2012 ÖÈÒÎËÎÃÈß Ò î ì 54, ¹ 6 ÔÓÍÊÖÈÎÍÀËÜÍÎÅ ÑÎÑÒÎßÍÈÅ ÐÅÃÓËÈÐÓÅÌÛÕ ÁÈÎÃÅÍÍÛÌÈ ÀÌÈÍÀÌÈ È ÀÖÅÒÈËÕÎËÈÍÎÌ ÑÈÃÍÀËÜÍÛÕ ÑÈÑÒÅÌ ÌÎÇÃÀ ÏÐÈ ÑÀÕÀÐÍÎÌ ÄÈÀÁÅÒÅ © À. Î. Øïàêîâ Èíñòèòóò ýâîëþöèîííîé ôèçèîëîãèè è áèîõèìèè èì. È. Ì. Ñå÷åíîâà, Ñàíêò-Ïåòåðáóðã; ýëåêòðîííûé àäðåñ: alex_shpakov@list.ru À. Î. Øïàêîâ Ðîëü ãîðìîíàëüíûõ ñèãíàëüíûõ ñèñòåì â ýòèîëîãèè è ïàòîãåíåçå ñàõàðíîãî äèàáåòà (ÑÄ) è âûçûâàåìûõ èì íåéðîäåãåíåðàòèâíûõ çàáîëåâàíèé â íàñòîÿùåå âðåìÿ èçó÷åíà íåäîñòàòî÷íî. Ïðèíÿòî ñ÷èòàòü, ÷òî îñíîâíûìè ïðè÷èíàìè ÑÄ 1-ãî è 2-ãî òèïîâ è èõ îñëîæíåíèé ñî ñòîðîíû ÖÍÑ ÿâëÿþòñÿ íàðóøåíèÿ, âîçíèêàþùèå â ñèãíàëüíûõ ñèñòåìàõ, ðåãóëèðóåìûõ èíñóëèíîì, ëåïòèíîì è ãëóòàìàòîì. Îäíàêî â ïîñëåäíèå ãîäû ïîÿâèëèñü ìíîãî÷èñëåííûå ñâèäåòåëüñòâà â ïîëüçó ó÷àñòèÿ â ðàçâèòèè ýòèõ çàáîëåâàíèé ñèãíàëüíûõ ñèñòåì ìîçãà, ðåãóëèðóåìûõ áèîãåííûìè àìèíàìè è àãîíèñòàìè õîëèíåðãè÷åñêèõ ðåöåïòîðîâ. Èçìåíåíèå ýêñïðåññèè è ôóíêöèîíàëüíîé àêòèâíîñòè ñèãíàëüíûõ áåëêîâ, êîìïîíåíòîâ ýòèõ ñèñòåì, à òàêæå íàðóøåíèå áèîñèíòåçà, òðàíñïîðòà è äåãðàäàöèè ðåãóëèðóþùèõ èõ ñèãíàëüíûõ ìîëåêóë âíîñÿò çíà÷èòåëüíûé âêëàä â ïàòîëîãè÷åñêèå ïðîöåññû, ïðîòåêàþùèå â ìîçãå ïðè ÑÄ, à â ðÿäå ñëó÷àåâ ñàìè ÿâëÿþòñÿ ïóñêîâûì ìåõàíèçìîì äëÿ ðàçâèòèÿ ýòîãî çàáîëåâàíèÿ. Âàæíåéøèìè ôàêòîðàìè, âûçûâàþùèìè íàðóøåíèÿ ôóíêöèîíèðîâàíèÿ äîôàìèíåðãè÷åñêîé, ñåðîòîíèíåðãè÷åñêîé, àäðåíåðãè÷åñêîé è õîëèíåðãè÷åñêîé ñèñòåì ìîçãà â óñëîâèÿõ ÑÄ, ÿâëÿþòñÿ ãèïåðãëèêåìèÿ è èíñóëèíîâàÿ ðåçèñòåíòíîñòü, à òàêæå ãèïîãëèêåìèÿ, âîçíèêàþùàÿ âñëåäñòâèå íåàäåêâàòíîé èíñóëèíîâîé òåðàïèè. Íàñòîÿùèé îáçîð ïîñâÿùåí ïðîáëåìå ôóíêöèîíàëüíîãî ñîñòîÿíèÿ ñèãíàëüíûõ ñèñòåì ìîçãà, ðåãóëèðóåìûõ áèîãåííûìè àìèíàìè è õîëèíåðãè÷åñêèìè àãîíèñòàìè, â óñëîâèÿõ ÑÄ, à òàêæå âçàèìîñâÿçè ìåæäó èçìåíåíèÿìè â ýòèõ ñèñòåìàõ è ðàçâèòèåì íåéðîäåãåíåðàòèâíûõ ïðîöåññîâ â äèàáåòè÷åñêîì ìîçãå. Ôóíêöèîíàëüíîå ñîñòîÿíèå ñèãíàëüíûõ ñèñòåì ìîçãà ïðè ñàõàðíîì äèàáåòå Ê ë þ ÷ å â û å ñ ë î â à: àäåíèëàòöèêëàçà, àöåòèëõîëèíîâûé ðåöåïòîð, áèîãåííûé àìèí, ãèïåðãëèêåìèÿ, äèàáåò, äîôàìèí, äîôàìèíîâûé ðåöåïòîð, ìîçã, ñåðîòîíèí, ñåðîòîíèíîâûé ðåöåïòîð. Ï ð è í ÿ ò û å ñ î ê ð à ù å í è ÿ: ÀÐ — àäðåíåðãè÷åñêèå ðåöåïòîðû, ÀÕ — àöåòèëõîëèí, ÀÖ — àäåíèëàòöèêëàçà, ÄÀ — äîôàìèí, ÄÀÐ — äîôàìèíîâûå ðåöåïòîðû, ÈÔÐ-1 — èíñóëèíîïîäîáíûé ôàêòîð ðîñòà-1, ÌÀÕÐ — ìóñêàðèíîâûå àöåòèëõîëèíîâûå ðåöåïòîðû, ÑÄ — ñàõàðíûé äèàáåò, ÑÄ1 è ÑÄ2 — ñàõàðíûé äèàáåò 1-ãî è 2-ãî òèïîâ, ÑÈÎÇÑ — ñåëåêòèâíûå èíãèáèòîðû îáðàòíîãî çàõâàòà ñåðîòîíèíà, ÑÐ — ñåðîòîíèíîâûå ðåöåïòîðû, ÔËÑ — ôîñôîëèïàçà Ñ. (ÈÔÐ-1) è ëåïòèíîì, ÷üè ôóíêöèè â íàèáîëüøåé ñòåïåíè ìåíÿþòñÿ ïðè ÑÄ (Clodfelder-Miller et al., 2006; Gelling et al., 2006; Shpakov et al., 2006; Kojima et al., 2009; Chistyakova et al., 2011), à òàêæå íàðóøåíèÿì â ãëóòàìàòåðãè÷åñêîé ñèñòåìå ìîçãà, èãðàþùåé âàæíóþ ðîëü â ïàòîãåíåçå íåéðîäåãåíåðàòèâíûõ çàáîëåâàíèé (Tomiyama et al., 2005; Anu et al., 2010). Îäíàêî â ïîñëåäíèå ãîäû âñå áîëüøå âíèìàíèÿ óäåëÿþò èçìåíåíèÿì â ñèãíàëüíûõ êàñêàäàõ, ðåãóëèðóåìûõ àãîíèñòàìè õîëèíåðãè÷åñêèõ ðåöåïòîðîâ è áèîãåííûìè àìèíàìè — äîôàìèíîì, ñåðîòîíèíîì è íîðàäðåíàëèíîì (Sumiyoshi et al., 1997; Jackson, Paulose, 1999; Padayatti, Paulose, 1999; Gireesh et al., 2008, 2009; Antony et al., 2010; Anu et al., 2010; Kumar et al., 2010; Peeyush et al., 2010; Shpakov et al., 2011, 2012). Ïðè ýòîì ìåíÿåòñÿ ôóíêöèîíàëüíàÿ àêòèâíîñòü êàê îòäåëüíûõ ñèãíàëüíûõ ñèñòåì, òàê è âñåé íåéðîíàëüíîé ñåòè, ÷òî â êîíå÷íîì èòîãå ïðèâîäèò ê íàðóøåíèþ ôóíêöèîíèðîâàíèÿ ðàçëè÷íûõ îòäåëîâ ìîçãà è êîíòðîëèðóåìûõ èìè ôèçèîëîãè÷åñêèõ è áèîõèìè÷åñêèõ ïðîöåññîâ. Âîçìîæíà è îáðàòíàÿ ñèòóàöèÿ, êîãäà íàðóøåíèÿ â ñèãíàëüíûõ ñèñòåìàõ ìîçãà ÿâëÿþòñÿ ïóñêîâûì ìåõàíèçìîì äëÿ ðàçâèòèÿ íåéðîäåãåíåðàòèâíûõ ïðîöåññîâ, ÷òî ïðèâîäèò ê èíñóëèíîâîé ðåçèñòåíòíîñòè, õàðàêòåðíîé Ñàõàðíûì äèàáåòîì (ÑÄ) â ìèðå ñòðàäàþò áîëåå 280 ìëí ÷åëîâåê, âñëåäñòâèå ÷åãî îí ïðåäñòàâëÿåò îñòðóþ ìåäèöèíñêóþ è ñîöèàëüíóþ ïðîáëåìó. Ýòî çàáîëåâàíèå õàðàêòåðèçóåòñÿ ãèïåðãëèêåìèåé, âîçíèêàþùåé âñëåäñòâèå íåäîñòàòî÷íîñòè èíñóëèíà ïðè ÑÄ 1-ãî òèïà (ÑÄ1) èëè ñíèæåíèÿ ÷óâñòâèòåëüíîñòè ê íåìó òêàíåé ïðè ÑÄ 2-ãî òèïà (ÑÄ2). ÑÄ âûçûâàåò îñëîæíåíèÿ ñî ñòîðîíû íåðâíîé ñèñòåìû, òàêèå êàê äèàáåòè÷åñêàÿ ýíöåôàëîïàòèÿ è áîëåçíü Àëüöãåéìåðà, ÷òî ñâèäåòåëüñòâóåò â ïîëüçó òåñíîé âçàèìîñâÿçè ìåæäó íåéðîäåãåíåðàòèâíûìè èçìåíåíèÿìè â ìîçãå, ñ îäíîé ñòîðîíû, è ìåòàáîëè÷åñêèìè íàðóøåíèÿìè, âîçíèêàþùèìè ïðè ÑÄ, — ñ äðóãîé (Biessels et al., 2001; De la Monte, 2009; Takeda et al., 2011). Ïðåäïîëàãàåòñÿ, ÷òî îäíîé èç ïåðâîïðè÷èí ðàçâèòèÿ íåéðîäåãåíåðàòèâíûõ çàáîëåâàíèé ïðè ÑÄ ÿâëÿþòñÿ èçìåíåíèÿ ôóíêöèîíàëüíîé àêòèâíîñòè ñèãíàëüíûõ ñèñòåì ìîçãà, ðåãóëèðóåìûõ ðàçëè÷íûìè ïî õèìè÷åñêîé ïðèðîäå ìîëåêóëàìè — ïåïòèäàìè èíñóëèíîâîãî ñóïåðñåìåéñòâà, íåéðîïåïòèäàìè, àìèíîêèñëîòàìè è èõ ïðîèçâîäíûìè, íóêëåîòèäàìè, õîëèíåðãè÷åñêèìè àãîíèñòàìè. Íà ïðîòÿæåíèè äëèòåëüíîãî âðåìåíè âåäóùóþ ðîëü çäåñü îòâîäèëè èçìåíåíèÿì â ñèãíàëüíûõ ñèñòåìàõ, ðåãóëèðóåìûõ èíñóëèíîì, èíñóëèíîïîäîáíûì ôàêòîðîì ðîñòà-1 459 460 À. Î. Øïàêîâ äëÿ ÑÄ2, èëè îñòðîé èíñóëèíîâîé íåäîñòàòî÷íîñòè, õàðàêòåðíîé äëÿ ÑÄ1. Íåéðîäåãåíåðàòèâíûå çàáîëåâàíèÿ â ýòîì ñëó÷àå ìîæíî êëàññèôèöèðîâàòü êàê ïðåäèàáåòè÷åñêèå ñîñòîÿíèÿ, êîòîðûå ïðè îòñóòñòâèè àäåêâàòíîãî ëå÷åíèÿ ðàçâèâàþòñÿ â ÑÄ (Cole et al., 2007; De la Monte, 2009; De la Monte et al., 2010). Ïðîáëåìå ôóíêöèîíàëüíîãî ñîñòîÿíèÿ äîôàìèíåðãè÷åñêîé, ñåðîòîíèíåðãè÷åñêîé, àäðåíåðãè÷åñêîé è õîëèíåðãè÷åñêîé ñèãíàëüíûõ ñèñòåì ìîçãà â óñëîâèÿõ ÑÄ, à òàêæå ðîëè èçìåíåíèé â ýòèõ ñèñòåìàõ â ðàçâèòèè ÑÄ è àññîöèèðîâàííûõ ñ íèì íåéðîäåãåíåðàòèâíûõ çàáîëåâàíèé ïîñâÿùåí íàñòîÿùèé îáçîð. Äîôàìèíåðãè÷åñêàÿ ñèãíàëüíàÿ ñèñòåìà Äîôàìèí (ÄÀ), âàæíåéøèé íåéðîòðàíñìèòòåð â ÖÍÑ, êîíòðîëèðóåò øèðîêèé ñïåêòð ôèçèîëîãè÷åñêèõ ôóíêöèé, âêëþ÷àÿ äâèãàòåëüíóþ àêòèâíîñòü, êîãíèòèâíûå ïðîöåññû, ýìîöèè, ïèùåâîå ïîâåäåíèå, ðåãóëèðóåò ýíäîêðèííóþ ñèñòåìó, äåéñòâóåò íà ïåðèôåðè÷åñêèå îðãàíû è òêàíè, îñóùåñòâëÿÿ ðåãóëÿöèþ ñåðäå÷íî-ñîñóäèñòîé è ïèùåâàðèòåëüíîé ñèñòåì. Ðåãóëÿòîðíûå ýôôåêòû ÄÀ ðåàëèçóþòñÿ ÷åðåç ïÿòü òèïîâ äîôàìèíîâûõ ðåöåïòîðîâ (ÄÀÐ), êîòîðûå ôóíêöèîíàëüíî ñîïðÿæåíû ñ ôåðìåíòîì àäåíèëàòöèêëàçîé (ÀÖ), ïðè÷åì ÷åðåç ÄÀÐ 1-ãî è 5-ãî òèïîâ îñóùåñòâëÿåòñÿ ñòèìóëÿöèÿ ÀÖ, à ÷åðåç ÄÀÐ 2, 3 è 4-ãî òèïîâ — åå èíãèáèðîâàíèå (Undieh, 2010).  ìîçãå ïàöèåíòîâ ñ ÑÄ2 è ýêñïåðèìåíòàëüíûõ æèâîòíûõ ñ õàðàêòåðíîé äëÿ ÑÄ2 èíñóëèíîâîé ðåçèñòåíòíîñòüþ ñíèæåíà àêòèâíîñòü äîôàìèíåðãè÷åñêîé ñèñòåìû, ÷òî ñâÿçûâàþò â îñíîâíîì ñî ñíèæåíèåì óðîâíÿ ÄÀ, íàðóøåíèåì ôóíêöèîíèðîâàíèÿ ÄÀÐ 2-ãî òèïà è ñîïðÿæåííûõ ñ íèì èíãèáèðóþùèì ñïîñîáîì öÀÌÔ-çàâèñèìûõ êàñêàäîâ (Pijl, Edo, 2002). Âîññòàíîâëåíèå àêòèâíîñòè äîôàìèíåðãè÷åñêîé ñèñòåìû äîñòèãàåòñÿ ñ ïîìîùüþ ñåëåêòèâíûõ àãîíèñòîâ ÄÀÐ 2-ãî òèïà, ÷òî íå òîëüêî ïîëîæèòåëüíî âëèÿåò íà ôóíêöèîíèðîâàíèå ÖÍÑ, íî è çàìåòíî óëó÷øàåò òå÷åíèå ÑÄ. Íàèáîëåå ýôôåêòèâíûì ñðåäè ïðèìåíÿåìûõ ïðåïàðàòîâ ÿâëÿåòñÿ âûäåëåííûé èç ñïîðûíüè àëêàëîèä áðîìîêðèïòèí, ñåëåêòèâíûé àãîíèñò ÄÀÐ 2-ãî òèïà, â îñíîâå äåéñòâèÿ êîòîðîãî ëåæèò åãî èíãèáèðóþùåå âëèÿíèå íà àêòèâíîñòü ãèïîòàëàìè÷åñêèõ íåéðîíîâ, êîòîðûå ðåãóëèðóþò ïîâûøåíèå ïðîäóêöèè ãëþêîçû è ñèíòåçà ëèïèäîâ â ïå÷åíè, à òàêæå àêòèâèðóþùåå âëèÿíèå íà äîôàìèíåðãè÷åñêèå íåéðîíû, êîíòðîëèðóþùèå ÷óâñòâèòåëüíîñòü òêàíåé ê èíñóëèíó (Scranton et al., 2007; Scranton, Cincotta, 2010).  ðåçóëüòàòå ëå÷åíèÿ áðîìîêðèïòèíîì ó ïàöèåíòîâ ñ ÑÄ2 íîðìàëèçóþòñÿ ìåòàáîëè÷åñêèå ïðîöåññû è ñíèæàåòñÿ ðèñê ïîâðåæäåíèÿ ÖÍÑ è ñåðäå÷íî-ñîñóäèñòîé ñèñòåìû. Íåîáõîäèìî ïîä÷åðêíóòü, ÷òî áðîìîêðèïòèí ñíèæàåò óðîâåíü ãëþêîçû áåç ñóùåñòâåííîãî ïîâûøåíèÿ óðîâíÿ èíñóëèíà è íå âûçûâàåò ãèïîãëèêåìè÷åñêèõ ýïèçîäîâ, êîòîðûå ñàìûì íåáëàãîïðèÿòíûì îáðàçîì âëèÿþò íà ÖÍÑ. Õîòÿ óñòàíîâëåíî, ÷òî ìîíîòåðàïèÿ áðîìîêðèïòèíîì íîðìàëèçóåò óðîâåíü ñàõàðà â êðîâè, ïðèâîäèò ê ñíèæåíèþ óðîâíåé ãëèêîçèëèðîâàííîãî ãåìîãëîáèíà, òðèãëèöåðèäîâ è ñâîáîäíûõ æèðíûõ êèñëîò, åãî òåðàïåâòè÷åñêèé ýôôåêò çíà÷èòåëüíî óñèëèâàåòñÿ ïðè ñî÷åòàíèè ñ ñàõàðîïîíèæàþùèìè ïðåïàðàòàìè è íåáîëüøèìè äîçàìè èíñóëèíà (Scranton et al., 2007).  îñíîâå äåéñòâèÿ áðîìîêðèïòèíà ëåæèò åãî ñïîñîáíîñòü ñåëåêòèâíî àêòèâèðîâàòü ÄÀÐ 2-ãî òèïà, êîòîðûå ñîïðÿæåíû ñ ãåòåðîòðèìåðíûìè G-áåëêàìè èíãèáèðóþùåãî òèïà (Gi), ÷òî âåäåò ê èíãèáèðîâàíèþ ÀÖ è öÀÌÔ-çàâèñèìûõ êàñêàäîâ â ãèïîòàëàìè÷åñêèõ íåéðîíàõ. Ñðåäè äðóãèõ ìîëåêóëÿðíûõ ìåõàíèçìîâ äåéñòâèÿ áðîìîêðèïòèíà íåîáõîäèìî îòìåòèòü åãî ñïîñîáíîñòü ìîäóëèðîâàòü àêòèâíîñòü a2-àäðåíåðãè÷åñêèõ ðåöåïòîðîâ (a2-ÀÐ), êîòîðûå èíãèáèðóþùèì ñïîñîáîì ñîïðÿæåíû ñ ÀÖ è âîâëå÷åíû â êîíòðîëü ôóíêöèé ÖÍÑ, à òàêæå åãî èíãèáèðóþùåå âëèÿíèå íà ñåêðåöèþ ïðîëàêòèíà ëàêòðîòðîôàìè ãèïîôèçà, îñóùåñòâëÿåìîå ÷åðåç ÄÀÐ 2-ãî òèïà, ëîêàëèçîâàííûå íà íåéðîíàõ äóãîîáðàçíîãî ÿäðà ãèïîòàëàìóñà. Ïðåäïîëàãàåòñÿ, ÷òî îáà ýòè ìåõàíèçìà âîâëå÷åíû â âûçûâàåìîå áðîìîêðèïòèíîì ïîíèæåíèå óðîâíÿ öåíòðàëüíîé è ïåðèôåðè÷åñêîé ãëþêîçû (Kerr et al., 2010). Ýôôåêòèâíîñòü áðîìîêðèïòèíà êàê àíòèäèàáåòè÷åñêîãî ïðåïàðàòà ïîäòâåðæäàåòñÿ ðåçóëüòàòàìè ýêñïåðèìåíòîâ ñ õîìÿ÷êàìè ñ ÑÄ2 (Luo et al., 2000). Ýòîò ïðåïàðàò óëó÷øàåò ôóíêöèîíàëüíîå ñîñòîÿíèå æèâîòíûõ, ïîâûøàåò èõ ÷óâñòâèòåëüíîñòü ê èíñóëèíó, ñíèæàåò ïîâûøåííûå â óñëîâèÿõ ÑÄ óðîâíè ãëþêîçû, èíñóëèíà è ñâîáîäíûõ æèðíûõ êèñëîò. Ïîêàçàíî òàêæå, ÷òî áðîìîêðèïòèí êîíòðîëèðóåò óðîâåíü áèîãåííûõ àìèíîâ â ñóïðàõèàçìàòè÷åñêîì ÿäðå ãèïîòàëàìóñà è ñóòî÷íûé ðèòì ñåêðåöèè ãîðìîíîâ, ðåãóëèðóþùèõ ìåòàáîëè÷åñêèå ïðîöåññû â îðãàíèçìå. Ó äèàáåòè÷åñêèõ æèâîòíûõ áðîìîêðèïòèí ñäâèãàåò ïèêè ñîäåðæàíèÿ ñåðîòîíèíà, ðåãóëÿòîðà ñåðîòîíèíåðãè÷åñêîé ñèñòåìû ìîçãà, è åãî îñíîâíîãî ìåòàáîëèòà 5-ãèäðîêñèèíäîëèëóêñóñíîé êèñëîòû íà 12 ÷ â òåìíûé ïåðèîä ñóòîê, ÷òî ïðèâîäèò ê ïîâûøåíèþ ñîäåðæàíèÿ ãèïîòàëàìè÷åñêîãî ñåðîòîíèíà è åãî ïðîèçâîäíûõ â íî÷íîå âðåìÿ äî çíà÷åíèé, íàáëþäàåìûõ ó çäîðîâûõ æèâîòíûõ, è íîðìàëèçóåò ôóíêöèîíèðîâàíèå íåéðîíàëüíîé ñåòè ìîçãà (Luo et al., 2000). Íàðÿäó ñ ÄÀÐ 2-ãî òèïà â óñëîâèÿõ ÑÄ íàáëþäàþòñÿ èçìåíåíèÿ ñòèìóëèðóþùèõ ÀÖ êàñêàäîâ, âêëþ÷àþùèõ â ñåáÿ ÄÀÐ 1-ãî òèïà, ñîïðÿæåííûõ ñ G-áåëêàìè ñòèìóëèðóþùåãî òèïà (Gs) (Kumar et al., 2010). Ñîâìåñòíîå ââåäåíèå àãîíèñòîâ ÄÀÐ 1-ãî è 2-ãî òèïîâ êðûñàì ñ ÑÄ1 è ìûøàì ëèíèè ob/ob ñ ÑÄ2 áîëåå ýôôåêòèâíî ïîäàâëÿåò àïïåòèò è ãèïåðôàãèþ, ÷åì ââåäåíèå òîëüêî îäíîãî àãîíèñòà ÄÀÐ 2-ãî òèïà (Bina, Cincotta, 2000; Kuo, 2006). Àíîðåêòè÷åñêèé ýôôåêò àãîíèñòîâ ÄÀÐ ñâÿçàí ñ èõ ñïîñîáíîñòüþ ê ñíèæåíèþ àêòèâíîñòè ãèïîòàëàìè÷åñêèõ íåéðîíîâ, êîòîðûå ðåãóëèðóþòñÿ íåéðîïåïòèäîì Y — âåùåñòâîì, ïîâûøàþùèì àïïåòèò. Ïðè ÑÄ óñèëèâàåòñÿ âûñâîáîæäåíèå íåéðîïåïòèäà Y è ïîâûøàåòñÿ ýêñïðåññèÿ ñâÿçûâàþùèõ åãî ðåöåïòîðîâ, âñëåäñòâèå ÷åãî ñíèæåíèå àêòèâíîñòè ãèïîòàëàìè÷åñêèõ íåéðîíîâ, âûçûâàåìîå àãîíèñòàìè ÄÀÐ 1-ãî è 2-ãî òèïîâ, íîðìàëèçóåò ïèùåâîå ïîâåäåíèå ó äèàáåòè÷åñêèõ æèâîòíûõ.  ñðàâíåíèè ñî çäîðîâûìè æèâîòíûìè ïîäàâëåíèå àïïåòèòà àãîíèñòàìè ÄÀÐ â óñëîâèÿõ ÑÄ âûðàæåíî â ìåíüøåé ñòåïåíè è òðåáóåò áîëåå âûñîêèõ èõ äîç, ÷òî, âåðîÿòíî, ñâÿçàíî ñ ïîâûøåííîé àêòèâíîñòüþ ãèïîòàëàìè÷åñêèõ íåéðîíîâ, îïîñðåäóþùèõ ýôôåêòû íåéðîïåïòèäà Y, è ñ îñëàáëåíèåì äîôàìèíåðãè÷åñêîé ñèñòåìû ìîçãà. Ëå÷åíèå èíñóëèíîì ïîëíîñòüþ âîññòàíàâëèâàåò ÷óâñòâèòåëüíîñòü ìîçãà äèàáåòè÷åñêèõ æèâîòíûõ ê àãîíèñòàì ÄÀÐ. Íàìè è äðóãèìè àâòîðàìè ïîêàçàíî, ÷òî èçìåíåíèÿ ôóíêöèîíèðîâàíèÿ äîôàìèíåðãè÷åñêîé ñèñòåìû ìîçãà ïðè ÑÄ ñâÿçàíû â îñíîâíîì ñ íà÷àëüíûìè åå êîìïîíåíòàìè — ÄÀÐ è Gi-áåëêàìè, ïðè÷åì â ðàçëè÷íûõ îòäåëàõ ìîçãà ýòè èçìåíåíèÿ ïðîÿâëÿþòñÿ ïî-ðàçíîìó (Øïàêîâ è äð., 2005, 2006, 2007à, 2007á; Kumar et al., 2010; Shpakov et al., 2012). Òàê, åùå â 1980-õ ãîäàõ áûëî îáíàðóæåíî, ÷òî â ñèíàïòîñîìàëüíûõ ìåìáðàíàõ ñòðèàòóìà êðûñ Ôóíêöèîíàëüíîå ñîñòîÿíèå ñèãíàëüíûõ ñèñòåì ìîçãà ïðè ñàõàðíîì äèàáåòå ñî ñòðåïòîçîòîöèíîâîé ìîäåëüþ ÑÄ1 â çíà÷èòåëüíîé ñòåïåíè ïîâûøàåòñÿ ñâÿçûâàíèå [3H]-ñïèïåðîíà, ñåëåêòèâíîãî àíòàãîíèñòà ÄÀÐ 2-ãî òèïà (Lozovsky et al., 1981; Trulson, Himmel, 1983). Äàëüíåéøèå èññëåäîâàíèÿ ïîêàçàëè, ÷òî â êîðå ìîçãà êðûñ ñî ñòðåïòîçîòîöèíîâûì ÑÄ1 ïîâûøàþòñÿ ýêñïðåññèÿ ÄÀÐ 1-ãî è 2-ãî òèïîâ è îáùåå ÷èñëî ÄÀÐ (Kumar et al., 2010).  ìîçæå÷êå íàáëþäàåòñÿ ñíèæåíèå ýêñïðåññèè ÄÀÐ 1-ãî òèïà è îáùåãî ñâÿçûâàíèÿ ÄÀÐ íà ôîíå íåçíà÷èòåëüíîãî ïîâûøåíèÿ ýêñïðåññèè ÄÀÐ 2-ãî òèïà, â ãèïîòàëàìóñå è ñòâîëå ìîçãà êðûñ ñ ÑÄ1 çíà÷èòåëüíî ñíèæàþòñÿ ýêñïðåññèÿ ÄÀÐ 2-ãî òèïà è èõ ïëîòíîñòü íà íåéðîíàëüíûõ êëåòêàõ (Shankar et al., 2007; Kumar et al., 2010). Ïîñêîëüêó ãèïîòàëàìóñ è ìîçãîâîé ñòâîë èãðàþò âàæíóþ ðîëü â êîíòðîëå óðîâíÿ ãëþêîçû è ðåãóëÿöèè ïèùåâîãî ïîâåäåíèÿ, èçìåíåíèå â íèõ àêòèâíîñòè ÄÀÐ ÿâëÿåòñÿ îäíîé èç ïðè÷èí ìåòàáîëè÷åñêèõ è ôóíêöèîíàëüíûõ íàðóøåíèé ïðè ÑÄ. Äðóãèì êîìïîíåíòîì äîôàìèíåðãè÷åñêîé ñèñòåìû ìîçãà, ôóíêöèè êîòîðîãî ñóùåñòâåííî ìåíÿþòñÿ ïðè ÑÄ, ÿâëÿþòñÿ Gi-áåëêè. Íàìè îáíàðóæåíî, ÷òî â êîðå ãîëîâíîãî ìîçãà è ñòðèàòóìå êðûñ ñ ÑÄ1 è íåîíàòàëüíîé ìîäåëüþ ÑÄ2 ÷óâñòâèòåëüíîñòü ÀÖ ê áðîìîêðèïòèíó ñíèæåíà (Øïàêîâ è äð., 2006, 2007à, 2007á). Íà ýòî óêàçûâàþò îñëàáëåíèå èíãèáèðóþùåãî ýôôåêòà áðîìîêðèïòèíà íà ñòèìóëèðîâàííóþ ôîðñêîëèíîì àêòèâíîñòü ÀÖ è ñíèæåíèå åãî ñòèìóëèðóþùåãî ýôôåêòà íà ÃÒÔ-ñâÿçûâàþùóþ ñïîñîáíîñòü Gi-áåëêîâ â ñèíàïòîñîìàëüíûõ ìåìáðàíàõ ìîçãà äèàáåòè÷åñêèõ êðûñ.  òî æå âðåìÿ ñâÿçûâàþùèå õàðàêòåðèñòèêè ÄÀÐ è êàòàëèòè÷åñêàÿ àêòèâíîñòü ôåðìåíòà ÀÖ â êîðå ãîëîâíîãî ìîçãà è ñòðèàòóìå êðûñ ñ îáîèìè òèïàìè ýêñïåðèìåíòàëüíîãî ÑÄ ìåíÿþòñÿ â íåçíà÷èòåëüíîé ñòåïåíè. Ýòî óêàçûâàåò íà òî, ÷òî îñëàáëåíèå ÷óâñòâèòåëüíîñòè ÀÖ ñèñòåìû ê äåéñòâèþ áðîìîêðèïòèíà ñâÿçàíî â îñíîâíîì ñî ñíèæåíèåì àêòèâíîñòè Gi-áåëêîâ. Ïîäòâåðæäåíèåì ýòîìó ÿâëÿþòñÿ ïîëó÷åííûå íàìè äàííûå î òîì, ÷òî ðåãóëÿòîðíûå ýôôåêòû äðóãèõ ãîðìîíîâ — ñîìàòîñòàòèíà, àãîíèñòîâ ñîìàòîñòàòèíîâûõ ðåöåïòîðîâ CH-275 è îêòðåîòèäà, à òàêæå 5-íîíèëîêñèòðèïòàìèíà è 5-ìåòîêñè-N,N-äèìåòèëòðèïòàìèíà, àãîíèñòîâ ñåðîòîíèíîâûõ ðåöåïòîðîâ (ÑÐ) 1-ãî òèïà, êîòîðûå, ïîäîáíî áðîìîêðèïòèíó, ÷åðåç ñîïðÿæåííûå ñ Gi-áåëêàìè ðåöåïòîðû âëèÿþò íà ñòèìóëèðîâàííóþ ôîðñêîëèíîì àêòèâíîñòü ÀÖ è ÃÒÔ-ñâÿçûâàþùóþ ñïîñîáíîñòü Gi-áåëêîâ, â ìîçãå äèàáåòè÷åñêèõ êðûñ òàêæå îñëàáëåíû (Øïàêîâ è äð., 2006, 2007à, 2007á; Shpakov et al., 2012). Çíà÷èòåëüíûé âêëàä â èçìåíåíèå àêòèâíîñòè äîôàìèíåðãè÷åñêîé ñèñòåìû ïðè ÑÄ âíîñèò ñíèæåíèå êîíöåíòðàöèè ÄÀ â ìîçãå âñëåäñòâèå ïîäàâëåíèÿ ýêñïðåññèè ãåíîâ, êîäèðóþùèõ ìåìáðàííûå òðàíñïîðòåðû ÄÀ (Carvelli et al., 2002; Garcia et al., 2005). Òðàíñïîðòåðû ÄÀ îáåñïå÷èâàþò îáðàòíûé çàõâàò íåéðîòðàíñìèòòåðà â ñèíàïòè÷åñêîé ùåëè è ïîñòóïëåíèå åãî â öèòîçîëü, ãäå îí íàêàïëèâàåòñÿ â âåçèêóëàõ è â äàëüíåéøåì âíîâü ñåêðåòèðóåòñÿ â ñèíàïòè÷åñêîå ïðîñòðàíñòâî. Ýêñïðåññèÿ ãåíîâ, êîäèðóþùèõ òðàíñïîðòåðû ÄÀ, êîíòðîëèðóåòñÿ ÷åðåç ñèãíàëüíûå ïóòè, âêëþ÷àþùèå â ñåáÿ ôîñôàòèäèëèíîçèòîë-3-êèíàçó (ÔÈ-3Ê) è Akt-êèíàçó, àêòèâíîñòü êîòîðûõ ðåãóëèðóåòñÿ èíñóëèíîì è ÈÔÐ-1.  óñëîâèÿõ ÑÄ íàáëþäàåòñÿ çíà÷èòåëüíîå îñëàáëåíèå ðåãóëÿòîðíîãî âëèÿíèÿ èíñóëèíà è ÈÔÐ-1 íà àêòèâíîñòü ÔÈ-3Ê è çàâèñèìûõ îò íåå ôåðìåíòîâ, â òîì ÷èñëå Akt-êèíàçû (Gelling et al., 2006). Ýòî ïðèâîäèò ê ñíèæåíèþ ýêñïðåññèè ãåíîâ, êîäèðóþùèõ òðàíñïîðòåðû ÄÀ, è ê ïîíèæåíèþ áàçàëüíîãî óðîâíÿ ÄÀ â íåéðîíàõ, ÷òî â íàèáîëüøåé ñòåïåíè âûðàæåíî ïðè ÑÄ1 â óñëîâèÿõ õðîíè÷åñêîé ãèïîèíñóëè- 461 íåìèè. Ïîêàçàíî, ÷òî â ãèïïîêàìïå êðûñ ñî ñòðåïòîçîòîöèíîâûì ÑÄ1 è êðûñ WBN/Kob ñî ñïîíòàííûì ÑÄ ñíèæàåòñÿ ÷èñëî òðàíñïîðòåðîâ ÄÀ, ÷òî âûçûâàåò íàðóøåíèå îáðàòíîãî çàõâàòà ÄÀ â ñèíàïòè÷åñêîì ïðîñòðàíñòâå è çíà÷èòåëüíî ñíèæàåò åãî êîíöåíòðàöèþ â ìîçãå (Yamato et al., 2004). Îáðàáîòêà èíñóëèíîì âîññòàíàâëèâàåò ñèãíàëüíûå êàñêàäû, ðåãóëèðóþùèå ýêñïðåññèþ ãåíîâ, êîäèðóþùèõ òðàíñïîðòåðû ÄÀ, ïîâûøàåò ÷èñëî àêòèâíûõ òðàíñïîðòåðîâ íà ïîâåðõíîñòè ñèíàïòîñîìàëüíûõ ìåìáðàí è íîðìàëèçóåò óðîâåíü ÄÀ â ìîçãå. Ñåðîòîíèíåðãè÷åñêàÿ ñèãíàëüíàÿ ñèñòåìà ×óâñòâèòåëüíûå ê ñåðîòîíèíó ñèãíàëüíûå ñèñòåìû ìîçãà âîâëå÷åíû â ðåãóëÿöèþ ïèùåâîãî ïîâåäåíèÿ, äâèãàòåëüíîé àêòèâíîñòè, áîëåâîé ÷óâñòâèòåëüíîñòè, ðåïðîäóêòèâíîãî ïîâåäåíèÿ, ôóíêöèé ñåðäå÷íî-ñîñóäèñòîé ñèñòåìû è ïîäæåëóäî÷íîé æåëåçû. Èçìåíåíèÿ àêòèâíîñòè ñåðîòîíèíåðãè÷åñêîé ñèñòåìû ìîçãà ïðè ÑÄ ïðèâîäÿò ê íàðóøåíèþ ñèíàïòè÷åñêîé ïëàñòè÷íîñòè, äèñáàëàíñó íåéðîíàëüíûõ ñâÿçåé è êàê ñëåäñòâèå — ê ðàçâèòèþ íåéðîäåãåíåðàòèâíûõ çàáîëåâàíèé. Ïðè÷èíàìè, âûçûâàþùèìè ýòè ïàòîëîãè÷åñêèå èçìåíåíèÿ, ÿâëÿþòñÿ íàðóøåíèå ñèíòåçà ñåðîòîíèíà, åãî îáðàòíîãî çàõâàòà è òðàíñïîðòà íåéðîíàëüíûìè êëåòêàìè, à òàêæå äèñôóíêöèè â ñåðîòîíèíîâîé ñèãíàëüíîé ñèñòåìå, âêëþ÷àþùàÿ â ñåáÿ ðàçëè÷íûå òèïû ÑÐ, êîòîðûå ÷åðåç G-áåëêè ñîïðÿæåíû ñ ÀÖ è ôîñôîèíîçèòèäçàâèñèìîé ôîñôîëèïàçîé Ñ (ÔËÑ). Ïðè ýòîì ÑÐ 1-ãî òèïà èíãèáèðóþò ÀÖ ÷åðåç Gi-áåëêè, ÑÐ 4, 6 è 7-ãî òèïîâ ñòèìóëèðóþò ÀÖ ÷åðåç Gs-áåëêè, â òî âðåìÿ êàê ÷åðåç ñîïðÿæåííûå ñ Gq/11-áåëêàìè ÑÐ 2-ãî òèïà îñóùåñòâëÿåòñÿ ðåãóëÿöèÿ ÔËÑ è Ca2+-çàâèñèìûõ ñèãíàëüíûõ ïóòåé (Pytliak et al., 2011). Ñåëåêòèâíûå èíãèáèòîðû îáðàòíîãî çàõâàòà ñåðîòîíèíà (ÑÈÎÇÑ) øèðîêî ïðèìåíÿþòñÿ äëÿ ëå÷åíèÿ äåïðåññèâíûõ ñîñòîÿíèé, êîòîðûå ÷àñòî âñòðå÷àþòñÿ ó ïàöèåíòîâ ñ ÑÄ. Ïðèìåíåíèå ÑÈÎÇÑ ïðè ÑÄ íå òîëüêî óëó÷øàåò èõ ïñèõè÷åñêîå ñîñòîÿíèå, íî è îêàçûâàþò âûðàæåííûé òåðàïåâòè÷åñêèé ýôôåêò íà òå÷åíèå îñíîâíîãî çàáîëåâàíèÿ (Goodnick, 2001; Lustman, Clouse, 2005). ÑÈÎÇÑ íîðìàëèçóþò óðîâåíü ãëþêîçû, ïîíèæàþò óðîâåíü ãëèêîçèëèðîâàííîãî ãåìîãëîáèíà, âûçûâàþò ñíèæåíèå âåñà è ïîâûøàþò ÷óâñòâèòåëüíîñòü òêàíåé ê èíñóëèíó. Íàðÿäó ñ ýòèì, âîññòàíàâëèâàÿ ôóíêöèîíàëüíóþ àêòèâíîñòü ñåðîòîíèíåðãè÷åñêîé ñèñòåìû ìîçãà, ÑÈÎÇÑ óñòðàíÿþò êîãíèòèâíûå äèñôóíêöèè, âûçûâàåìûå ÑÄ (Van Tilburg et al., 2001). Îáíàðóæåíî, ÷òî ëå÷åíèå äèàáåòè÷åñêèõ ïàöèåíòîâ ñ äåïðåññèåé ôëóîêñåòèíîì (ÑÈÎÇÑ) óñòðàíÿåò ó íèõ äåïðåññèâíûå ñîñòîÿíèÿ è ïîâûøàåò ÷óâñòâèòåëüíîñòü ìîçãà è ïåðèôåðè÷åñêèõ òêàíåé ê èíñóëèíó (Lustman et al., 2000). Òàêèì îáðàçîì, ñ ïîìîùüþ ÑÈÎÇÑ ìîæíî îïòèìèçèðîâàòü ìåòàáîëè÷åñêèé êîíòðîëü ó ïàöèåíòîâ ñ ÑÄ (Zhou et al., 2007).  êîíöå 1970-õ ãîäîâ áûëî îáíàðóæåíî, ÷òî â ìîçãå êðûñ ñ ÑÄ1 ñèëüíî ñíèæåí óðîâåíü òðèïòîôàíà, ìåòàáîëè÷åñêîãî ïðåäøåñòâåííèêà ñåðîòîíèíà (Macrenzie, Trulson, 1978).  äàëüíåéøåì áûëî óñòàíîâëåíî, ÷òî êîíöåíòðàöèÿ ñåðîòîíèíà è 5-ãèäðîêñèèíäîëóêñóñíîé êèñëîòû, îñíîâíîãî ìåòàáîëèòà ñåðîòîíèíà, à òàêæå ïðåâðàùåíèå 5-ãèäðîêñèèíäîëóêñóñíîé êèñëîòû â ñåðîòîíèí â çíà÷èòåëüíîé ñòåïåíè ñíèæåíû â ðàçëè÷íûõ îòäåëàõ ìîçãà ó êðûñ ñ ïðîäîëæèòåëüíûì ÑÄ1 è â ãèïïîêàìïå êðûñ ñî ñïîíòàííûì ÑÄ (Sandirini et al., 1997; Jackson, Paulose, 1999; Yamato et al., 2004). Îñíîâíûìè ïðè÷èíàìè ñíèæå- 462 À. Î. Øïàêîâ íèÿ óðîâíÿ ñåðîòîíèíà ÿâëÿþòñÿ ñíèæåíèå ïîñòóïëåíèÿ òðèïòîôàíà â ìîçã è èíãèáèðîâàíèå àêòèâíîñòè òðèïòîôàí-5-ãèäðîêñèëàçû 2 — ôåðìåíòà, ëèìèòèðóþùåãî ñêîðîñòü áèîñèíòåçà ñåðîòîíèíà (Mackenzie, Trulson, 1978; Yamato et al., 2004; Herrera et al., 2005). Èçâåñòíî, ÷òî èíñóëèí ñíèæàåò êîíöåíòðàöèþ â ïëàçìå êðîâè àëèôàòè÷åñêèõ è àðîìàòè÷åñêèõ àìèíîêèñëîò (âàëèíà, ëåéöèíà, èçîëåéöèíà, ôåíèëàëàíèíà, òèðîçèíà), êîòîðûå êîíêóðèðóþò ñ òðèïòîôàíîì çà òðàíñïîðò â ìîçã. Ïîñêîëüêó â óñëîâèÿõ ÑÄ êîíöåíòðàöèÿ íåéòðàëüíûõ àìèíîêèñëîò èìååò òåíäåíöèþ ê çíà÷èòåëüíîìó âîçðàñòàíèþ, ýòî ïðèâîäèò ê èíãèáèðîâàíèþ ïîñòóïëåíèÿ òðèïòîôàíà â ìîçã, âûçûâàÿ äåôèöèò ñåðîòîíèíà. Ó ïàöèåíòîâ ñ ÑÄ è ïðåääèàáåòè÷åñêèìè ñîñòîÿíèÿìè ñíèæàåòñÿ íå òîëüêî êîíöåíòðàöèÿ îáùåãî òðèïòîôàíà, íî è óðîâåíü ñâîáîäíîãî òðèïòîôàíà è ñîîòíîøåíèå ñâîáîäíîãî è îáùåãî òðèïòîôàíà, ÷òî â êîíå÷íîì èòîãå âëèÿåò íà áèîäîñòóïíîñòü ýòîé àìèíîêèñëîòû (Herrera et al., 2005; Manjarrez et al., 2006; Herrera-Marquez et al., 2011). Êîëåáàíèÿ êîíöåíòðàöèè ñåðîòîíèíà è 5-ãèäðîêñèèíäîëóêñóñíîé êèñëîòû â ìîçãå ïðè ÑÄ ïðèâîäÿò ê èçìåíåíèþ ÷èñëà ÑÐ è èõ àôôèííîñòè ê ñåðîòîíèíó. Ýòè èçìåíåíèÿ ÿâëÿþòñÿ ñïåöèôè÷íûìè êàê â îòíîøåíèè îòäåëîâ ìîçãà, òàê è â îòíîøåíèè òèïîâ ÑÐ è ñèëüíî çàâèñÿò îò ïðîäîëæèòåëüíîñòè ÑÄ, âûðàæåííîñòè ãèïåðãëèêåìèè è ÷àñòîòû ãèïîãëèêåìè÷åñêèõ ýïèçîäîâ.  áîëüøåé ñòåïåíè ïðè ÑÄ ìåíÿþòñÿ ÑÐ 2-ãî òèïà, êîòîðûå ñîïðÿæåíû ñ ÔËÑ ÷åðåç Gq-áåëîê, è ÑÐ 1-ãî òèïà, êîòîðûå ñîïðÿæåíû ñ ÀÖ ÷åðåç Gi-áåëîê. Îáíàðóæåíî, ÷òî â ëîáíûõ äîëÿõ è ñòâîëå ìîçãà êðûñ ñ ÑÄ1 ïëîòíîñòü ÑÐ 2À-ïîäòèïà ñèëüíî ïîâûøåíà, â òî âðåìÿ êàê â êîðå áîëüøèõ ïîëóøàðèé îíà ïðàêòè÷åñêè íå ìåíÿåòñÿ (Sandrini et al., 1997; Jackson, Paulose, 1999). Àôôèííîñòü ÑÐ 2À-ïîäòèïà ê ñåëåêòèâíûì àãîíèñòàì ïîâûøàåòñÿ â êîðå áîëüøèõ ïîëóøàðèé, íå ìåíÿåòñÿ â ëîáíîé äîëå è ëèøü íåçíà÷èòåëüíî ñíèæàåòñÿ â ñòâîëå ìîçãà. Íåñìîòðÿ íà òî ÷òî áîëüøèíñòâî ýòèõ èçìåíåíèé íîñèò êîìïåíñàòîðíûé õàðàêòåð è íàïðàâëåíî íà ïîâûøåíèå ýôôåêòèâíîñòè âîñïðèÿòèÿ ñåðîòîíèíîâîãî ñèãíàëà â óñëîâèÿõ äåôèöèòà ãîðìîíà, óæå ÷åðåç 1 íåä ïîñëå îáðàáîòêè êðûñ ñòðåïòîçîòîöèíîì ôèçèîëîãè÷åñêèå ýôôåêòû 1-(2,5-äèìåòîêñè-4-èîäôåíèë)-2-àìèíîïðîïàíà (DOI), ñåëåêòèâíîãî àãîíèñòà ÑÐ 2À-ïîäòèïà, ñèëüíî îñëàáëÿþòñÿ (Li, France, 2008). Ñõîäíàÿ êàðòèíà íàáëþäàåòñÿ è äëÿ ÑÐ 1-ãî òèïà. ×èñëî ýòèõ ðåöåïòîðîâ è èõ àôôèííîñòü ê àãîíèñòàì â ìîçãå êðûñ ñ ÑÄ1 íå ìåíÿþòñÿ èëè íåñêîëüêî ïîâûøåíû â ñðàâíåíèè ñ êîíòðîëüíûìè æèâîòíûìè, â òî âðåìÿ êàê ðåãóëÿòîðíûå ýôôåêòû ñóìàòðèïòàíà, àãîíèñòà ÑÐ 1-ãî òèïà, 8-ãèäðîêñè-2-(äè-í-ïðîïèëàìèíî)òåòðàëèíà (8-OH-DPAT), ñåëåêòèâíîãî àãîíèñòà ÑÐ 1À-ïîäòèïà, è 5-íîíèëîêñèòðèïòàìèíà, ñåëåêòèâíîãî àãîíèñòà ÑÐ 1B-ïîäòèïà, ñíèæåíû (Øïàêîâ è äð., 2007à; Li, France, 2008; Shpakov et al., 2012). Îñíîâíàÿ ïðè÷èíà ñíèæåíèÿ àêòèâíîñòè ñèãíàëüíûõ ïóòåé, âêëþ÷àþùèõ â ñåáÿ ÑÐ 1-ãî òèïà, ñîñòîèò â îñëàáëåíèè ôóíêöèè Gi-áåëêîâ, ïîñêîëüêó, êàê îòìå÷àëîñü âûøå, â ìîçãå äèàáåòè÷åñêèõ æèâîòíûõ îñëàáëåíû è äðóãèå ñèãíàëüíûå êàñêàäû, âêëþ÷àþùèå â ñåáÿ Gi-áåëêè.  òî æå âðåìÿ ìîëåêóëÿðíûå ìåõàíèçìû, ëåæàùèå â îñíîâå îñëàáëåíèÿ ÷óâñòâèòåëüíîñòè ñåðîòîíèíåðãè÷åñêîé ñèñòåìû ìîçãà ê àãîíèñòàì ÑÐ 2À-ïîäòèïà, ïîêà íå èçó÷åíû, òåì áîëåå ÷òî ýêñïðåññèÿ è ôóíêöèîíàëüíàÿ àêòèâíîñòü Gq-áåëêîâ â ìîçãå ïðè ÑÄ ñóùåñòâåííî íå ìåíÿþòñÿ. Ïðåäïîëàãàåòñÿ, ÷òî ñíèæåíèå àêòèâíîñòè ñèãíàëüíûõ ïóòåé, âêëþ÷àþùèõ â ñåáÿ ÑÐ 2À-ïîäòèïà, ñâÿçàíî ñ íèæåëåæàùèìè ýôôåêòîðíûìè áåëêàìè. Ïîñêîëüêó èõ àêòèâàöèÿ ïðèâîäèò ê ñíèæåíèþ ñèíòåçà è ñåêðåöèè èíñóëèíà b-êëåòêàìè ïîäæåëóäî÷íîé æåëåçû è óñóãóáëÿåò èíñóëèíîâóþ íåäîñòàòî÷íîñòü, â óñëîâèÿõ ÑÄ1 çàïóñêàþòñÿ êîìïåíñàòîðíûå ìåõàíèçìû, ñíèæàþùèå èõ àêòèâíîñòü, ÷òî âûçûâàåò îñëàáëåíèå âêëþ÷àþùèõ ýòè áåëêè êàñêàäîâ, â òîì ÷èñëå àêòèâèðóåìûõ àãîíèñòàìè ÑÐ 2À-ïîäòèïà (Li, France, 2008). Îáðàáîòêà èíñóëèíîì âîçâðàùàåò àêòèâíîñòü ÑÐ 1-ãî òèïà è 2À-ïîäòèïà ê íîðìå (Bhattacharya, Saraswati, 1991; Li, France, 2008). Ñâÿçûâàþùèå õàðàêòåðèñòèêè è ÷èñëî ÑÐ, ñòèìóëèðóþùèì ñïîñîáîì ñîïðÿæåííûõ ñ ÀÖ, â óñëîâèÿõ ÑÄ ñóùåñòâåííî íå ìåíÿþòñÿ. Íàìè îáíàðóæåíî, ÷òî ñòèìóëèðóþùèå ýôôåêòû ñåðîòîíèíà è EMD-386088, ñåëåêòèâíîãî àãîíèñòà ñîïðÿæåííîãî ñ Gs-áåëêàìè ÑÐ 6-ãî òèïà, íà ÀÖ è ÃÒÔ-ñâÿçûâàíèå Gs-áåëêîâ â ìîçãå çäîðîâûõ êðûñ è êðûñ ñ ýêñïåðèìåíòàëüíûì ÑÄ1 è ÑÄ2 ïðàêòè÷åñêè íå ðàçëè÷àþòñÿ (Shpakov et al., 2012). Ýòî ñîãëàñóåòñÿ ñ òåì ôàêòîì, ÷òî ñèãíàëüíûå ïóòè, âêëþ÷àþùèõ â ñåáÿ Gs-áåëêè, â ìîçãå äèàáåòè÷åñêèõ æèâîòíûõ ìåíÿþòñÿ â ñóùåñòâåííî ìåíüøåé ñòåïåíè, ÷åì òàêîâûå, ñîïðÿæåííûå ñ Gi-áåëêàìè (Øïàêîâ, 2005, 2006, 2007à). Èçìåíåíèÿ àêòèâíîñòè ñåðîòîíèíåðãè÷åñêîé ñèñòåìû ìîçãà ìîãóò áûòü êàê ñëåäñòâèåì ÑÄ, òàê è åãî ïðè÷èíîé, âûçûâàÿ ãèïåðôàãèþ è äðóãèå íàðóøåíèÿ ïèùåâîãî ïîâåäåíèÿ, ïðèâîäÿùèå ê îæèðåíèþ, èíñóëèíîâîé ðåçèñòåíòíîñòè è â êîíå÷íîì èòîãå ê ÑÄ2 (Heisler et al., 2002). Êëþ÷åâóþ ðîëü çäåñü èãðàþò ñîïðÿæåííûå ñ Gq-áåëêàìè ÑÐ 2Ñ-ïîäòèïà, êîíòðîëèðóþùèå ìåëàíîêîðòèíîâóþ ñèãíàëüíóþ ñèñòåìó ìîçãà, êîòîðàÿ âêëþ÷àåò â ñåáÿ ìåëàíîêîðòèíîâûå ðåöåïòîðû 3-ãî è 4-ãî òèïîâ (Zhou et al., 2007; Nonogaki et al., 2008). Íåîáõîäèìî îòìåòèòü, ÷òî êàê ÑÐ 2Ñ-ïîäòèïà, òàê è ìåëàíîêîðòèíîâûå ðåöåïòîðû ëîêàëèçîâàíû â íåéðîíàõ äóãîîáðàçíîãî ÿäðà ãèïîòàëàìóñà, ÷óâñòâèòåëüíûõ ê ïðî-îïèîìåëàíîêîðòèíó. Ýòè íåéðîíû ÿâëÿþòñÿ ïîòåíöèàëüíîé ìèøåíüþ äëÿ àãîíèñòîâ ÑÐ 2Ñ-ïîäòèïà, ïîñêîëüêó íåïîñðåäñòâåííî êîíòàêòèðóþò ñ íåéðîíàìè çàäíåãî ÿäðà øâà ñòâîëà ìîçãà, êîòîðûå ñåêðåòèðóþò ñåðîòîíèí è ôóíêöèîíàëüíî ñâÿçàíû ñ îáëàñòÿìè ìîçãà, êîíòðîëèðóþùèìè ýíåðãåòè÷åñêèé áàëàíñ îðãàíèçìà. Òàêèì îáðàçîì, ñåðîòîíèí è àãîíèñòû ÑÐ 2Ñ-ïîäòèïà àêòèâèðóþò ñåðîòîíèíåðãè÷åñêóþ ñèñòåìó â íåéðîíàõ äóãîîáðàçíîãî ÿäðà ãèïîòàëàìóñà, àêòèâèðóþò ìåëàíîêîðòèíîâóþ ñèãíàëüíóþ ñèñòåìó, ïîâûøàþò ÷óâñòâèòåëüíîñòü ïåðèôåðè÷åñêèõ òêàíåé ê ãëþêîçå, ñíèæàþò óðîâåíü èíñóëèíà è, òàêèì îáðàçîì, ïðåäîòâðàùàþò ðàçâèòèå ìåòàáîëè÷åñêîãî ñèíäðîìà è ÑÄ2. Âàæíî ïîä÷åðêíóòü, ÷òî ïðè ÑÄ óëó÷øåíèå ïîêàçàòåëåé óãëåâîäíîãî îáìåíà îòìå÷åíî ïðè èñïîëüçîâàíèè î÷åíü íèçêèõ êîíöåíòðàöèé àãîíèñòîâ ÑÐ 2Ñ-ïîäòèïà, êîòîðûå ïðàêòè÷åñêè íå âëèÿþò íà ïèùåâîå ïîâåäåíèå, ýíåðãåòè÷åñêèé áàëàíñ è äâèãàòåëüíóþ àêòèâíîñòü äèàáåòè÷åñêèõ æèâîòíûõ (Zhou et al., 2007).  ïîëüçó òåñíîé âçàèìîñâÿçè ìåæäó ôóíêöèîíèðîâàíèåì ÑÐ 2Ñ-ïîäòèïà è ðàçâèòèåì ÑÄ2 ñâèäåòåëüñòâóþò ðåçóëüòàòû ãåíåòè÷åñêèõ èññëåäîâàíèé. Ó ìûøåé, íîêàóòíûõ ïî ãåíó, êîäèðóþùåìó ÑÐ 2Ñ-ïîäòèïà, ðàçâèâàþòñÿ èíñóëèíîâàÿ ðåçèñòåíòíîñòü è ÑÄ2 ñ ñèëüíî âûðàæåííûìè ãèïåðôàãèåé è îæèðåíèåì (Nonogaki et al., 2008). Àêòèâàöèÿ ÑÐ 1-ãî òèïà ì-õëîðôåíèëïèïåðàçèíîì, ñìåøàííûì àãîíèñòîì ÑÐ 1B- è 2Ñ-ïîäòèïîâ, ïðèâîäèò ê ñíèæåíèþ àïïåòèòà ó ìûøåé, ëèøåííûõ ÑÐ 2Ñ-ïîäòèïà, è ÷àñòè÷íî âîññòàíàâëèâàåò ÷óâñòâèòåëüíîñòü òêàíåé ê èíñóëèíó. Ýòî ìîæåò ñâèäåòåëüñòâîâàòü â ïîëüçó âçàèìîäåéñòâèÿ ìåæäó ñèãíàëüíûìè ïóòÿìè, êîòîðûå âêëþ÷àþò Ôóíêöèîíàëüíîå ñîñòîÿíèå ñèãíàëüíûõ ñèñòåì ìîçãà ïðè ñàõàðíîì äèàáåòå â ñåáÿ ÑÐ 1-ãî è 2-ãî òèïîâ è ìåëàíîêîðòèíîâûå ðåöåïòîðû è îòâåòñòâåííû çà ïèùåâîå ïîâåäåíèå. Îáíàðóæåíî òàêæå, ÷òî ìóòàöèè â ïðîìîòîðíîé îáëàñòè ãåíà, êîäèðóþùåãî ÑÐ 2Ñ-ïîäòèïà ÷åëîâåêà, ïðåäñòàâëÿþùèå ñîáîé îäèíî÷íûå çàìåùåíèÿ íóêëåîòèäîâ (G D A â ïîçèöèè –995, C D T â ïîçèöèè –759, G D C â ïîçèöèè –697) è ïîëèìîðôèçì äèíóêëåîòèäíîãî ïîâòîðà (GT)n, ñ âûñîêîé ÷àñòîòîé âñòðå÷àþòñÿ ó ïàöèåíòîâ ñ ÑÄ2 (Yuan et al., 2000). Àäðåíåðãè÷åñêàÿ ñèãíàëüíàÿ ñèñòåìà Íîðàäðåíàëèí, àäðåíàëèí è èõ àíàëîãè, äåéñòâóþùèå ÷åðåç ðàçëè÷íûå òèïû ÀÐ, àêòèâèðóþò êàê ïðåñèíàïòè÷åñêèå, òàê è ïîñòñèíàïòè÷åñêèå ÀÐ â öåíòðàëüíûõ ñèíàïñàõ è ðåãóëèðóþò, òàêèì îáðàçîì, êðàòêîâðåìåííóþ è äîëãîâðåìåííóþ ïàìÿòü, ïîâåäåí÷åñêèå ðåàêöèè è äðóãèå íåéðîôèçèîëîãè÷åñêèå ïðîöåññû. Ñâÿçûâàíèå íîðàäðåíàëèíà è àäðåíàëèíà ñ ÀÐ ïðèâîäèò ê èíãèáèðîâàíèþ (b2-ÀÐ) èëè ñòèìóëÿöèè (b-ÀÐ) ÀÖ, âûçûâàÿ ñîîòâåòñòâåííî ñíèæåíèå èëè ïîâûøåíèå óðîâíÿ âíóòðèêëåòî÷íîãî öÀÌÔ, à òàêæå ê ñòèìóëÿöèè ÔËÑ (a1-ÀÐ), ðåçóëüòàòîì ÷åãî ÿâëÿþòñÿ ñèíòåç ôîñôàòèäèëèíîçèòîë-3,4,5-òðèôîñôàòà è äèàöèëãëèöåðèíà è ïîâûøåíèå êîíöåíòðàöèè âíóòðèêëåòî÷íîãî Ca2+ (Civantos Calzada, Aleixandre de Artinano, 2001). Âñëåäñòâèå ýòîãî ïîâûøàåòñÿ ñïîñîáíîñòü ñèíàïñîâ ê ôóíêöèîíàëüíûì è ìîðôîëîãè÷åñêèì ïåðåñòðîéêàì â ïðîöåññå ñèíàïòè÷åñêîé àêòèâíîñòè, ÷òî ïîçèòèâíî âëèÿåò íà ïðîöåññû çàïîìèíàíèÿ è õðàíåíèÿ èíôîðìàöèè (Tully, Bolshakov, 2010). Òàêèì îáðàçîì, íàðóøåíèÿ, âîçíèêàþùèå â ñèãíàëüíûõ ïóòÿõ ìîçãà, ðåãóëèðóåìûõ ëèãàíäàìè ÀÐ, ìîãóò ïðèâîäèòü ê êîãíèòèâíûì äèñôóíêöèÿì, äåïðåññèâíûì ñîñòîÿíèÿì è ãèïåðàêòèâíîñòè.  óñëîâèÿõ ÑÄ âûÿâëåíû èçìåíåíèÿ â ýêñïðåññèè íà÷àëüíîãî, ðåöåïòîðíîãî, êîìïîíåíòà àäðåíåðãè÷åñêîé ñèãíàëüíîé ñèñòåìû ìîçãà, êîòîðûå, êàê è â ñëó÷àå ðåöåïòîðîâ äðóãèõ áèîãåííûõ àìèíîâ, ÿâëÿþòñÿ ñïåöèôè÷íûìè â îòíîøåíèè êàê òèïîâ ÀÐ, òàê è îòäåëîâ ìîçãà. Ïîêàçàíî, ÷òî ïëîòíîñòü a1- è a2-ÀÐ âî ôðîíòàëüíîé êîðå, îáëàñòè ïåðåãîðîäêè ìîçãà, ìèíäàëåâèäíîì òåëå, ãèïîòàëàìóñå è ïðîäîëãîâàòîì ìîçãå ìûøåé db/db è â ýïèôèçå êðûñ ëèíèè Goto-Kakizaki, äëÿ êîòîðûõ õàðàêòåðíû èíñóëèíîâàÿ ðåçèñòåíòíîñòü è äðóãèå ïðèçíàêè ÑÄ2, ñèëüíî ïîâûøåíà â ñðàâíåíèè ñ êîíòðîëåì (Garris, 1990; Bach et al., 2010). Ýòî ïîâûøåíèå òåì áîëüøå, ÷åì áîëåå âûðàæåíû ìåòàáîëè÷åñêèå íàðóøåíèÿ, âûçâàííûå ÑÄ. Óâåëè÷åíèå ÷èñëà a1- è a2-ÀÐ ðåöåïòîðîâ íå ÿâëÿåòñÿ êîìïåíñàòîðíîé ðåàêöèåé íà óìåíüøåíèå êîíöåíòðàöèè íîðàäðåíàëèíà, ñîäåðæàíèå êîòîðîãî â áîëüøèíñòâå îòäåëîâ ìîçãà ïîâûøåíî (Garris, 1990). Íà ôîíå ïîâûøåíèÿ ïëîòíîñòè a-ÀÐ ÷èñëî è ôóíêöèîíàëüíàÿ àêòèâíîñòü b-ÀÐ, íàïðîòèâ, ñíèæàþòñÿ, ÷òî óñèëèâàåò äèñáàëàíñ ìåæäó àäðåíåðãè÷åñêèìè ñèãíàëüíûìè êàñêàäàìè â ìîçãå ïðè ÑÄ2. Ó êðûñ ñ íåîíàòàëüíûì ÑÄ2 ïðîäîëæèòåëüíîñòüþ 80 è 180 ñóò íå âûÿâëåíî ñóùåñòâåííûõ èçìåíåíèé â ñâÿçûâàþùèõ õàðàêòåðèñòèêàõ b-ÀÐ è ÷óâñòâèòåëüíîñòè ÀÖ ñèñòåìû ê èçîïðîòåðåíîëó, ñåëåêòèâíîìó àãîíèñòó b-ÀÐ (Øïàêîâ è äð., 2007à; Shpakov et al., 2012). Îäíàêî ïðè óâåëè÷åíèè ïðîäîëæèòåëüíîñòè ÑÄ äî 280 ñóò íàáëþäàëîñü çàìåòíîå ñíèæåíèå ðåãóëÿòîðíûõ ýôôåêòîâ èçîïðîòåðåíîëà íà ÀÖ è Gs-áåëêè, õîòÿ ÷èñëî è àôôèííîñòü b-ÀÐ ê àãîíèñòàì ïðè ýòîì ìåíÿëèñü íåçíà÷èòåëüíî. 463  ñòâîëå ìîçãà êðûñ ñ ÑÄ1 íàáëþäàåòñÿ îñëàáëåíèå ôóíêöèîíàëüíîé àêòèâíîñòè a2-ÀÐ, ÷òî âûðàæàåòñÿ â ñíèæåíèè ÷èñëà ðåöåïòîðîâ è èõ àôôèííîñòè ê ñåëåêòèâíûì àãîíèñòàì (Padayatti, Paulose, 1999).  òî æå âðåìÿ â ñòâîëå ìîçãà, ãèïîòàëàìóñå, òàëàìóñå è ìèíäàëåâèäíîì òåëå ó æèâîòíûõ ñ ÑÄ1 íàáëþäàåòñÿ ïîâûøåíèå ÷èñëà b1-ÀÐ, à òàêæå ñîäåðæàíèÿ àäðåíàëèíà è ñêîðîñòè ïðåâðàùåíèÿ íîðàäðåíàëèíà â àäðåíàëèí (Bitar, DeSouza, 1990; Padayatti, Paulose, 1999). Òàêèì îáðàçîì, â óñëîâèÿõ äåôèöèòà èíñóëèíà ïðè ÑÄ1 îñëàáëÿþòñÿ ñèãíàëüíûå ïóòè, âêëþ÷àþùèå â ñåáÿ a2-ÀÐ, ñîïðÿæåííûå ñ ÀÖ ÷åðåç Gi-áåëêè, è óñèëèâàþòñÿ ïóòè, âêëþ÷àþùèå â ñåáÿ b-ÀÐ, ñîïðÿæåííûå ñ ÀÖ ÷åðåç Gs-áåëêè, ÷òî â êîíå÷íîì èòîãå ïðèâîäèò ê óñèëåíèþ ñòèìóëèðóþùèõ ÀÖ êàñêàäîâ. Ýòè èçìåíåíèÿ ñóùåñòâåííî îòëè÷àþòñÿ îò òàêîâûõ, íàáëþäàåìûõ ïðè ÑÄ2, è, âåðîÿòíåå âñåãî, âûçâàíû èíñóëèíîâîé íåäîñòàòî÷íîñòüþ, ïîñêîëüêó ëå÷åíèå æèâîòíûõ èíñóëèíîì ïîëíîñòüþ âîññòàíàâëèâàåò ôóíêöèîíàëüíóþ àêòèâíîñòü àäðåíåðãè÷åñêîé ñèñòåìû (Padayatti, Paulose, 1999). Ñëåäóåò ðàçëè÷àòü èçìåíåíèÿ â àêòèâíîñòè àäðåíåðãè÷åñêîé ñèñòåìû â íåéðîíàëüíûõ êëåòêàõ è â ñòåíêàõ ìèêðîñîñóäîâ ìîçãà. Ìîðôîëîãè÷åñêèå è áèîõèìè÷åñêèå èçìåíåíèÿ ìèêðîñîñóäîâ, ôóíêöèîíèðîâàíèå êîòîðûõ êîíòðîëèðóåòñÿ ÷åðåç ðàçëè÷íûå ñèãíàëüíûå ñèñòåìû, â ïåðâóþ î÷åðåäü ÷åðåç àäðåíåðãè÷åñêóþ ñèñòåìó, âûçûâàþò íàðóøåíèÿ ìèêðîöèðêóëÿöèè â ìîçãå, ÷òî ïðèâîäèò ê ãèïîêñèè, ãèáåëè íåéðîíîâ è ðàçâèòèþ íåéðîäåãåíåðàòèâíûõ çàáîëåâàíèé. Ïîêàçàíî, ÷òî ÷èñëî b-ÀÐ â ìèêðîñîñóäàõ ìîçãà êðûñ ëèíèè fa/fa, ñòðàäàþùèõ îæèðåíèåì, è êðûñ ñ ÑÄ1 ñóùåñòâåííî ñíèæåíî (Magnoni et al., 1984).  ìèêðîñîñóäàõ ìîçãà äèàáåòè÷åñêèõ êðûñ â çíà÷èòåëüíîé ñòåïåíè îñëàáëåíî ñòèìóëèðóþùåå âëèÿíèå èçîïðîòåðåíîëà íà àêòèâíîñòü ÀÖ è öÀÌÔ-çàâèñèìûå ñèãíàëüíûå ïóòè (Mooradian, Scarpace, 1992). Òàêèì îáðàçîì, îñëàáëåíèå àêòèâíîñòè b-ÀÐ â ìèêðîñîñóäàõ ìîçãà ìîæåò âíîñèòü ñóùåñòâåííûé âêëàä â ðàçâèòèå íåéðîäåãåíåðàòèâíûõ èçìåíåíèé ïðè îáîèõ òèïàõ ÑÄ, íåñìîòðÿ íà òî ÷òî â íåéðîíàëüíûõ êëåòêàõ ïðè ÑÄ1 íàáëþäàåòñÿ óñèëåíèå ñîïðÿæåííûõ ñ b-ÀÐ ñèãíàëüíûõ ïóòåé, à ïðè ÑÄ2 ýòè ïóòè ìåíÿþòñÿ â ìåíüøåé ñòåïåíè. Õîëèíåðãè÷åñêàÿ ñèãíàëüíàÿ ñèñòåìà  ìîçãå àöåòèëõîëèí (ÀÕ) âûïîëíÿåò ôóíêöèè íåéðîìîäóëÿòîðà è íåéðîòðàíñìèòòåðà, êîòîðûé ÷åðåç ìåòàáîòðîïíûå ìóñêàðèíîâûå àöåòèëõîëèíîâûå ðåöåïòîðû (ÌÀÕÐ) ðåãóëèðóåò ñëîæíîîðãàíèçîâàííóþ ñåòü ñèãíàëüíûõ êàñêàäîâ, êîíòðîëèðóÿ, òàêèì îáðàçîì, âîçáóäèìîñòü íåéðîíîâ è ñèíàïòè÷åñêóþ ïëàñòè÷íîñòü (Alkondon et al., 2000; Dani, 2001). ÀÕ òàêæå àêòèâèðóåò èîíîòðîïíûå íèêîòèíîâûå àöåòèëõîëèíîâûå ðåöåïòîðû, îáðàçóþùèå â ïëàçìàòè÷åñêèõ ìåìáðàíàõ íåéðîíàëüíûõ êëåòîê è íåðâíî-ìûøå÷íûõ ñîåäèíåíèé ëèãàíäóïðàâëÿåìûå èîííûå êàíàëû. Àêòèâàöèÿ ýòèõ ðåöåïòîðîâ âûçûâàåò äåïîëÿðèçàöèþ ïëàçìàòè÷åñêîé ìåìáðàíû, ãåíåðèðóåò âîçáóæäàþùèé ïîñòñèíàïòè÷åñêèé ïîòåíöèàë, ñòèìóëèðóåò àêòèâíîñòü ïîòåíöèàëçàâèñèìûõ èîííûõ êàíàëîâ, ïîâûøàåò ïðîíèöàåìîñòü ìåìáðàíû äëÿ Ca2+. Íàðóøåíèå ôóíêöèîíèðîâàíèÿ àöåòèëõîëèíîâûõ ðåöåïòîðîâ ïðèâîäèò ê ðàçâèòèþ íåéðîäåãåíåðàòèâíûõ çàáîëåâàíèé è êîãíèòèâíîìó äåôèöèòó.  óñëîâèÿõ ýêñïåðèìåíòàëüíîãî ÑÄ1 îñíîâíûå èçìåíåíèÿ â ôóíêöèîíèðîâàíèè õîëèíåðãè÷åñêîé ñèñòåìû 464 À. Î. Øïàêîâ ìîçãà ñâÿçàíû ñ ÌÀÕÐ 1-ãî è 3-ãî òèïîâ, êîòîðûå ÷åðåç Gq-áåëêè ñîïðÿæåíû ñ ÔËÑ (Gireesh et al., 2008, 2009; Antony et al., 2010; Peeyush et al., 2010; Peeyush Kumar et al., 2011). ÌÀÕÐ 1-ãî è 3-ãî òèïîâ â çíà÷èòåëüíûõ êîëè÷åñòâàõ ýêñïðåññèðóþòñÿ â îáëàñòÿõ ìîçãà, îòâåòñòâåííûõ çà êîãíèòèâíûå ôóíêöèè, ÷òî óêàçûâàåò íà âêëàä íàðóøåíèé â ðåãóëèðóåìûõ ÷åðåç ýòè ðåöåïòîðû ñèãíàëüíûõ êàñêàäàõ â êîãíèòèâíûé äåôèöèò, âîçíèêàþùèé ïðè ÑÄ (Porter et al., 2002). Èçìåíåíèÿ ôóíêöèé ÌÀÕÐ 1-ãî è 3-ãî òèïîâ ÿâëÿþòñÿ ñïåöèôè÷íûìè â îòíîøåíèè ðàçëè÷íûõ îáëàñòåé ìîçãà è çàâèñÿò îò òèïà è ïðîäîëæèòåëüíîñòè ÑÄ, âûðàæåííîñòè ãèïåðãëèêåìèè è ãèïîãëèêåìè÷åñêèõ ýïèçîäîâ. Òàê, â êîðå áîëüøèõ ïîëóøàðèé, ãèïîòàëàìóñå è ñòâîëå ìîçãà êðûñ ñ ÑÄ1 ýêñïðåññèÿ ãåíîâ, êîäèðóþùèõ ÌÀÕÐ 1-ãî òèïà, è îáùåå ÷èñëî ÌÀÕÐ ñíèæàþòñÿ (Gireesh et al., 2008; Balakrishnan et al., 2009; Peeyush Kumar et al., 2011).  òî æå âðåìÿ ñðîäñòâî ÌÀÕÐ 1-ãî òèïà ê àãîíèñòàì ïîâûøàåòñÿ, ÷òî ÿâëÿåòñÿ êîìïåíñàòîðíîé ðåàêöèåé íà ñíèæåíèå ÷èñëà ýòèõ ðåöåïòîðîâ.  ìîçæå÷êå äèàáåòè÷åñêèõ êðûñ îáùåå ÷èñëî ÌÀÕÐ 1-ãî è 3-ãî òèïîâ è ýêñïðåññèÿ êîäèðóþùèõ ýòè ðåöåïòîðû ãåíîâ, íàïðîòèâ, ïîâûøàþòñÿ. Ïîâûøåíèå ÷èñëà ÌÀÕÐ 1-ãî òèïà îòìå÷àåòñÿ òàêæå â ïîëîñàòîì òåëå, ÌÀÕÐ 3-ãî òèïà — â êîðå áîëüøèõ ïîëóøàðèé è ñòâîëå ìîçãà (Balakrishnan et al., 2009; Antony et al., 2010; Peeyush et al., 2010; Peeyush Kumar et al., 2011; Sherin et al., 2011). Èçìåíåíèå ÷èñëà ÌÀÕÐ 1-ãî è 3-ãî òèïîâ â óñëîâèÿõ ïðîäîëæèòåëüíîé ãèïîãëèêåìèè, âûçûâàåìîé âûñîêèìè äîçàìè ïåðèôåðè÷åñêîãî èíñóëèíà, âûðàæåíî â åùå áîëüøåé ñòåïåíè, ÷åì ó äèàáåòè÷åñêèõ êðûñ ñ óìåðåííîé ãèïåðãëèêåìèåé (Gireesh et al., 2009; Antony et al., 2010; Sherin et al., 2011). Ýòî ñâèäåòåëüñòâóåò î òîì, ÷òî ãëþêîçíûé ãîìåîñòàç â ìîçãå èãðàåò êëþ÷åâóþ ðîëü â êîíòðîëå ýêñïðåññèè è ôóíêöèîíàëüíîé àêòèâíîñòè ÌÀÕÐ. Óâåëè÷åíèå ïðîäîëæèòåëüíîñòè ÑÄ1 ñ 7 äî 90 íåä ïî-ðàçíîìó âëèÿåò íà ýêñïðåññèþ ãåíîâ äëÿ ÌÀÕÐ â ðàçëè÷íûõ îáëàñòÿõ ìîçãà. Òàê, â êîðå áîëüøèõ ïîëóøàðèé ÷èñëî ÌÀÕÐ 1-ãî òèïà ó êðûñ ñ ÑÄ ïðîäîëæèòåëüíîñòüþ 7 íåä ñíèæàåòñÿ íà 28 %, à ó êðûñ ñ ÑÄ ïðîäîëæèòåëüíîñòüþ 90 íåä, íàïðîòèâ, ïîâûøàåòñÿ íà 43 % (Savitha et al., 2010). Ó æèâîòíûõ ñ îæèðåíèåì è ãèïåðèíñóëèíåìèåé, õàðàêòåðíûõ äëÿ ìåòàáîëè÷åñêîãî ñèíäðîìà è ÑÄ2, îòìå÷åíî óñèëåíèå âàãóñíîãî âëèÿíèÿ íà ðèòì è ïðîâîäèìîñòü ñåðäöà, îñóùåñòâëÿåìîãî ÷åðåç ÌÀÕÐ 3-ãî òèïà, ëîêàëèçîâàííûå êàê â ìîçãå, òàê è â ïåðèôåðè÷åñêèõ òêàíÿõ (Yamada et al., 2001; Gautam et al., 2008). Íîêàóò ÌÀÕÐ 3-ãî òèïà èëè èõ áëîêèðîâàíèå ñ ïîìîùüþ ñåëåêòèâíûõ àíòàãîíèñòîâ ïðèâîäèò ê âîññòàíîâëåíèþ ÷óâñòâèòåëüíîñòè òêàíåé ê èíñóëèíó, íîðìàëèçóåò óðîâåíü ãëþêîçû è, òàêèì îáðàçîì, çàùèùàåò æèâîòíûõ îò ðàçëè÷íûõ ôîðì ýêñïåðèìåíòàëüíîãî èëè ãåíåòè÷åñêè îáóñëîâëåííîãî îæèðåíèÿ è ñâÿçàííûõ ñ ýòèì ìåòàáîëè÷åñêèõ ðàññòðîéñòâ. Òàê, ó ìûøåé, íîêàóòíûõ ïî ãåíó, êîäèðóþùåìó ÌÀÕÐ 3-ãî òèïà, ïðèìåíåíèå îáîãàùåííîé æèðàìè äèåòû, ïîâðåæäåíèå ãèïîòàëàìè÷åñêèõ íåéðîíîâ ñ ïîìîùüþ òèîãëþêîçû è íîêàóò ãåíà, êîäèðóþùåãî ëåïòèí, ðåãóëèðóþùèé ïèùåâîå ïîâåäåíèå è ýíåðãåòè÷åñêèé ãîìåîñòàç, íå ïðèâîäÿò ê èíñóëèíîâîé ðåçèñòåíòíîñòè, ãèïåðèíñóëèíåìèè è ãèïåðãëèêåìèè, êîòîðûå ðàçâèâàþòñÿ ó ìûøåé, èìåþùèõ ôóíêöèîíàëüíî àêòèâíûé ãåí äëÿ ýòîãî ðåöåïòîðà. Ôóíêöèîíèðîâàíèå èîíîòðîïíûõ íèêîòèíîâûõ àöåòèëõîëèíîâûõ ðåöåïòîðîâ ïðè ÑÄ èçó÷åíî â ìåíüøåé ñòåïåíè, ÷åì ÌÀÕÐ, íåñìîòðÿ íà òî ÷òî îíè èãðàþò íå ìåíåå âàæíóþ ðîëü â ýòèîëîãèè è ïàòîãåíåçå ìíîãèõ íåéðîäåãåíåðàòèâíûõ çàáîëåâàíèé, â òîì ÷èñëå áîëåçíè Àëüöãåéìåðà. Ñòèìóëÿöèÿ èîíîòðîïíûõ àöåòèëõîëèíîâûõ ðåöåïòîðîâ â áîëüøèíñòâå ñâîåì ïðèâîäèò ê ôèçèîëîãè÷åñêèì è ïîâåäåí÷åñêèì ðåàêöèÿì, êîòîðûå ïðîòèâîïîëîæíû òåì, êîòîðûå âûçûâàþòñÿ ÷åðåç ïîñðåäñòâî ÌÀÕÐ. Íàïðèìåð, íèêîòèí, äåéñòâóþùèé ÷åðåç èîíîòðîïíûå ðåöåïòîðû, ñíèæàåò ïîòðåáëåíèå ïèùè, ïîâûøàåò ñêîðîñòü îáìåííûõ ïðîöåññîâ è ñíèæàåò ìàññó òåëà (Li et al., 2003), â òî âðåìÿ êàê àêòèâàöèÿ ÌÀÕÐ 3-ãî òèïà, íàïðîòèâ, âûçûâàåò ïåðååäàíèå è óâåëè÷åíèå ìàññû òåëà (Gautam et al., 2008). Ïðåäïîëàãàåòñÿ, ÷òî ïðè ÑÄ â ðàçëè÷íûõ îòäåëàõ ìîçãà ìåíÿåòñÿ ñîîòíîøåíèå ìåæäó ôóíêöèîíàëüíîé àêòèâíîñòüþ ÌÀÕÐ è èîíîòðîïíûõ àöåòèëõîëèíîâûõ ðåöåïòîðîâ è íàðóøàåòñÿ ñîãëàñîâàííàÿ ðàáîòà õîëèíåðãè÷åñêèõ ñèãíàëüíûõ ïóòåé, ÷òî â êîíå÷íîì èòîãå ïðèâîäèò ê äèñôóíêöèÿì ôèçèîëîãè÷åñêèõ è ìåòàáîëè÷åñêèõ ïðîöåññîâ â ÖÍÑ è ïåðèôåðè÷åñêèõ îðãàíàõ è òêàíÿõ, êîíòðîëèðóåìûõ ÷åðåç ýòè ïóòè. Îöåíèâàÿ ôóíêöèîíàëüíóþ àêòèâíîñòü õîëèíåðãè÷åñêîé ñèñòåìû ìîçãà ïðè ÑÄ, íåîáõîäèìî ïðèíèìàòü âî âíèìàíèå àêòèâíîñòü ôåðìåíòîâ, îòâåòñòâåííûõ çà áèîõèìè÷åñêèå ïðåâðàùåíèÿ ÀÕ.  ïåðâóþ î÷åðåäü ýòî àöåòèëõîëèíýñòåðàçà, êîòîðàÿ êàòàëèçèðóåò ãèäðîëèç ÀÕ äî õîëèíà è óêñóñíîé êèñëîòû, è õîëèíàöåòèëòðàíñôåðàçà, êîòîðàÿ êàòàëèçèðóåò ñèíòåç ÀÕ èç àöåòèë êîýíçèìà À, ïðîäóöèðóåìîãî â íåðâíûõ îêîí÷àíèÿõ, è õîëèíà, àêòèâíî ïîãëîùàåìîãî èç âíåêëåòî÷íîé æèäêîñòè. Òàê, íåñìîòðÿ íà òî ÷òî â êîðå ãîëîâíîãî ìîçãà êðûñ ñ ÑÄ1 ïîâûøåíà ýêñïðåññèÿ a7-íèêîòèíîâûõ àöåòèëõîëèíîâûõ ðåöåïòîðîâ, ôóíêöèîíàëüíàÿ àêòèâíîñòü õîëèíåðãè÷åñêîé ñèñòåìû ñíèæåíà (Peeyush Kumar et al., 2011). Ïðè÷èíàìè ýòîãî ÿâëÿþòñÿ ïîâûøåíèå ýêñïðåññèè àöåòèëõîëèíýñòåðàçû, ðàçðóøàþùåé ÀÕ, è ïîíèæåíèå ýêñïðåññèè õîëèíàöåòèëòðàíñôåðàçû, îñóùåñòâëÿþùåé òðàíñïîðò íåéðîìåäèàòîðà â ñèíàïòè÷åñêóþ ùåëü. Ïîâûøåíèå ïëîòíîñòè a7-íèêîòèíîâûõ ðåöåïòîðîâ íå ìîæåò â ïîëíîé ìåðå êîìïåíñèðîâàòü ñíèæåíèå êîíöåíòðàöèè ÀÕ â ñèíàïòè÷åñêîì ïðîñòðàíñòâå. Ïîñêîëüêó a7-íèêîòèíîâûå ðåöåïòîðû âîâëå÷åíû â êîíòðîëü ïàìÿòè, âíèìàíèÿ è ïðîöåññîâ îáðàáîòêè èíôîðìàöèè (Picciotto et al., 2000), îñëàáëåíèå ïåðåäà÷è ÷åðåç íèõ ñèãíàëà ïðèâîäèò ê êîãíèòèâíîìó äåôèöèòó, êîòîðûé â çíà÷èòåëüíîé ñòåïåíè óñòðàíÿåòñÿ ïðè äëèòåëüíîì ëå÷åíèè æèâîòíûõ àãîíèñòàìè a7-íèêîòèíîâûõ ðåöåïòîðîâ (Hashimoto et al., 2008). Èíñóëèíîâàÿ òåðàïèÿ íîðìàëèçóåò ýêñïðåññèþ àöåòèëõîëèíýñòåðàçû è õîëèíàöåòèëòðàíñôåðàçû â êîðå ãîëîâíîãî ìîçãà êðûñ ñ ÑÄ1 è îäíîâðåìåííî ñ ýòèì ñíèæàåò ïîâûøåííóþ ýêñïðåññèþ a7-íèêîòèíîâûõ ðåöåïòîðîâ, ÷òî ïîçâîëÿåò â çíà÷èòåëüíîé ñòåïåíè âîññòàíîâèòü êîãíèòèâíûå ôóíêöèè (Peeyush Kumar et al., 2011). Çàêëþ÷åíèå Ïðåäñòàâëåííûå â îáçîðå äàííûå óáåäèòåëüíî ñâèäåòåëüñòâóþò î òîì, ÷òî ïðè ðàçëè÷íûõ ôîðìàõ ÑÄ â ìîçãå ìåíÿåòñÿ íå òîëüêî àêòèâíîñòü ñèãíàëüíûõ ñèñòåì, ðåãóëèðóåìûõ ïåïòèäíûìè ãîðìîíàìè, â òîì ÷èñëå èíñóëèíîì è ëåïòèíîì, è ãëóòàìàòåðãè÷åñêîé ñèãíàëüíîé ñèñòåìû, îòâåòñòâåííîé çà íåéðîòîêñè÷íîñòü, íî è àêòèâíîñòü ñèãíàëüíûõ ñèñòåì, ðåãóëèðóåìûõ áèîãåííûìè àìèíàìè è ÀÕ. Ïîñêîëüêó âñå ñèãíàëüíûå ñèñòåìû ìîçãà òåñíî ñâÿçàíû ìåæäó ñîáîé è îáðàçóþò èíòåãðàòèâíóþ íåéðîíàëüíóþ ñåòü, íàðóøåíèÿ â îäíîé ñèñòåìå íåèçáåæíî Ôóíêöèîíàëüíîå ñîñòîÿíèå ñèãíàëüíûõ ñèñòåì ìîçãà ïðè ñàõàðíîì äèàáåòå ïðèâîäÿò ê èçìåíåíèþ àêòèâíîñòè ôóíêöèîíàëüíî ñâÿçàííîé ñ íåé äðóãîé ñèñòåìû, è äàëåå ïî «ïðèíöèïó äîìèíî» íàðóøàåòñÿ âñÿ ñåòü ñèãíàëüíûõ êàñêàäîâ. Ïðè ýòîì íà íà÷àëüíûõ ýòàïàõ ðàçâèòèÿ ÑÄ, à â ðÿäå ñëó÷àåâ íà ñòàäèè ïðåääèàáåòà, â óñëîâèÿõ ïîâòîðÿþùèõñÿ ãèïåðãëèêåìè÷åñêèõ è ãèïîãëèêåìè÷åñêèõ ýïèçîäîâ è èíñóëèíîâîé ðåçèñòåíòíîñòè íàðóøåíèÿ ìîãóò âîçíèêàòü íà ðàçëè÷íûõ ñòàäèÿõ ïåðåäà÷è ãîðìîíàëüíîãî ñèãíàëà è çàòðàãèâàòü îäíó èëè íåñêîëüêî âçàèìîñâÿçàííûõ ñèãíàëüíûõ ñèñòåì.  ýòîé ñâÿçè ìîæíî ïðåäëîæèòü íåñêîëüêî íàèáîëåå âåðîÿòíûõ ìåõàíèçìîâ ðàçâèòèÿ òàêèõ íàðóøåíèé. Ïåðâûé âêëþ÷àåò â ñåáÿ âîçíèêíîâåíèå ëîêàëüíûõ íàðóøåíèé òîëüêî â îäíîé ñèãíàëüíîé ñèñòåìå, ÷òî ìîæåò áûòü ñâÿçàíî ñ èçìåíåíèåì ýêñïðåññèè èëè àêòèâíîñòè êàêîãî-òî îïðåäåëåííîãî ñåíñîðíîãî, àäàïòîðíîãî èëè ýôôåêòîðíîãî áåëêà, êîìïîíåíòà ñèãíàëüíîé ñèñòåìû, à òàêæå ñ äåôèöèòîì èëè, íàïðîòèâ, ñ èçáûòêîì ãîðìîíà èëè íåéðîìåäèàòîðà, ñïåöèôè÷åñêîãî ðåãóëÿòîðà ýòîé ñèñòåìû. Âîçíèêàþùèå íàðóøåíèÿ ìîãóò áûòü ðåçóëüòàòîì ãèïåðàêòèâàöèè, îñëàáëåíèÿ èëè ìîäèôèêàöèè ôóíêöèé ñèãíàëüíîãî áåëêà âñëåäñòâèå ìóòàöèé â òðàíñëèðóåìûõ ó÷àñòêàõ ãåíà, êîäèðóþùåãî ýòîò áåëîê, èëè â íåòðàíñëèðóåìûõ åãî îáëàñòÿõ. Äðóãîé èõ ïðè÷èíîé ÿâëÿåòñÿ íîêàóò ãåíà, ÷òî ïðèâîäèò ê áëîêèðîâàíèþ ñèãíàëüíîãî êàñêàäà, âêëþ÷àþùåãî â ñåáÿ êîäèðóåìûé ýòèì ãåíîì áåëîê. Èçìåíåíèÿ êîíöåíòðàöèè ñèãíàëüíûõ ìîëåêóë âñëåäñòâèå íàðóøåíèÿ èõ ñèíòåçà, òðàíñïîðòà è äåãðàäàöèè òàêæå âíîñÿò ñóùåñòâåííûé âêëàä â ôóíêöèîíàëüíóþ àêòèâíîñòü ñèãíàëüíûõ ñèñòåì ïðè ÑÄ. Êîëåáàíèÿ êîíöåíòðàöèè ãîðìîíîâ è íåéðîòðàíñìèòòåðîâ, âûçâàííûå ìåòàáîëè÷åñêèìè íàðóøåíèÿìè, âîçíèêàþùèìè ïðè ÑÄ, ïðèâîäÿò ê êîìïåíñàòîðíûì èçìåíåíèÿì â ñèãíàëüíûõ ñèñòåìàõ, ÷òî âïîñëåäñòâèè íàðóøàåò âñþ íåéðîíàëüíóþ ñåòü ìîçãà. Ñëåäóåò îòìåòèòü, ÷òî íà ðàííèõ ñòàäèÿõ ðàçâèòèÿ ÑÄ íàðóøåíèÿ â ñèãíàëüíûõ ñèñòåìàõ ìîçãà ÿâëÿþòñÿ îáðàòèìûìè è ìîãóò áûòü âîññòàíîâëåíû ñ ïîìîùüþ àäåêâàòíîé òåðàïèè. Íà ïîçäíèõ ñòàäèÿõ íàðóøåíèÿ ñòàíîâÿòñÿ áîëåå âûðàæåííûìè, çàòðàãèâàþò áîëåå øèðîêèé êðóã ñèãíàëüíûõ ñèñòåì è â êîíå÷íîì èòîãå ïðèîáðåòàþò íåîáðàòèìûé õàðàêòåð. Âñëåäñòâèå ýòîãî ñòðàòåãèÿ ëå÷åíèÿ ðàííèõ ñòàäèé ÑÄ, îðèåíòèðîâàííàÿ íà âîññòàíîâëåíèå ãîðìîíàëüíûõ ñèãíàëüíûõ ñèñòåì ìîçãà, äîëæíà ñóùåñòâåííî îòëè÷àòüñÿ îò òàêîâîé íà ïîçäíèõ ñòàäèÿõ çàáîëåâàíèÿ. Âòîðîé ìåõàíèçì îñíîâàí íà ñèñòåìíîì îòâåòå ãîðìîíàëüíûõ ñèãíàëüíûõ ñèñòåì ìîçãà íà çíà÷èòåëüíûå ïî âåëè÷èíå è ïðîäîëæèòåëüíîñòè èçìåíåíèÿ ãëþêîçíîãî ãîìåîñòàçà, âûðàæåííóþ ãèïåðãëèêåìèþ è ïîâòîðÿþùèåñÿ ñ âûñîêîé ÷àñòîòîé è èíòåíñèâíîñòüþ ãèïîãëèêåìè÷åñêèå ýïèçîäû, âîçíèêàþùèå âñëåäñòâèå íåàäåêâàòíîé òåðàïèè ïåðèôåðè÷åñêèì èíñóëèíîì. Âàæíóþ ðîëü çäåñü òàêæå èãðàåò ðàçðóøèòåëüíîå âëèÿíèå ðàçâèâàþùåãîñÿ â óñëîâèÿõ ÑÄ îêèñëèòåëüíîãî ñòðåññà íà íåéðîíàëüíûå è ãëèàëüíûå êëåòêè. Èçìåíåíèÿ â ýòîì ñëó÷àå ìîãóò âîçíèêàòü â ðàçëè÷íûõ áëîêàõ äâóõ è áîëåå ñèãíàëüíûõ ñèñòåì ìîçãà. Ñíà÷àëà îíè ÿâëÿþòñÿ îáðàòèìûìè è âîññòàíàâëèâàþòñÿ ïðè íîðìàëèçàöèè ãëþêîçíîãî ãîìåîñòàçà è îêèñëèòåëüíî-âîññòàíîâèòåëüíîãî áàëàíñà, íî ïðè äëèòåëüíûõ ìåòàáîëè÷åñêèõ íàðóøåíèÿõ è ïðîäîëæèòåëüíîì îêèñëèòåëüíîì ñòðåññå ñòàíîâÿòñÿ íåîáðàòèìûìè, îõâàòûâàþò âñþ íåéðîíàëüíóþ ñåòü, ÷òî ïðèâîäèò ê ðàçâèòèþ íåéðîäåãåíåðàòèâíûõ çàáîëåâàíèé. Òîò ôàêò, ÷òî íàðóøåíèÿ â ñèãíàëüíûõ ñèñòåìàõ, ðåãóëèðóåìûå áèîãåííûìè àìèíàìè è ÀÕ, ìîãóò âûçûâàòü íåéðîäåãåíåðàòèâíûå èçìåíåíèÿ â ìîçãå è, ñëåäîâàòåëü- 465 íî, íàðóøàòü ôóíêöèîíèðîâàíèå âñåé íåéðîíàëüíîé ñåòè, óêàçûâàåò íà âîçìîæíîñòü öåíòðàëüíîãî ïðîèñõîæäåíèÿ ÑÄ. Äðóãèìè ñëîâàìè, íåéðîäåãåíåðàòèâíûå èçìåíåíèÿ â ìîçãå â ýòîì ñëó÷àå ÿâëÿþòñÿ íå îñëîæíåíèÿìè ÑÄ, à åãî ïðåäøåñòâåííèêàìè (Cole et al., 2007; De la Monte, 2009; Shpakov et al., 2011). Òàê, ñíèæåíèå àêòèâíîñòè ìåëàíîêîðòèíîâîé ñèñòåìû ìîçãà ëèáî âñëåäñòâèå íàðóøåíèÿ â ñèãíàëüíûõ êàñêàäàõ, ðåãóëèðóåìûõ àãîíèñòàìè ìåëàíîêîðòèíîâûõ ðåöåïòîðîâ, ëèáî âñëåäñòâèå áëîêàäû ìåëàíîêîðòèíîâûõ ðåöåïòîðîâ 3-ãî è 4-ãî òèïîâ ñåëåêòèâíûìè àíòàãîíèñòàìè, àãóòè-ðîäñòâåííûì ïåïòèäîì èëè àíòèòåëàìè ê âíåêëåòî÷íûì ó÷àñòêàì ýòèõ ðåöåïòîðîâ ïðèâîäèò ê ÑÄ2, è â ýòîì ñëó÷àå ÑÄ2 áóäåò èìåòü öåíòðàëüíûé ãåíåç (Balthasar et al., 2005; Nogueiras et al., 2007; Hofbauer et al., 2008; Peter et al., 2010). Ïîñêîëüêó â ìîçãå ñåðîòîíèíåðãè÷åñêàÿ è äîôàìèíåðãè÷åñêàÿ ñèñòåìû âçàèìîäåéñòâóþò ñ ìåëàíîêîðòèíîâîé ñèñòåìîé è êîíòðîëèðóþò åå àêòèâíîñòü, îïîñðåäîâàííî è ýòè ñèñòåìû ìîãóò áûòü âîâëå÷åíû â ðàçâèòèå ÑÄ, êàê ýòî äîêàçàíî äëÿ ñèãíàëüíûõ êàñêàäîâ, ðåàëèçóåìûõ ÷åðåç ÑÐ 2Ñ-ïîäòèïà, è ïðåäïîëàãàåòñÿ äëÿ ñèãíàëüíûõ êàñêàäîâ, âêëþ÷àþùèõ â ñåáÿ ÑÐ 1B-ïîäòèïà. Äîôàìèíåðãè÷åñêàÿ è ñåðîòîíèíåðãè÷åñêàÿ ñèñòåìû ìîçãà òåñíî ñâÿçàíû ñ èíñóëèíîâîé è ëåïòèíîâîé ñèñòåìàìè, ðîëü êîòîðûõ â ðàçâèòèè ÑÄ ÿâëÿåòñÿ îáùåïðèçíàííîé. Âñëåäñòâèå ýòîãî äèñôóíêöèè â êîíòðîëèðóåìûõ äîôàìèíîì è ñåðîòîíèíîì ñèãíàëüíûõ ïóòÿõ ñàìûì íåïîñðåäñòâåííûì îáðàçîì âëèÿþò íà ÷óâñòâèòåëüíîñòü ìîçãà è ïåðèôåðè÷åñêèõ òêàíåé ê èíñóëèíó è ëåïòèíó è ìîãóò ñòàòü ïåðâîïðè÷èíîé ÑÄ (Van der Heide et al., 2005; Roseberry et al., 2007; Weng et al., 2007). Òàêèì îáðàçîì, èçó÷åíèå ìîëåêóëÿðíûõ ìåõàíèçìîâ, ëåæàùèõ â îñíîâå ðàçâèòèÿ ÑÄ è åãî îñëîæíåíèé ñî ñòîðîíû ÖÍÑ, íå òîëüêî îòêðûâàåò íîâûå ïåðñïåêòèâû äëÿ èõ ëå÷åíèÿ è ðàííåé äèàãíîñòèêè, íî ïîçâîëÿåò âûÿâèòü êîðíè ýòèõ çàáîëåâàíèé è èäåíòèôèöèðîâàòü ñèãíàëüíûå áëîêè è êàñêàäû, èçìåíåíèÿ ôóíêöèîíàëüíîé àêòèâíîñòè êîòîðûõ ÿâëÿþòñÿ ïóñêîâûì ìåõàíèçìîì äëÿ ðàçâèòèÿ ÑÄ è àññîöèèðîâàííûõ ñ íèì íåéðîäåãåíåðàòèâíûõ çàáîëåâàíèé. 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Identification of polymorphic loci in the promoter 468 À. Î. Øïàêîâ region of the serotonin 5-HT2C receptor gene and their association with obesity and type II diabetes. Diabetologia. 43 : 373—376. Zhou L., Sutton G. M., Rochford J. J., Semple R. K., Lam D. D., Oksanen L. J., Thornton-Jones Z. D., Clifton P. G., Yueh C. Y., Evans M. L., McCrimmon R. J., Elmquist J. K., But- ler A. A., Heisler L. K. 2007. Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell. Metab. 6 : 398—405. Ïîñòóïèëà 1 II 2012 THE FUNCTIONAL STATE OF BIOGENIC AMINES- AND ACETYLCHOLINE-REGULATED SIGNALING SYSTEMS OF THE BRAIN IN DIABETES MELLITUS A. O. Shpakov I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS, St. Petersburg; e-mail: alex_shpakov@list.ru The role of hormonal signaling systems in the etiology and pathogenesis of diabetes mellitus (DM) and the neurodegenerative diseases induced by them is currently poorly understood. It is generally accepted that the main causes of diabetes of types 1 and 2 and their CNS complications are disturbances in signaling systems regulated by insulin, leptin and glutamate. However, in recent years, there are many evidences in favor of participation of the brain signaling systems regulated by biogenic amines and cholinergic receptor agonists in the development of these diseases. The alterations in the expression and functional activity of signal proteins, the components of these systems, as well as the disturbances of the biosynthesis, transport and degradation of signal molecules for their regulation contribute significantly to the pathological processes in the brain in DM, and in some cases themselves are a trigger for the development of this disease. The main factors that cause dysfunctions of dopaminergic, serotonergic, adrenergic and cholinergic systems of the brain in DM are hyperglycemia and insulin resistance, and hypoglycemia that occurs as a result of inadequate insulin therapy. This review is devoted to the functional state of the brain signaling systems regulated by biogenic amines and cholinergic agonists in DM, as well as the relationship between the changes in these systems and the development of neurodegenerative processes in the diabetic brain. K e y w o r d s: adenylyl cyclase, acetylcholine receptors, biogenic amine, hyperglycemia, diabetes mellitus, dopamine, dopamine receptor, brain, serotonin, serotonin receptor.