Pharmacological strategies in CNS trauma

Faden, Alan I.; Salzman, Steven K.

doi:10.1016/0165-6147(92)90013-v

Cited by 204 publications

(77 citation statements)

References 28 publications

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“…As mentioned, there has been consistent evidence that, in addition to its role as an opioid, dynorphin has potent non-opioid actions that are mediated by glutamatergic receptors (21,23,46,48,50,56,79,(87)(88)(89). Glutamate antagonists attenuate the deleterious effects of dynorphin in experimental models of hyperalgesia and/or spinal cord injury, and dynorphin fragments lacking the amino-terminal tyrosine necessary for opioid activity, remain toxic (21,23,27,44,46,48,50,56,78,79) and have a longer half-life in vivo and in vitro (94). The dichotomous actions at κ opioid and NMDA receptors may be intrinsic features of the dynorphin A peptide itself (87) or dynorphin may induce glutamate release and/or accumulation during injury (50,62).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to their known actions as opioids, dynorphin A and dynorphin A (1-13) (a major bioactive product of dynorphin A) (19,29), may impact secondary neuronal injury through non-opioid mechanisms (9)(10)(11)18,23,45,49,56). Unlike other opioid peptides, opioid antagonists cannot block many of the effects of dynorphin.…”

Section: Introductionmentioning

confidence: 99%

“…Although dynorphin and other related opioid peptides have a defined role as inhibitory neurotransmitters in pain reduction, there is growing evidence that exposure to high concentrations of dynorphin can induce hyperalgesia, allodynia, and/or may contribute to neurodegeneration (21,23,27,36,56,78,79). Dynorphin A-derived peptides are significantly elevated following neurotrauma and sustained exposure to these peptides is neurotoxic (21,23,27,56,58,78,79).…”

Section: Introductionmentioning

confidence: 99%

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Dynorphin A (1–13) Neurotoxicity in Vitro: Opioid and Non-Opioid Mechanisms in Mouse Spinal Cord Neurons

Hauser

Foldes

Turbek

1999

Experimental Neurology

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Dynorphin A is an endogenous opioid peptide that preferentially activates κ opioid receptors and is antinociceptive at physiological concentrations. Levels of dynorphin A and a major metabolite, dynorphin A (1-13), increase significantly following spinal cord trauma and reportedly contribute to neurodegeneration associated with secondary injury. Interestingly, both κ opioid and N-methyl-D-aspartate (NMDA) receptor antagonists can modulate dynorphin toxicity, suggesting that dynorphin is acting (directly or indirectly) through κ opioid and/or NMDA receptor (NMDAR) types. Despite these findings, few studies have systematically explored dynorphin toxicity at the cellular level in defined populations of neurons co-expressing κ opioid and NMDA receptors. To address this question, we isolated populations of neurons enriched in both κ opioid and NMDA receptors from embryonic mouse spinal cord and examined the effects of dynorphin A (1-13) on intracellular calcium concentration ([Ca 2+ ] i ) and neuronal survival in vitro. Time-lapse photography was used to repeatedly follow the same neurons before and during experimental treatments. At micromolar concentrations, dynorphin A (1-13) elevated [Ca 2+ ] i and caused a significant loss of neurons. The excitotoxic effects were prevented by MK-801 (Dizocilpine) (10 μM), 2-amino-5-phosphopentanoic acid (AP-5) (100 μM), or 7-chlorokynurenic acid (100 μM)-suggesting that dynorphin A (1-13) was acting (directly or indirectly) through NMDA receptors. In contrast, co-treatment with (−)-naloxone (3 μM), or the more selective κ opioid receptor antagonist nor-binaltorphimine (3 μM), exacerbated dynorphin A (1-13)-induced neuronal loss; however, cell losses were not enhanced by the inactive stereoisomer (+)-naloxone (3 μM). Neuronal losses were not seen with exposure to the opioid antagonists alone (10 μM). Thus, opioid receptor blockade significantly increased toxicity, but only in the presence of excitotoxic levels of dynorphin. This provided indirect evidence that dynorphin also stimulates κ opioid receptors and suggests that κ receptor activation may be moderately neuroprotective in the presence of an excitotoxic insult. Our findings suggest that dynorphin A (1-13) can have paradoxical effects on neuronal viability through both opioid and non-opioid (glutamatergic) receptor-mediated actions. Therefore, dynorphin A potentially modulates secondary neurodegeneration in the spinal cord through complex interactions involving multiple receptors and signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dynorphin A (1–13) Neurotoxicity in Vitro: Opioid and Non-Opioid Mechanisms in Mouse Spinal Cord Neurons

Hauser

Foldes

Turbek

1999

Experimental Neurology

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“…8), ïðîÿâ-ëÿâøèé ñâîéñòâà àíàëüãåòèêà â äîçå 0,00052 -0,0012 ìã/êã [30]. Êðîìå òîãî, áûëà ïîêàçàíà âûñîêàÿ ïðîòèâîýïèëåïòè÷åñêàÿ è íåéðîïðîòåêòîðíàÿ àêòèâ-íîñòü âåùåñòâà íà ðàçëè÷íûõ ìîäåëÿõ ýïèëåïòîãåíåçà [89,90], à òàêaeå ïðè èøåìè÷åñêèõ è òðàâìàòè÷åñêèõ ïîâðåaeäåíèÿõ ìîçãà [91,92]. Ïðè ýòîì ïîëàãàëè, ÷òî àíòèíîöèöåïòèâíûé, àíòèãèïåðàëüãåòè÷åñêèé è àíòè-àëëîäèíè÷åñêèé ýôôåêòû GR89,696 îáóñëîâëåíû àê-òèâàöèåé ñïèíàëüíûõ k 2 -ðåöåïòîðîâ è ïîñëåäóþùåé îïîñðåäîâàííîé èìè èíãèáèöèåé ñïèíàëüíûõ NMDA-ðåöåïòîðîâ [93 -95].…”

Section: -(1-áåíçîôóðàí-4-èë)-n-ìåòèë-n-[(5r7s8s)-7-ïèððîëèäèí-1-èunclassified

Опиоидные Κ-Рецепторы Как Молекулярная Мишень Для Создания Нового Поколения Обезболивающих Лекарственных Средств

Гречко¹,

Спасов²,

Штарёва³

2016

Хим.-фарм. ж.

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ÎÏÈÎÈÄÍÛÅ k-ÐÅÖÅÏÒÎÐÛ ÊÀÊ ÌÎËÅÊÓËßÐÍÀß ÌÈØÅÍÜ ÄËß ÑÎÇÄÀÍÈß ÍÎÂÎÃÎ ÏÎÊÎËÅÍÈß ÎÁÅÇÁÎËÈÂÀÞÙÈÕ ËÅÊÀÐÑÒÂÅÍÍÛÕ ÑÐÅÄÑÒÂ 1 Âîëãîãðàäñêèé ãîñóäàðñòâåííûé ìåäèöèíñêèé óíèâåðñèòåò, Ðîññèÿ, Âîëãîãðàä 2 Âîëãîãðàäñêèé ìåäèöèíñêèé íàó÷íûé öåíòð, Ðîññèÿ, 400131, Âîëãîãðàä, ïë. Ïàâøèõ Áîðöîâ, 1 Â îáçîðå êðàòêî îïèñàíû îñíîâíûå îñîáåííîñòè ñòðîåíèÿ è ôóíêöèé êàïïà-îïèîèäíîãî ðåöåïòîðà, ïðèâåäåíà õàðàêòåðèñòèêà åãî àãîíèñòîâ è ïåðñïåêòèâà èõ èñïîëüçîâàíèÿ â ìåäèöèíå. Èç âñåõ ïîäòèïîâ îïèîèäíûõ ðåöåïòîðîâ èìåííî k-ðåöåïòîðû ÿâëÿþòñÿ íàè-áîëåå ïðèâëåêàòåëüíûìè äëÿ ñîçäàíèÿ íîâûõ ïðåïàðàòîâ ñ ìèíèìàëüíûì êîëè÷åñòâîì íåaeåëàòåëüíûõ ýôôåêòîâ. Îïèîèäíûé k-ðåöåïòîð -ïðåäñòàâèòåëü ñóïåðñåìåéñòâà ìå-òàáîòðîïíûõ G-áåëîê ñîïðÿaeåííûõ ðåöåïòîðîâ. Îïèîèäíûå k-ðåöåïòîðû øèðîêî ïðåä-ñòàâëåíû êàê â ÖÍÑ, òàê è íà ïåðèôåðèè. Îíè âîâëå÷åíû â ìíîãî÷èñëåííûå ôèçèîëîãè-÷åñêèå ïðîöåññû, âêëþ÷àÿ àíàëüãåçèþ, ðåãóëÿöèþ íåéðîýíäîêðèííîé ñåêðåöèè, âîäíîãî áàëàíñà, ïèòüåâîãî è ïèùåâîãî ïîâåäåíèÿ, âåãåòàòèâíûõ ôóíêöèé, ìåõàíèçìîâ îáó÷å-íèÿ, ïàìÿòè. Íà ñåãîäíÿøíèé äåíü èìååòñÿ èíôîðìàöèÿ î ñóùåñòâîâàíèè 3 ïîäòèïîâ k-îïèîèäíûõ ðåöåïòîðîâ, íî èçó÷åííîé ÿâëÿåòñÿ ëèøü ìîëåêóëÿðíàÿ õàðàêòåðèñòèêà ïåðâîãî ïîäòèïà (k 1 ).Êëþ÷åâûå ñëîâà: îïèîèäíàÿ ñèñòåìà; îïèîèäíûé k-ðåöåïòîð; àãîíèñòû îïèîèäíîãî k-ðåöåïòîðà.Îïèîèäíàÿ ðåöåïòîðíàÿ ñèñòåìà ñîñòîèò èç 4 òèïîâ ãåòåðîãåííûõ G-áåëîê-ñîïðÿaeåííûõ (GPCR) m-, d-, k-è ORL 1 (îïèîèäîïîäîáíûõ) ðåöåïòîðîâ, êîòîðûå ôàð-ìàêîëîãè÷åñêè îõàðàêòåðèçîâàíû, êëîíèðîâàíû, ðàç-ëè÷àþòñÿ ïåðâè÷íîé ñòðóêòóðîé, àíàòîìè÷åñêèì ðàñ-ïðåäåëåíèåì, ïðîôèëåì ôàðìàêîëîãè÷åñêîé àêòèâíî-ñòè, ôèçèîëîãè÷åñêèìè ôóíêöèÿìè [1 -3]. Ñòðîåíèå îïèîèäíîãî k-ðåöåïòîðàÁåëîê k-ðåöåïòîðà ïðèíàäëåaeèò ê À êëàññó ñóïåð-ñåìåéñòâà ìåòàáîòðîïíûõ GPCR [4,5], ñîñòîèò èç 380 àìèíîêèñëîòíûõ îñòàòêîâ, 7 ãèäðîôîáíûõ Ü-ñïèðà-ëåé, èíòåãðèðîâàííûõ â êëåòî÷íóþ ìåìáðàíó, à òàêaeå N-ãëèêîçèëèðîâàííîãî è Ñ-ïàëüìèòèðîâàííîãî êîíöå-âûõ ôðàãìåíòîâ (ðèñ. 1) [6].Ïîëàãàþò, ÷òî âòîðàÿ è òðåòüÿ âíåêëåòî÷íûå ïåòëè, à òàêaeå âåðõóøêà ÒÌ-4 ÿâëÿþòñÿ êëþ÷åâûìè ôðàã-ìåíòàìè äëÿ âûñîêîñåëåêòèâíîãî ñâÿçûâàíèÿ ðåöåï-òîðà ñ ëèãàíäàìè [7]. Èçó÷åíèå õèìåðíûõ ñòðóêòóð ïîêàçàëî, ÷òî ïåòëÿ EL-2 íåîáõîäèìà äëÿ ïðîÿâëåíèÿ àêòèâíîñòè äèíîðôèíà [8]. Êàïïà-áåëîê ñîäåðaeèò îñ-òàòîê Glu 297 íà òðåòüåé âíåêëåòî÷íîé ïåòëå, êîòîðûé ÿâëÿåòñÿ åãî "àäðåñíûì" ôðàãìåíòîì äëÿ âûñîêîàô-ôèííîãî ñâÿçûâàíèÿ ñ norBNI (íîðáèíàëòîðôèìèí). Âíóòðèêëåòî÷íàÿ ÷àñòü ðåöåïòîðà ñîäåðaeèò 2 îñòàòêà òèðîçèíà Tyr 87 è Tyr 157 , ÿâëÿþùèõñÿ ìèøåíÿìè äëÿ ôîñôîðèëèðîâàíèÿ òèðîçèíêèíàçîé. Ôîñôîðèëèðîâà-íèå ýòèõ îñòàòêîâ ìîaeåò îêàçûâàòü ðàçëè÷íûå ýôôåê-òû íà ÃÒÔ-çàâèñèìîå ñâÿçûâàíèå G-áåëêîâ ñ äðóãèìè êëåòî÷íûìè áåëêàìè, òàêèìè êàê b-àððåñòèí èëè RGS áåëêàìè (ðåãóëÿòîð G-áåëîê ñèãíàëèçàöèè) è ìîäóëè-ðîâàòü àêòèâíîñòü îïèîèäíûõ k-ðåöåïòîðîâ [9, 10]. Äðóãèì âàaeíûì ó÷àñòêîì ôîñôîðèëèðîâàíèÿ ÿâëÿåò-ñÿ îñòàòîê ñåðèíà Ser 369 íà C-òåðìèíàëè [11]. Ðàñïðåäåëåíèå è ôóíêöèè îïèîèäíûõ k-ðåöåïòîðîâÎïèîèäíûå k-ðåöåïòîðû ïðåäñòàâëåíû êàê â ÖÍÑ [5,12], òàê è íà ïåðèôåðèè [13,14], è ñïåöèôè÷åñêè àêòèâèðóþòñÿ ýíäîãåííûìè ëèãàíäàìè, îáðàçóþùè-ìèñÿ èç ïðîäèíîðôèíà [...

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“…[2] The primary tissue damage caused by the mechanical effects of head trauma cannot be treated, [3] but efforts are made to modify the processes and minimize the consequences of secondary brain injury that occurs within minutes, hours, or days after the trauma. [4][5][6] Posttraumatic brain edema is one of the pathophysiologic events occurring late as a secondary injury mechanism, and is thought to be generated in part by vasogenic edema due to blood brain barrier (BBB) breakdown and in part by cytotoxic edema. [7] Increases in brain cyclooxygenase-2 (COX-2) are associated with the central inflammatory response and delayed neuronal death, both of which cause secondary insults after traumatic brain injury (TBI).…”

Section: Sonuçmentioning

confidence: 99%

The effects of lornoxicam on brain edema and blood brain barrier following diffuse traumatic brain injury in rats

Topçu

Gümüşer²,

Bayram³

et al. 2013

Ulus Travma Acil Cerrahi Derg

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Pharmacological strategies in CNS trauma

Cited by 204 publications

References 28 publications

Dynorphin A (1–13) Neurotoxicity in Vitro: Opioid and Non-Opioid Mechanisms in Mouse Spinal Cord Neurons

Dynorphin A (1–13) Neurotoxicity in Vitro: Opioid and Non-Opioid Mechanisms in Mouse Spinal Cord Neurons

Опиоидные Κ-Рецепторы Как Молекулярная Мишень Для Создания Нового Поколения Обезболивающих Лекарственных Средств

The effects of lornoxicam on brain edema and blood brain barrier following diffuse traumatic brain injury in rats

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