Kholo et al a, 2010). Ntle le moo, li-neuron tsa LH OX li hlahisoa ke lits'ebetso tse amanang le moputso oa lijo tse kang lijo (Harris et al a, 2005), ho fana ka maikutlo a karolo e ka bang teng ea sistimi ea OX ho araba mekhoa ea tikoloho e kantle e amanang le likarolo tsa kelello tsa ho fepa.

Litlaleho tsa morao-rao li tšehetsa karolo ea ho supa ha OX litlamorao tsa matla a susumetsang le tlhabollo ea lithethefatsi tsa tlhekefetso (Harris et al a, 2005; Borgland et al a, 2006; Jupp et al a, 2011; bakeng sa tlhahlobo, bona Bonci le Borgland, 2009; Martin-Fardon et al a, 2010). Kahoo, blockade ea OX1R e fokotseha ethanol (Lawrence et al a, 2006) le nikotine ho itaola (Hollander et al a, 2008), e thibella ho khutlisetsoa hoa moea oa cue-ikiwa kapa ho khothaletsoa hape ha ethanol- (Lawrence et al a, 2006), koae-Smith et al a, 2010), le morphine-searchHarris et al a, 2005), hape e bonts'a ho khutlisetsoa hoa khatello ea kelello ke koae- (Boutrel et al a, 2005)Richards et al a, 2008). Ho feta moo, bopaki ba morao-rao bo boetse bo hokahanya OX2Mekhoa e khethang-joala ea ho fumana moputso oa joala le boits'oaro.Shoblock et al a, 2011).

Bopaki bo ntse bo bokella hore ho ja lijo tse ngata ka tlasa maemo a itseng ho hlahisa boits'oaro le liphetoho bokong bo tšoanang le boemo ba bokhoba ba tahi (Gold et al a, 2003; Kenny, 2011; Pelchat et al a, 2004; Li-oats et al a, 2008; Ifland et al a, 2009; Gearhardt et al a, 2011a). Litsamaiso tsa Neural tse khothatsang le ho tiisa tšebeliso e mpe ea lithethefatsi le tsona li khothalelitsoe ho ba le boitšoaro bo bobe bo amanang le ho qobella ho batla lijo le ho ja lijo tse ngata (Johnson le Kenny, 2010; Hoebel, 1985; Volkow le Bohlale, 2005; Corwin et al a, 2011; Gearhardt et al a, 2011b; Wang et al a, 2011). Liphumano tsena li hlahisa potso ea hore na ebe tsamaiso ea OX e kanna ea ba le karolo ho mafu a ho ja a tšoaetsitsoeng ke likarolo tse qobelloang tsa mofuta oa ho itlopa lijo, joalo ka bulimia manthaosa le BED.

Ka hona, thuto ena e ne e reretsoe ho etsa lipatlisiso ka litlamorao tsa OX tse peli1/ OX2R mohanyetsi SB-649868 (N-[((2S)-1-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}-2-piperidinyl)methyl]-1-benzofuran-4-carboxamide) (Di Fabio et al a, 2011), OX e khethiloeng1R antagonist GSK1059865 (5-bromo-N- [(2S,5S)-1-(3-fluoro-2-methoxybenzoyl)-5-methylpiperidin-2-yl]methyl-pyridin-2-amine) (Gozzi et al a, 2011), le OX e khethiloeng2R mohanyetsi JNJ-10397049 (N- (2,4-dibromophenyl) -N′ - [(4S,5S) -2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl] urea) (McAtee et al a, 2004; Dugovic et al a, 2009) ho mofuta oa BE o hlalositsoeng ke Cifani et al a (2009), eo likarolo tsa HPF tsa HPF li tsubeloang ho likhoto tsa basali ka methapo ea thibelo ea lijo / ho fepa hape le khatello e matla ea maikutlo. Bahanyetsi ba bararo ba ile ba hlahlojoa pele a vitro ho ROP e kopanang1R le OX2R ho lekola boteng ba tsona le ho netefatsa khetho ea tsona bakeng sa li-subtypes tse peli tse amohelang. Li-pharmacokinetics tsa bona (PKs) li ile tsa hlahlojoa mme litekanyetso li ka khona ho hlahisa litlamorao tsa khatello ea kelello li ile tsa khethoa mohlaleng oa litekanyetso tsa boroko. Kamora nako, likhokahanyo li ile tsa lekoa ho litekanyetso tse boletsoeng ho mofuta oa BE.

LISEBELISOA LE MEKHOA

Animals

Liphuputso tsohle tse amanang le liphoofolo li entsoe ho latela taelo ea Europe ea 86/609 / EEC e laolang boiketlo ba liphoofolo le ts'ireletso, e amoheloang ke Molao oa Molao oa Italy oa no. 116, 27 Pherekhong 1992, mme ho latela tlhahlobo ea kahare e entsoeng ke Komiti ea GlaxoSmithKline ea Lipatlisiso tsa Liphoofolo le Boitšoaro (CARE) le ho Leano la k'hamphani mabapi le Tlhokomelo le Ts'ebeliso ea Liphoofolo tsa Laboraro.

lithethefatsi

SB-649868 (Di Fabio et al a, 2011), GSK1059865 (Gozzi et al a, 2011), le JNJ-10397049 (McAtee et al a, 2004) li entsoe ka lilaboratori tsa GSK. OXA e fanoe ke California Peptides Research (katse. No. 471-99, CA). Myo- [1,2-3H(N)] inositol (NET-906, ts'ebetso e ikhethang: 51 Ci / mol) le li-ytrium silicate RNA lieta tse tlamang (RPNQ0013) li ile tsa rekoa ho tloha Perkin-Elmer (Italy). Topiramate (Topamax; Janssen-Cilag) e ile ea rekoa ho Janssen-Cilag. E ne e fumaneha litafoleng, tse ileng tsa fokotsoa hore e be phofo pele ho tsamaiso.

Teko ea 1: Antagonism ea SB-649868, JNJ-10397049, le GSK1059865 ho Rat OX1R le Rat OX2R

Tloaelo ea sele

Lisele tsa "basophil leukemia" li fetisoa ka mokhoa o tsitsitseng le rat OX1R (rOX1R) kapa ho lekanya OX2R (rOX2R) li ile tsa kenngoa cultured ho α-MEM (Invitrogen / GIBCO) tlatselletsoa ka 10% fetal bovine serum (FBS, PAA), 100 U / ml penicillin G, 100 U / ml streptomycin (Pen / Strep; Attitrogen / GIBCO), le 400 μg / ml geneticin (Invitrogen / GIBCO), ho 37 ° C ka 5% CO2 maemong a tlotlollohileng.

Ho eketseha ha [3H] inositol phosphates (IPs)

Ho eketseha ha [3H] inositol phosphates (IPs) e lekantsoe joalo ka ha ho hlalositsoe pele (Brandish et al a, 2003) le liphetoho tse latelang. Mehala ea sele e bonts'a ROX hantle1R kapa rOX2R li ne li jaloa ka har'a li-plates tsa setso tsa 96-hantle lithong ho 3 × 104 lisele ka hantle le 1.5 × 104 lisele ka hantle, ka ho latellana, ho α-MEM e tlatselletsoa ka 10% FBS le Pen / Strep ntle le geneticin. Kamora hore 24 h, setso sa setso se lakatsehe 'me 100 μl ea mahareng e kenyelletsoeng le 10 μCi / ml NET-906 (Perkin-Elmer) e ile ea eketsoa liseleng; ka hona, 1 μCi ea radiolabeled inositol e sebelisitsoe selibeng. Kamora 16 h ea ho kenella, lisele li ile tsa hlatsuoa makhetlo a mabeli ka buffer ea assay (1 × HBSS, 20 mM HEPES (pH 7.4), le 0.1% bovine serum albin le 10 mM LiCl), pele ho kenyelletsoa ha agonists kapa bahanyetsi. Ma-antagonists a ile a qobelloa bakeng sa 30 min ho 37 ° C pele a susumetsoa ke agonist. Li-curvecent-reaction curves (CRCs) tsa OXA ho tloha 0.0001 ho 10 μM li entsoe. Kamora 1 h ea ho incubation ho 37 ° C, buffer ea assay e ne e lakatseha, 80 μl ka sediba se seng sa 0.1 M lehloa le batang le ile la eketsoa, ​​'me lisele li ile tsa siuoa 30 min incubation ka mocheso oa kamore. Tekanyo ea 20 μl ea selikalikoe sa sele e kentsoe 80 μl ea lieta tsa silika tsa yttrium (YSi SPA; Perkin-Elmer; 12.5 mg / ml), e ts'oeroe ka 1 h ka mocheso oa kamore, 'me e tlohile ka 4 ° C bakeng sa 2 h ho bala lipalo-palo tsa Packard Top-Count NXT Microplate Scintillation.

Lintlha li hlahisitsoe e le karabo e kholo ea agonist e baloang ka mokhoa o latelang: karabo e kholo ea agonist = (cpmmohanyetsi−cpmbasal) / cpmmaxagonistresponse−cpmbasal) × 100.

In vitro tlhahlobo ea data

Li-CRC li ne li hlophisoa ke tekolo ea mohala oa morao-rao o sa sebelisengar ho sebelisa software ea GraphPad Prism 5.0 (Software ea GraphPad, San Diego, CA) ho fumana EC ea agonist50 (khatello ea kelello ea agonist e hlokoa ho fumana 50% ea karabelo e kholo).

Potency (KB= antagonist dissociation khafetsa) bahanyetsi ba sa feteng letho ba ile ba khethoa ka ho sebelisa equation ea mofuta oa ts'ebeliso bakeng sa likhang tse seng tsa tlholisano (Kenakin et al a, 2006). The KB Boleng ba bahanyetsi ba fetelletseng bo baliloe ka tlhahlobo ea Schild (Arunlakshana le Schild, 1959). Bakeng sa SB-649868 feela antagonist IC50 e baliloe. Re rerile karabo e hlahisitsoeng ke 1 μM OXA ka ho ba sieo le ha ho na le likhatiso tse 'ne tse fapaneng tsa mohanyetsi. KEA BONA50 e hlalosoa e le khatello ea maikutlo ea antagonist e hlokahalang ho thibela le 50% karabelo e hlahisoang ke agonist. Liphetho li hlahisitsoe e le pEC50 (−log10 EC50), leqKB (−log10 KB), kapa pIC50 (−log10 IC50), 'me li hlahisoa e le ho hloka ± SEM kapa ho bolela ka meeli ea kholiseho ea 95% (95% CL) ea bonyane liteko tse tharo tse ikemetseng. Lithethefatsi tsohle tse lekiloeng li ile tsa qhaloa ho dimethyl sulfoxide (DMSO) mme tsa kenngoa ka har'a buffer ea assay ho fana ka mahloriso a ho qetela a DMSO a sa feteng 0.5%.

Teko 2: Qeto ea PK ho litekanyetso tsa banna le tsa basali

Ho lekola ponelopele ea mali ea PK bakeng sa boroko le lithuto tsa BE, lipatlisiso tsa li-complex tsa PK li se li hlahlobisitsoe ho likhoto tsa banna le basali maemong a lekang a boroko le liteko tsa BE. Lifaele tsa PK li ile tsa hlahlojoa kamora ho tsamaisoa ke taolo ea 3 mg / kg SB-649868 ka likhoto tsa basali le tsa banna, tsamaiso ea methapo ea 10 mg / kg ho basali le 5 mg / kg ho likhoto tsa banna tsa JNJ-10397049, le tsamaiso ka gavage in likhoto tsa basali le tsamaiso e kenelletseng ea likhoto tsa banna tsa 10 mg / kg ea GSK1059865. Lisampole tsa mali li ile tsa bokelloa ka mothapo oa tšehali ka linako tse ling ho fihlela 4 h kamora tsamaiso. Mehlala ea brain e ile ea bokelloa qetellong ea liteko. Khokahano ea SB-649868, JNJ-10397049, le GSK1059865 ka har'a sampole ea mali le bokong e ile ea ikemisetsa ho sebelisa mokhoa o thehiloeng ho ts'ebetso ea protheine e lateloang ke tlhahlobo ea HPLC-MS / MS. Litekanyetso tsa PK tse sa kenngoeng ka polokelo li ile tsa fumanoa liprofinseng tsa nako ea mali − ho sebelisa sephutheloana sa software WinNonlin v.4.0 (Pharsight, Mountain View, CA). Litekanyetso tsa PK li hlahisoa e le ntho e bolelang ± SD (Bala le Braggio, 2010).

Teko ea 3: Phello ea SB-649868, JNJ-10397049, le GSK1059865 ho Model Rat robala

Animals

Male Sprague-Dawley rats (275-300 g; Charles River, Calco, Como, Italy) li ne li behiloe ka mokhoa o le mong mochineng oa leseli oa lefifi la 12-h (lebone ho 0300 h) 1 bekeng pele ho ts'ebetso ea bongaka. Ho fihlella lijo le metsi ho ne ho lumelloa ad libitum. Ho bokella matšoao a biopotential, transmitter telemetric miniature (TL10M3-F40-EET; Thutong ea Saense ea Int.) E kentsoe ka bohlale liphoofolong. Li-electrode tse peli li ne li beoa ka ho sa feleng ka samente ea meno ho lehata ho rekota cortical electroencephalogram (EEG). Ba ne ba ikopanya ka kotloloho le nako e telele ka likoti tse peli tse chekiloeng sebakeng sa Fronto-parietal. Li-elektrone tse ling tse peli li ne li behiloe mesifa ea molala, bakeng sa ho rekota electromyogram (EMG) kapa sebakeng sa periorbital ea leihlo ho rekota li-electrooculogram (EOG).

Ho rekota

Kamora ho hlaphoheloa opereisheneng, liphoofolo li ile tsa bolokiloe ka hara lehae la tsona sebakeng se laoloang ke mocheso (21 ± 1 ° C) le phihlello ea lijo le metsi. ad libitum. Liphoofolo tse ts'oaretsoeng li bonts'itse mokhoa o tloaelehileng oa boits'oaro hang hoba a hlaphoheloe opereisheneng. Leha ho le joalo, ho lumella mekhoa e tloaelehileng ea ho robala ho theha botjha, liphoofolo li ile tsa sebelisoa kamora nako ea beke ea 3. Maemo a tikoloho a hlalositsoeng kaholimo a ne a bolokoa lithutong tsohle tsa boroko. Nako eohle ea nako ea tlhahlobo, liphoofolo tse tsamaeang ka bolokolohi li ile tsa sala malapeng a tsona ho bao ba li fumanang. Matšoao a EEG le EMG kapa EOG a hatisitsoe a sa khaotse a sebelisa DSI Dataquest ART Mofuta oa EEG, o arotsoe ka li-epochs tsa 10-s, o fetotsoe ka di-digitally (phetoho ea FFT) ho fana ka tlhaiso ea matla δ, θ, α, 'me β lihlopha ho khetholla mekhoa e meraro e fapaneng ea ts'ebetso ho rat (tsoha, boroko ba NREM, le boroko ba REM). Matšoao a abeloang ke sistimi ea scging ea automated system (Sleep level, DSI) e ile ea fetisetsoa ponts'ong ea dijithale ea EEG mme hamorao a netefatsoa ke tlhahlobo e bonoang ea likotsi tsa EEG le EMG / EOG ke basebetsi ba koetlisitsoeng, ba sa boneng kalafo ea lithethefatsi. Tlhahlobo ea litekanyetso tsa boroko e kenyellelitsoe: latency ho robala ha NREM (nako ea ho robala ho tse tšeletseng tse latellanang tsa ho robala tsa NREM kamora ho ente), latency ho REM robala (nako ea nako ea ho robala ea REM pele kamora ente), boroko ba NREM, boroko ba REM, le kakaretso nako ea ho robala.

Phekolo ea lithethefatsi

Mekhoa ea kalafo ea lithethefatsi e ile ea etsoa ho ea ka moralo oa "crossover" o hlophisitsoeng ka mokhoa o ikemetseng moo, ka linako tse fapaneng tsa liteko, phoofolo e 'ngoe le e' ngoe e amohelang kapa e sebelisa lithethefatsi. Likhoto li ile tsa tšoaroa ka liteko tsa liteko kapa koloi e tsamaeang le eona, ka bongata ba 2 ml / kg, 6 h kamora ho tima lebone (Nako ea Circadian (CT) 18). Rekoto e ile ea etsoa bakeng sa nako ea tlhahlobo ea 3-h e ileng ea latela. SB-649868 e qhibilihile ho 0.5% HPMC (hydroxy-propyl-methyl-cellulose) (w / v) ka metsing a felletseng mme e ne e tsamaisoa ka li-davage ka tekanyetso ea 3 le 10 mg / kg. JNJ-10397049 e felisitsoe ho mygliol 812N, mme e ne e sebetsoa ka hloko ka tekanyo ea XDUMX le 5 mg / kg. GSK25 e qhibilihile ho 1059865% HPMC (w / v) ka metsing a se nang metsi mme e laoloa ka mokhoa o sa tsotelleng litekanyetso tsa 0.5 le 5 mg / kg.

Tlhahlobo ea lintlha

Lintlha tsohle li hlahisoa e le moelelo oa ± SEM. Liphetho li ile tsa hlahlojoa ho sebelisoa tlhahlobo e le 'ngoe ea phapang (ANOVA). Post-hoc papiso e entsoe le teko ea Dunnett. Bohlokoa ba lipalo-palo bo behiloe ho P

Teko ea 4: Ho ja ho ja

Animals

Ho sebelisitsoe likhoto tsa basali tsa Sprague-Dawley (Charles River). Boima ba 'mele oa bona e ne e le 225-250 g qalong ea liteko. Likhoto li ne li kengoe lebokose le leng tlasa 12-h light / potoloho e lefifi (lebone ho 0800 h) le ad libitum chow le metsi bakeng sa libeke tsa 2 pele ho liteko. Li ne li bolokiloe ka phapusing e nang le mocheso o sa khaotseng (20-22 ° C) le mongobo (45-55%). Likhoto li ne li bolokiloe ka koateng e le 'ngoe e nang le marako a tšepe; mokatong le leboteng la ka pele li ne li entsoe ka gridi ea tšepe. Bophahamo ba mokatong oa likhokho e ne e le 30 cm x 30 cm; cage e ne e le 30 cm cm. Monyako o ka pele (30 cm x 20 cm) o kentsoeng gridi ea tšepe e ne e le teng ka leboteng la kantle la terata ho lumella ho kenella kahare ea kh'harale. Karolo e setseng ea lebota le ka pele e ne e e-na le lefapha la ho noesa.

seratsoana

Liphoofolo li ne li fuoa li-pellets tsa lijo tsa litekete tse tloaelehileng, 4RF18 (Meduola; Settimo Milanese, Milano, Italy; 2.6 kcal / g). HPF e ne e le paseka e lokiselitsoeng ka ho kopanya Nutella (Ferrero, Alba, Torino, Italy) tranelate ea chokolete (5.33 kcal / g; 56%, 31%, le 7% e tsoang ho carbohydrate, mafura, le protheine, ka ho latellana), li-pellets tsa lijo tse halikiloeng ( 4RF18; Meduola; Settimo Milanese), le metsi ka tekanyo e latelang ea karolo ea boima: boima ba 52% Nutella, 33% li-pellets tsa lijo, le metsi a 15%. Lijo tsa HPF li ne li e-na le "caloric" ea 3.63 kcal / g. Li-pellets tse tloaelehileng li ne li fanoa ka har'a sejana sa tšepe se entsoeng ka tšepe se neng se fanyehiloe leboteng le ka ntle la kasebele; e ne e tlosoa ka sejelong ho lekanya boima ba eona ho bona hore na ho ja lijo tse ngata hakae. HPF e fanoe ka senoelo sa kofi; letsoho la senoelo le ne le kentsoe ka har'a gridi ea tšepe e ka ntle ea khareji ebe e kenella leboteng.

Tsamaiso ea khatello ea maikutlo

Bakeng sa 15 min, senoelo sa kofi sa China se nang le HPF se ile sa kenngoa ka har'a sejana sa tšepe se neng se fanyehiloe leboteng le ka ntle la kharetene. Maemong ana, phoofolo e ne e khona ho bona senoelo seo e fumanang HPF ka matsatsi a 5, 6, 13, le 14 ea potoloho e 'meli ea pele, e khona ho bona HPF ka boeona, hape le ho fofonela monko oa eona. Lekhetlong lena la 15-min, rat e ile ea nka mehato e pheta-phetoang ea phatla-pele, hlooho le kutu, sepheo sa eona ho fumana HPF, empa ha ea ka ea e fihlela.

Sena se hlahisitse boemo bo sithabetsang bo bonolo bo bakang keketseho e kholo ea maemo a serum corticosterone (Cifani et al a, 2009). Kamora metsotso ea 15, senoelo se ile sa beoa kahare ho likhoto tsa lihlopha tsa khatello, e le hore HPF e ka ba fihlella.

Phekolo ea lithethefatsi

Ka letsatsi 25, likhakanyo kapa koloi e fapaneng e ile ea fuoa pele ho phihlello ea HPF. SB-649868 e qhibilihile ho 0.5% HPMC (w / v) ka metsing a nang le metsi 'me e ne e tsamaisoa ke li-davage ka tekanyetso ea 1 le 3 mg / kg. Topiramate e qhibilihile ho 0.5% HPMC (w / v) ka metsing a se nang metsi 'me e ile ea tsamaisoa ke gavage ka tekanyo ea 60 mg / kg. JNJ-10397049 e qhibilihile ho 0.5% HPMC (w / v) ka metsing a se nang metsi mme e ne e tsamaisoa ka mokhoa o sa tsotelleng litekanyetso tsa 1 le 3 mg / kg. GSK1059865 e qhibilihile ho 0.5% HPMC (w / v) ka metsing a se nang metsi mme e tsamaisoa ke li-davage ho tekanyetso ea 10 le 30 mg / kg. Lithethefatsi tsohle kapa koloi ea bona e ne e tsamaisoa 1 h pele ho fihlella HPF.

Teko ea 4A: Phello ea SB-649868 le Topiramate

Ho hlahloba karolo ea bahanyetsi ba OXR ho BE, mohanyetsi oa OXR ea sa khethang, SB-649868, o ile a lekoa mohlaleng oa rona oa BE.

Liphoofolo li ne li arotsoe ka lihlopha tse 'ne tsa liphoofolo tsa 27 e' ngoe le e 'ngoe, e tsamaeang le boima ba' mele le lijo tsa letsatsi le letsatsi: (1) sehlopha se sa thibeloang ebile se sa pepesetsoe khatello ea khatello ea maikutlo (NR + NS); (2) sehlopha se thibetsoeng mme se sa pepesoa khatello ea maikutlo (R + NS) sehlopha; (3) sehlopha se sa thibeloang ebile se pepesitsoe khatello ea maikutlo (NR + S) sehlopha; le (4) sehlopha se thibetsoeng ebile se pepesitsoe khatello ea maikutlo (R + S). Ha a qeta ho abeloa e 'ngoe ea lihlopha tsena, likhoto li ile tsa lula sehlopheng seo nakong ea thuto eohle. Likhoto tse pepesitsoeng khatello ea maikutlo li ile tsa rorisoa ka phapusing e fapaneng le ea lihlopha tse sa pepesitsoeng khatello ea maikutlo. Likhoto li ile tsa pepesetsoa makhetlo a mararo a latellanang a matsatsi a 8 a lateloang ke tlhahlobo ea ho qetela ka letsatsi 25 (Lethathamo 1):

Lethathamo 1 

Kemiso e Fumelletsoe ho Fokotsa Ho ja
  1. sehlopha sa NR + NS se ne se na le chow ad libitum bakeng sa matsatsi a 4, ka matsatsi 5 le 6 ba amohetse chow + HPF bakeng sa 2 h; ka matsatsi 7 le 8 ba ne ba na le chow ad libitum; 'me ka letsatsi 25 ba ne ba sa pepesetsoa khatello ea maikutlo;
  2. sehlopha sa bobeli se ne se na le chow le HPF e le NR + NS, empa ka letsatsi la liteko (ka letsatsi 25) ba ile ba pepesetsoa khatello ea maikutlo (NR + S);
  3. sehlopha sa boraro (R + NS) se ne se khinnetse ho 66% ea tšebeliso e tloaelehileng ea matsatsi a 4, ba ne ba fuoa chow le HPF (2 h) ka matsatsi 5 le 6 le chowon feela ka matsatsi 7 le 8; ka letsatsi 25 ba ne ba sa pepesetsoa khatello ea maikutlo.
  4. sehlopha sa R ​​+ S se ne se khinnetse ho 66% ea tšebeliso e tloaelehileng ea matsatsi a 4, ba ne ba fuoa chow le HPF (2 h) ka matsatsi a 5 le 6 mme e le 'chow feela ka matsatsi 7 le 8; mme ka letsatsi 25 ba ile ba pepesetsoa khatello ea maikutlo.

Potoloho ea letsatsi ea 8 e phetoa makhetlo a mararo, empa ka potoloho ea boraro liphoofolo li ne li se na mokhoa oa ho fumana lijo tsa HPF.

Ka letsatsi 25, sehlopha ka seng sa likhoto tsa 27 se ne se arotsoe likarolo tse tharo 'me se alafshoa, ka koloi, SB-649868, 1 kapa 3 mg / kg, e fanoeng ke gavage 1 h pele ho fihlella HPF.

Tloaelo ea HPF e hlahisitsoe e le kcal / kg e kenelletseng ± SEM; Tšebeliso ea HPF e lekantsoe ho 15, 30, 60, le 120 min kamora ho qala ho fihlella. Ts'ebetso ea lijo tsa pellet e lekantsoe feela ho 120 min, ka lebaka la liphuputso tse fumanoeng liphuputso tse fetileng li bonts'ang hore ho ja lijo tsa pellet ho ne ho le nyane haholo, le ho qoba ho sitisa liphoofolo nakong ea teko.

Topiramate, e sebelisitsoeng joalo ka karolo ea litšupiso bakeng sa paradigm ena ea liteko (Cifani et al a, 2009), e ile ea lekoa ka likhoto tse tšoanang, matsatsi a 10 kamora ho fela ha liteko tsa SB-649868. Ho liphoofolo tsena tsa 108, 72 e ile ea aroloa ka lihlopha tse 'ne tse tšoanang (liphoofolo tsa 18 bakeng sa sehlopha ka seng) se hlalositsoeng pele. Kamora ho qeta letsatsi le le leng qetellong ea teko ea pele, lihlopha tsena tsa likhoto li amohetse potoloho ea matsatsi a 8 e 'ngoe: Lihlopheng tsa NR + NS le NR + S li bile le matsatsi a 8 ad libitum, athe lihlopha tsa R + NS le R + S li ne li e-na le matsatsi a 4 chow li behetsoe ho 66% ea tšebeliso e tloaelehileng e lateloang ke matsatsi a 4 ad libitum. Mothating ona o ekelitsoeng, lihlopha tsohle li ne li sena monyetla oa ho fumana HPF. Letsatsing le hlahlamang, lihlopha tsa NR + S le R + S li ile tsa pepesoa khatello ea maikutlo, athe lihlopha tsa NR + NS le R + NS li ne li le sieo. Ka letsatsi lena, topiramate (60 mg / kg) kapa koloi ea eona e ne e tsamaisoa ke gavage 1 h pele ho fihlella HPF.

Teko ea 4B: Phello ea JNJ-10397049 le GSK1059865

Ho etsa lipatlisiso mabapi le OXR e kenyelletsang ho fokotsa likarolo tsa BE, OX e khethiloeng2R antagonist, JNJ-10397049, le OX ea khethang1R antagonist, GSK1059865, e ile ea lekoa mohlaleng oa rona oa BE.

Lirosa tsa basali tsa 54 tse eketsehileng, tse arotsoeng ka lihlopha tse peli (NR + NS le R + S) tsa likhoto tsa 27, li ile tsa romelloa ts'ebetsong e tšoanang ea liteko joaloka ho liteko tsa 4A. Ke lihlopha tse peli feela tsa likhoto tse sebelisitsoeng tekong ena kaha litleloubu tsa NR + S le R + NS ha li bonts'e BE. Letsatsing la liteko (ka letsatsi 25), 1 h pele ho phihlello ea HPF, likhoto li ile tsa tšoaroa ka mokhoa o makatsang ka JNJ-10397049 (1 le 3 mg / kg) kapa koloi ea eona.

Kamora ho qeta letsatsi le le leng qetellong ea tlhahlobo ea JNJ-10397049, sehlopha se tšoanang sa likhoto se ile sa fumana potoloho ea letsatsi ea 8 e lateloang ka letsatsi 10 (joalo ka ha ho hlalositsoe ho teko e fetileng) ka kalafo ea GSK1059865. GSK1059865 (10 le 30 mg / kg) kapa koloi ea eona e ne e tsamaisoa ke gavage 1 h pele ho fihlella HPF.

Tlhahlobo ea lintlha

Lintlha tsohle li hlahisoa e le moelelo oa "SEM" 'me boleng bo bong le bo bong bo bonts'a moelelo oa palo ea liphoofolo ka sehlopha ka seng ha ho hlalositsoe litšōmong. Lintlha li ile tsa hlahlojoa ke ANOVA ea tsela e 'meli ka lipapiso tse lipakeng tsa thuto-leseling bakeng sa lihlopha tsa liteko kapa kalafo ea lithethefatsi, le papiso e ka hare ho taba bakeng sa nako ea ho shebella. Post-hoc papiso e entsoe ke tlhahlobo ea Bonferroni. Bohlokoa ba lipalo bo thehiloe ho P

LIPOTSO

Teko ea 1: Antagonism ea SB-649868, JNJ-10397049, le GSK1059865 ho rOX1R le ROX2R

OXA (0.1 nM-10 μM) e holisitse [3H] Ho bokelloa ha IPs ka tsela e itšetlehileng ka khatello le pEC50 boleng ba 7.79 ± 0.04 (n= 16) le 7.68 ± 0.04 (n= 16) ho rOX1R le ROX2R, ka ho latellana. Ho ROX1R, JNJ-10397049 (1 μM-33 μM; Setšoantšo sa 1a) le GSK1059865 (0.3 nM-10 nM; Setšoantšo sa 2a) hlahisitse mohanyetsi o ke keng oa lekanngoa ka phetoho e nepahetseng ea tokelo ea OXA EC50 le ho fokotseha ho tšoanang ha karabelo e matla ea agonist. E baliloe pKB boleng e ne e le 5.73 ± 0.16 (n= 3) le 8.77 ± 0.12 (n= 3) ea JNJ-10397049 le GSK1059865, ka ho latellana. SB-649868 (0.1, 0.3, 0.6, le 1 nM) (Setšoantšo sa 3a) e hlahisitse phokotso e kholo ea karabelo e kholo ea OXA, ntle le phetoho ea agonist EC50. PIC e lekantsoeng50 boleng e ne e le 9.46 ± 0.02 (n= 3). Ho ROX2R JNJ-10397049 (10 nM – 0.3 μM) (Setšoantšo sa 1b) le GSK1059865 (0.1-3.3 μM) (Setšoantšo sa 2b) e hlahisitse boemo ba boemo bo holimo bo fetisisang ka phetoho e tšoanang ea letsoho la OXA EC50 ntle le khatello ea maikutlo ea karabo e phahameng ea agonist. Meepa e fumanoeng ke tlhahlobo ea khatello ea Schild e ne e le 1.17 (95% CL 0.92-1.42) le 0.86 (95% CL 0.71-1.00) bakeng sa JNJ-10397049 le GSK1059865, ka ho latellana, 'me li ne li sa fapane ka lipalo ho tse ling (P> 0.05). Ho thibela matsoapo ho ea ho le leng, leqKB boleng e ne e le 8.49 (95% CL 8.34-8.63; n= 3) le 6.90 (95% CL 6.80-6.99; n= 3) ea JNJ-10397049 le GSK1059865, ka ho latellana. SB-649868 (0.1-3.3 nM) (Setšoantšo sa 3b) e hlahisitse phetoho e nepahetseng e thehiloeng ho litekanyetso ea OXA EC50, e tsamaeang le phokotso ea karabelo e kholo ea agonist. Ka ho sebelisa mokhoa oa ts'ebetso bakeng sa tlhahlobo ea litheko ntle le tlholisano, joalo ka ha ho hlalositsoe ho Lisebelisoa le Mekhoa, apKB boleng ba 9.35 ± 0.15 (n= 3) e baliloe.

Setšoantšo sa 1 

[3H] inositol phosphates (IPs) bokella bo hlahisoa ke ho tsitsisa ha mahlakore a mahlano (CRC) a orexin-A (OXA) (•) ka lisele tsa basophil leukemia (RBL) tse hlalosang: rat OX1R (rOX1R) (a) boteng ba 1 (Δ), 3.3 (▾), 10 ...
Setšoantšo sa 2 

[3H] inositol phosphates (IPs) bokella bo hlahisoa ke ho tsitsisa ha mahlakore a mahlano (CRC) a orexin-A (OXA) (•) ka lisele tsa basophil leukemia (RBL) tse hlalosang: ROX1R (a) boteng ba 0.3 (▴), 1 (▾), 3.3 (♦) ...
Setšoantšo sa 3 

[3H] inositol phosphates (IPs) bokella bo hlahisoa ke ho tsitsisa ha mahlakore a mahlano (CRC) a orexin-A (OXA) (•) ka lisele tsa basophil leukemia (RBL) tse hlalosang: rat rOX1R (rOX1R) (a) boteng ba 0.1 (□), 0.3 (Δ), ...

Teko 2: Qeto ea PK ho litekanyetso tsa banna le tsa basali

Qeto ea PK ho likhoto tsa banna e ile ea etsoa lipatlisiso maemong a tšoanang a liteko joaloka liteko tsa 3, 'me li bontšitsoe ho Lethathamo 2.

Lethathamo 2 

Paramente ea Pharmacokinetic ea SB-649868, JNJ-10397049, le GSK1059865 ho Male Sprague-Dawley Rats

C, max ea SB-649868 ho 3 mg / kg e ne e le 333 ± 52 ng / ml le AUC 1260 ± 262 ng*h / ml.

C, max ea JNJ-10397049 ho 5 mg / kg e ne e le 14.2 ± 1.0 ng / ml le AUC 64 ± 4.3 ng*h / ml.

C, max ea GSK1059865 ho 10 mg / kg e ne e le 366 ± 70 ng / ml le AUC 1290 ± 320 ng*h / ml.

Liqeto tsa PK litotong tsa basali li ile tsa hlahlojoa maemong a liteko a tšoanang le a liteko tsa 4, 'me li bonts'itsoe ho Lethathamo 3.

Lethathamo 3 

Paramente ea Pharmacokinetic ea SB-649868, JNJ-10397049, le GSK1059865 ho Female Sprague-Dawley Rats

C, max ea SB-649868 ho 3 mg / kg e ne e le 572 ± 115 ng / ml le AUC 1708 ± 331 ng*h / ml.

C, max ea JNJ-10397049 ho 10 mg / kg e ne e le 369 ± 97 ng / ml le AUC 457 ± 224 ng*h / ml.

C, max ea GSK1059865 ho 10 mg / kg e ne e le 268 ± 29 ng / ml le AUC 768 ± 46 ng*h / ml.

Teko ea 3: Phello ea SB-649868, JNJ-10397049, le GSK1059865 ho Model Rat robala

Sebaka sa hypnotic sa bahanyetsi ba OXR se ile sa hlahlojoa nako e fetang ea 3-h mokhatlong o sebetsang oa rat, ho qala karolo ea ho rekota ho CT 18 (mabone a tloha ho X 12) a potoloho ea leseli-lefifi. CT 18 e ile ea khethoa ka ho khetheha ho lumella fensetere e kholo ho lekola litlamorao tsa hypnotic tsa likhomphutha.

Maemong ana a liteko, OX e habeli1/ OX2R antagonist SB-649868 (3 le 10 mg / kg, ka gavage) e bakile ho fokotseha ho matla hoa tsoha (F (2, 21) = 22.9; P<0.01), le phokotso ea latency ea boroko (F (2, 21) = 9.11; P<0.01) ha e bapisoa le sehlopha sa taolo. Teko ea Dunnett kamora ANOVA e bonts'itse palo ea lipalo ho 3 le 10 mg / kg (P<0.01) ka mekhahlelo ka bobeli ea boroko. Ho hlahlojoa ha mekhoa ea boroko ho bonts'a keketseho ea boroko ba NREM le REM maemong a mabeli (Lethathamo la 4a).

Lethathamo la 4a 

Kameho ea SB-649868 (ka Gavage) ho Litulo tsa Boroko ho Lits'ireletso

OX e khethiloeng2R antagonist JNJ-10397049 (5 le 25 mg / kg, intraperitoneally) e bonts'itse phello ea hypnotic, joalo ka ha ho senotsoe ke ho fokotseha ha ho tsoha (F (2, 14) = 18.8; P<0.01) le latency ea ho robala (F (2, 14) = 4.8; P<0.05). Teko ea Dunnett e latelang ANOVA e bontšitse hore phokotso eo e ne e le bohlokoa ho lipalo ho 5 le 25 mg / kg ka bobeli (P<0.01 ea ho tsoha le P<0.05 bakeng sa latency ea boroko). Keketseho ea boroko ba NREM e ile ea bonoa ka tekanyetso ka bobeli (P<0.01), empa ha ho na phello e bonoeng boroko ba REM (Lethathamo la 4b).

Lethathamo la 4b 

Litlamorao tsa JNJ-10397049 (ip) ho Paramente ea Boroko ho Lits'oaetso

OX e khethiloeng1R antagonist GSK1059865 (5 le 25 mg / kg, intraperitoneally) e hlahisitse tšekamelo ea phokotso ea ho phaphama (F (2, 14) = 3.27; P<0.05) le latency ea ho robala (F (2, 20) = 1.73; P> 0.05). Tlhatlhobo ea mekhoa ea boroko e bontšitse keketseho feela borokong ba NREM, lipalo-palo li le maemong a holimo a lekiloeng (P<Teko ea Dunnett e latelang ANOVA); ha ho na phello e ileng ea bonoa boroko ba REM (Lethathamo la 4c).

Lethathamo la 4c 

Kameho ea GSK1059865 (ip) ho Paramente ea Boroko ho Lits'oaetso

Teko 4A. ETSA: Phello ea SB-649868 le Topiramate

ANOVA e senotse phapang e kholo ea tšebeliso ea 2-h HPF lihlopheng tse 'ne tsa likhoto tse latelang taolo ea makoloi (F (3, 32) = 13.81; P<0.01). Joalokaha ho bontšitsoe ho Setšoantšo sa 4, lits'ebetso tse latelang tsa tsamaiso ea likoloi HPF sehlopheng sa R ​​+ S e ne e phahame haholo ho feta ea sehlopha sa taolo (NR + NS). Takatso ea HPF ea likhoto tsa R + S e ile ea phatlalatsoa haholo ho min ea 15 ea pele ea ho e fumana; Ts'ebetso ea HPF ea sehlopha sa NR + S e ne e sa fapane haholo le ea li-control (NR + NS), e bonts'a hore khatello ea maikutlo e ne e sa lekana ho etsa BE. Ntle le moo, tšebeliso ea HPF ea sehlopha sa R ​​+ NS e ne e sa fapane haholo le ea li-control (NR + NS), e bonts'a hore ho potoloha ha lijo ha hoa lekana ho susumetsa BE. Ka hona, BE e kanna ea bakoa ke tšebelisano e ikhethang lipakeng tsa ho ja le khatello ea maikutlo.

Setšoantšo sa 4 

Kameho ea SB-649868 (1 le 3 mg / kg, ka gavage) kapa koloi ea eona lijong tse fumanehang habonolo (HPF). Lits'ebetso li hlahisoa joalo ka mokhoa o hlokang ± SEM ea likotlo tse robong. **P<0.01, phapang ho likhoto tse tšoaroang ke koloi; moo ho sa bontšoang, ...

Takatso ea li-pellets tsa lijo tse tloaelehileng e ne e le nyane haholo (hoo e ka bang 3-4% ea likhakanyo tsa khalori ka kakaretso tlhahlobong ea 2 h), mme e ne e sa angoe ke thibelo ea lijo, khatello ea maikutlo kapa ho kopana ha bobeli.

Joalokaha ho bontšitsoe ho Setšoantšo sa 4, SB-649868 e fokotsitse tšebeliso ea HPF haholo sehlopheng sa R ​​+ S (F (2, 24) = 18.63; P<0.01), empa eseng lihlopheng tse ling: NR + NS (F (2, 24) = 0.91; P> 0.05); R + NS (F (2, 24) = 0.16; P> 0.05); NR + S (F (2, 24) = 1.1; P> 0.05). Post-hoc papiso e senotse hore phello ea SB-649868 sehlopheng sa R ​​+ S e ne e le bohlokoa ho lipalo ka linako tsohle ho arabela tekanyo e phahameng ka ho fetisisa ea 3 mg / kg. Tekanyetso ea 1 mg / kg sehlopheng sa R ​​+ S e bonts'itse mokhoa oa phokotso o neng o se bohlokoa lipalo.

Teko ea topiramate e senotse phapang e kholo haholo ea ho kenella ha 2-h HPF (F (3, 32) = 3.93; P<0.01) ea lihlopha tse fapaneng tse latelang tsamaiso ea makoloi. Topiramate e tsamaisoang ka khetho ea 60 mg / kg e fokotsa tlhahiso ea HPF (F (1, 16) = 6.57; P<0.01) sehlopheng sa R ​​+ S (Setšoantšo sa 5), empa eseng ka lihlopha tsa NR + NS, NR + S, le R + NS. Boitsebiso ba lihlopha tsa NR + S le R + NS ha bo bontšoe.

Setšoantšo sa 5 

Kameho ea topiramate (60 mg / kg, ka gavage) kapa koloi ea eona lijong tse matlafatsoang haholo (HPF). Lits'ebetso li hlahisoa joalo ka mokhoa o hlokang ± SEM ea likotlo tse robong. *P<0.05, phapang ho likhoto tse tšoaroang ke koloi; moo ho sa bontšoang, phapang ...

Teko ea 4B. ETSA: Phello ea JNJ-10397049 le GSK1059865

Ha e le teko ea nakong e fetileng, ANOVA e netefalitse hore sehlopha sa R ​​+ S se bontšitse keketseho e kholo ea tšebeliso ea HPF (F (1, 16) = 16.17; P<0.01). JNJ-10397049 ha ea ka ea ama ho fepa ka sehlopha sa NR + NS (F (2, 26) = 0.23; P> 0.05) kapa sehlopheng sa R ​​+ S (F (2, 24) = 0.49; P> 0.05) (Setšoantšo sa 6a).

Setšoantšo sa 6 

Liphetoho tsa tšebeliso ea lijo tsa JNJ-10397049 (1 le 3 mg / kg, intraperitoneally) (a) kapa GSK1059865 (10 le 30 mg / kg, ka gavage) (b) lijong tse fumanehang habonolo (HPF). Lits'ebetso li hlahisoa joalo ka mokhoa o hlokang ± SEM ea likotlo tse robong. *P<0.05, phapang ...

Liphetho tse fumanoeng li bonts'a OX2R antagonism ha e ame boitšoaro ba ho fepa. Kahoo, litlamorao tse neng li bonoe pele le SB-649868 li ne li ka botsoa ka ho hlaka ka OX1Mechato. Ho netefatsa phumano ena, OX e ikhethileng1R antagonist GSK1059865 (10 le 30 mg / kg) e ile ea lekoa. ANOVA e bontšitse phapang e kholo lipakeng tsa lihlopha tse arabelang kalafo ea koloi (F (1, 16) = 17.1; P<0.01), e netefatsang phello ea BE sehlopheng sa R ​​+ S. GSK1059865 (ka tekanyetso ea 10 le 30 mg / kg) ha ea ka ea ama ho fepa sehlopheng sa NR + NS (F (2, 24) = 0.10; P> 0.05). Sehlopha sa R ​​+ S, ANOVA e bontšitse phello e kholo (F (2, 23) = 4.20, P<0.05) (Setšoantšo sa 6b). Post-hoc papiso e senotse hore phello ea GSK1059865 sehlopheng sa R ​​+ S ka tekanyetso ea 10 le 30 mg / kg e ne e le bohlokoa ho lipalo ho 15, 30, le 60 min kamora ho fihlella mahala ho HPF.

TŠOHLOA

Bopaki bo bongata bo fana ka maikutlo a hore ho ja, khatello ea maikutlo le linaha tse mpe tse amanang le tsona li emela lisosa tsa BE ho bakuli ba nang le BED kapa bulimia amanosa (Wardle et al a, 2000; Freeman le Gil, 2004). Ho joalo, linako tsa ho ja li atile haholo nalaneng ea batho ba jang ho itlopa joala, leha tlala ka boeona e sa bonahale e lekane ho khothaletsa HA ho se na khatello ea maikutlo le boemo bo bobe ba khang (Polivy et al a, 1994; Metsi et al a, 2001). Bopaki bo bongata bo ka bonts'a hore BE e kanna ea bakoa ke tšebelisano e ikhethang lipakeng tsa ho ja le khatello ea maikutlo; ka hona, khatello ea tikoloho le nalane ea lithibelo tsa lijo tsa potoloho e ka ikarabella bakeng sa pula le tlhokomelo ea eona (Stice et al a, 2001; Crowther et al a, 2001; Wolff et al a, 2000). Ka hona, lithibelo tse ipheta-phetang tsa lijo e ba moetapele ea matla oa ho ja haholo ho arabela khatello ea maikutlo (Wardle et al a, 2000).

Motsoako oa ho ja le khatello ea maikutlo le ona o bapala karolo ea bohlokoa ntlafatsong ea BE mohlaleng oa rona oa mantlha. Mohlaleng o ntlafalitsoeng ke Cifani et al a (2009), BE e khahloa ke ho e-ja ho ja le ho pepesetsoa khatello ea maikutlo ho HPF. Mohlaleng ona, likhoto tsa basali li pepesetsoa nako ea thibelo le ts'ebetso e sithabetsang e bonts'itsoeng ke ho pepesehela liphoofolo HPF ntle le monyetla oa ho e fumana.

Joalokaha ho boletsoe ho Selelekela, mekhoa ea OX e kentse letsoho taolong ea ho fepa ka lapeng le ka moputso, hammoho le ho susumetsa lithethefatsi tsa tlhekefetso (Bonci le Borgland, 2009). Ho tsamaellana le mohopolo oa hore lits'ebetso tsa neural tse susumetsang le ho tiisa ts'ebeliso e mpe ea lithethefatsi le tsona li ka ba le boitšoaro bo amanang le ho batla lijo le ho ja haholo (Gearhardt et al a, 2011b), thuto ena e fuputse bokhoni ba mohanyetsi oa OXR ba ho thibela likarolo tsa BE le ho lekola ho kenya letsoho ha OX1 le OX2 mekhoa ea ho laola likarolo tsa BE.

Ka lebaka lena, likhokahanyo tse tharo li tlalehiloe ka har'a lingoliloeng hore li na le khetho e fapaneng vs OX1 le OX2 li-receptor tsa batho li ile tsa lekoa: li-OX tse peli1/ OX2R antagonist (SB-649868), OX ea khethang2R antagonist (JNJ-10397049), le OX ea khethang1R antagonist (GSK1059865). Ho sebelisa litekanyetso tse amanang le pharmacological, bahanyetsi ba bararo ba OXR ba ile ba hlahlojoa pele a vitro ho ROP e kopanang1R le OX2R ho khetholla potency le ho netefatsa khetho ea bona mofuteng ona oa phoofolo. OX e fapaneng1/ OX2Khetho ea R e netefalitsoe ho likhoto li sebelisa [3H] inositol assay.

Ho lekola ponelopele ea mali ea PK ho ts'ehetsa boroko le lithuto tsa BE, lipatlisiso tsa li-complication tsa PK li se li hlahlobisitsoe ho likhoto tsa banna le basali, kaha tsena e ne e le tsona tsa thobalano tse sebelisitsoeng boroko le liteko tsa BE, ka ho latellana.

Ka mor'a moo, litekanyetso li khona ho hlahisa litlamorao tsa hypnotic li ile tsa khethoa mohlaleng oa litekanyetso tsa boroko. Kamora nako, likhokahanyo li ile tsa lekoa ho litekanyetso tse boletsoeng ho mofuta oa BE.

OX1R le OX2R antagonists ho tlalehoa ka har'a lingoliloeng hore ba kenye letsoho taolong ea boroko, haholo-holo ho susumetsa litlamorao tsa hypnotic (Di Fabio et al a, 2011; Gozzi et al a, 2011; Dugovic et al a, 2009). Ka mohlala oa boroko bo itlhommeng pele lithutong tsa banna, liphetho tse fumanoeng li bonts'a hore OX e kopane1/ OX2R antagonist, SB-649868, e kentse tšusumetso e matla ea hypnotic, ka bobeli ho bokhoni ba ho susumetsa le ho boloka boroko, ho fihlella phello e kholo ea lipalo ho 3 mg / kg. E tšoana le SB-649868, OX2R antagonist JNJ-10397049 o bontšitse phello e ntle ea hypnotic ka phokotseho e kholo ea nako e sebelisitsoeng a falimehile ho 5 mg / kg. Ho fapana le moo, OX1R antagonist GSK1059865 e bonts'itse bokhoni bo bobe haholo ba ts'usumetso ea ho susumetsa le ho boloka boroko. Liphumano tsena li tsamaellana le litlaleho tse ling tse fanang ka maikutlo a hore OX2R e kanna ea ba ea bohlokoa ho feta OX1R ho hohanela phello ea OX boroko (Sakurai, 2007; Brisbare-Roch et al a, 2007; Malherbe et al a, 2009; Dugovic et al a, 2009; Di Fabio et al a, 2011).

SB-649868, e lekoa maemong a mane a fapaneng a khatello le thibelo ea lijo (NR + NS, R + NS, NR + S, R + S), e atlehile ho fokotsa tšebeliso ea HPF feela sehlopheng sa R ​​+ S. Ho 3 mg / kg, SB-649868 e bile le phello e ts'oanang le e bonoang ka topiramate. Joalo ka topiramate, SB-649868 ha e-ea fetola phepelo ea HPF maemong a mang a thibelo ea lijo le khatello ea maikutlo.

OX2R antagonist, JNJ-10397049, e ileng ea lekoa maemong a tšoanang ha ea ka ea bonts'a tšebeliso ea phepelo ea HPF maemong ohle a mane a liteko.

Liphetho tsena li bontša ka ho hlaka hore OX1R e kenya letsoho taolong ea li-episode tsa BE mme e fana ka tlhahiso ea karolo e ka bang teng ea OX1R antagonists ho khutlisa likarolo tsa Epola tse bakiloeng ke khatello ea maikutlo le lijo tse thibeloang. Ho netefatsa khopolo ena, OX e khethiloeng1R antagonist GSK1059865 e ile ea hlahlojoa ho liphoofolo tse thibetsoeng le tse hatelletsoeng. Liphetho tse fumanoeng li netefalitse hore OX1R antagonists e thibetse keketseho ea phepelo ea HPF ho likhoto tsa R + S, ntle le ho ama ts'ebeliso ea lijo ho li-control (NR + NS).

Ho haella ha phello ea JNJ-10397049 ho ke ke ha hlahisoa ka ho pepeseha ho sa lekana hoa phoofolo ho liphoofolo tse tlisitsoeng ho mofuta oa BE. Tlhahlobo ea PK ea JNJ-10397049 e bontšitse phapang ea thobalano, e tšehali e pepesitsoe ho feta likhoto tsa banna ka tekanyo e le 'ngoe ea JNJ-10397049 (10 mg / kg). Likhakanyo tsa AUC tse hakantsoeng e ne e le 64 ng*h / ml ho likhoto tsa banna vs 457 ng*h / ml ka likhoto tsa basali (hoo e ka bang makhetlo a supileng ho feta). Ka hona, ho fihlela qeto ea hore phoofolo e senoletsoe ho mofuta oa BE ho 1 le 3 mg / kg JNJ-10397049 li ne li le kaholimo ho tse fumanoeng lithutong tsa boroko ho 5 le 25 mg / kg. Ka lehlakoreng le leng, ho ne ho se na phapang lipakeng tsa thobalano ho PK ea SB-649868 le GSK1059865, 'me litlatsetso tse fumanehang mefuteng ena e' meli li ne li tletse lipakeng tsa banna le basali.

Joalokaha ho boletsoe ho Selelekela, khatello ea maikutlo ke senotlolo sa BE. Lisebelisoa tse 'maloa tsa data li hlahisitsoe lilemong tse leshome tse fetileng tse tšehetsang karolo ea li-peptide tsa OX libakeng tse phahameng haholo, ho kenyelletsa khatello ea maikutlo, ea morao-rao e amahanngoa le litheko tse phahameng haholo tsa methapo ea methapo ea kutlo ea OXergic. Li-neuron tsa OX tse ho potileng - dorsomedial hypothalamus li hlahisitsoe ka morero oa ho sebetsa ts'ebetsong ea khatello ea maikutlo (Harris le Aston-Jones, 2006, bakeng sa tlhahlobo, bona Koob, 2008). Mohlomong, OXA e tsoang sebakeng sena sa hypothalamic e kenya li-neuron tse hlahisang CRF mokokotlong oa "patothricular" oa hypothalamus le karolong e bohareng ea amygdala (Sakamoto et al a, 2004). Ka lebaka leo, OX1R antagonists e thibela ho khutlisetsoa hoa ethanol le ho batla ho ts'oaroa ke mohokahanyi oa pharmacological yohimbine (Richards et al a, 2008) mme OXA e khutlisetsa boits'oaro bo batlang cocaine (Boutrel et al a, 2005). Morao tjena, Kuwaki (2011) e fumane hore Sisteme ea OX ke e 'ngoe ea li-modulators tsa bohlokoa lipotolohong tsa neural tse laolang mesebetsi ea boikemelo le boitšoaro ba maikutlo. Liphuputso tsa pejana ke Johnson et al a (2010) e bonts'a hore OX e khethiloeng1R antagonist SB334867 e kentse boits'oaro bo joalo ka ho tšoenyeha, 'me ea thibela ho eketseha ha sekhahla, pelo le karabelo ea khatello ea mali e hlahisoang ke phephetso ea sodium lactate ho rat.

Boithuto bo 'maloa bo fana ka maikutlo a hore molao o fetotsoeng oa striatal dopamine (DA) o ka ba teng ho bakuli ba nang le bulimia amanosa le BED (Bello le Hajnal, 2010; Broft et al a, 2011; Wang et al a, 2011). Lithuto tsa Hoebel le basebetsi-mmoho (bakeng sa tlhahlobo, bona Avena le Bocarsly, 2011) li senotse liphetoho liphatlalatsong tsa DA tsa litlamo le li-receptor binding, tse ts'oanang le tse bonoang karabong ea lithethefatsi tsa tlhekefetso. Li-neuropeptides tse hlahisoang ho LH li ka fetola tšebetso ea VTA-DA le li-neuron tsa striatal. Morero oa li-neurons o nang le OX o tsoang ho LH ho ea VTA, moo OX1R e bapala karolo ea bohlokoa ho laola phetiso ea mesolimbic DA le thepa e ruisang ea lithethefatsi tse fapaneng tsa tlhekefetso le lijo (Cason et al a, 2010; Uramura et al a, 2001; Zheng et al a, 2007). Ntle le moo, likarolo tsa BE li ka laoloa ka tšusumetso e itseng ea meputso le lits'ebetso tsa ho matlafatsa tsa HPF. Mabapi le taba ena, ho a thabisa ho tseba hore li-neuron tsa OX tse ho LH li hlahisitsoe ho buella ts'ebetso ea moputso (bakeng sa tlhahlobo, bona Koob, 2008). Kahoo, ho khothalletsoa hore li-neuron tsa OX ho LH li hlahisoe ke mekhoa e amanang le meputso, e kang lijo kapa lithethefatsi, le ho tsosa li-neurons tsa OX ho LH ho khutlisetsa litlhare tse batlang litlamong (Harris et al a, 2005).

Sehlopha sa rona se sa tsoa supa ka mokhoa o ikhethileng oa MRI oo OX1R ho fapana le OX2Rula ka mokhoa o ikhethileng oa sebaka sa boko ba mesolimbic le karolo ea cortical ea insula, libaka tse kentsoeng ts'ebetsong e khotsofatsang (Gozzi et al a, 2011). Lintlha tsena li tiisa le ho holisa liphetho tsa pejana tseo OX1R e bapala karolo ea ts'ebetso ea moputso le pula ea mokhoa oa ho batla lithethefatsi (Boutrel et al a, 2005; Lawrence et al a, 2006; Hollander et al a, 2008; Smith et al a, 2010). Ka hona, ho tla hlokahala mosebetsi o eketsehileng ho lekola hore na phello ea khatello ke ea ha u tsosoa ke OX1R antagonists e amana le tšusumetso ea bona khatello ea maikutlo kapa mekhoa ea meputso, kapa ka bobeli.

Qetellong, sephetho se fumanoeng thutong ena se sebelisa lihanyetsi tse tharo tsa OXR tse khethiloeng ka mokhoa o fapaneng oa OX1R vs OX2R o bontšitse ka ho hlaka karolo e fapaneng ea OXR taolong ea li-episode tsa BE le ho fetoheng ha boroko. Lintlha tsa rona li netefalitse karolo e ka sehloohong ea OX2Mekhoa ea ho laola boroko. Ntle le moo, li bonts'a lekhetlo la pele hore OX1Mehato ea R e bapala karolo e kholo taolong ea li-episode tsa BE. Liphumano tsena li fana ka maikutlo a hore ho lebisa ho OX1R e ka emela mokhoa o khahlisang oa meriana oa ho phekola maloetse a amanang le BE.

lumela hore baa fokola

Re leboha Dr Charles Pickens bakeng sa khalemelo e ngotsoeng ka letsoho.

Notes

EM-P ke mosebeletsi oa nako eohle oa GSK.

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