intranasal-administration-of-cns-therapeutics-to-awake-mice

Intranasal Administration of CNS Therapeutics to Awake Mice

Intranasal administration is a method of delivering  therapeutic agents to the central nervous system (CNS). It is  non-invasive and allows large ...

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Arachidonic acid (AA), released in response to muscarinic acetylcholine receptor (mAChR) stimulation, previously has been reported to function as a reversible feedback inhibitor of the mAChR. To determine if the effects of AA on binding to the mAChR are subtype specific and whether AA inhibits ligand binding to other G protein-coupled receptors (GPCRs), the effects of AA on ligand binding to the mAChR subtypes (M1, M2, M3, M4, and M5) and to the micro-opioid receptor, beta2-adrenergic receptor (beta2-AR), 5-hydroxytryptamine receptor (5-HTR), and nicotinic receptors were examined. AA was found to inhibit ligand binding to all mAChR subtypes, to the beta2-AR, the 5-HTR, and to the micro-opioid receptor. However, AA does not inhibit ligand binding to the nicotinic receptor, even at high concentrations of AA. Thus, AA inhibits several types of GPCRs, with 50% inhibition occurring at 3-25 MuM, whereas the nicotinic receptor, a non-GPCR, remains unaffected. Further research is needed to determine the mechanism by which AA inhibits GPCR function.

Inhibition of ligand binding to G protein-coupled receptors by arachidonic acid.

Lib&eacute;r&eacute; en r&eacute;ponse &agrave; la stimulation des r&eacute;cepteurs (mAChR) muscariniques de l&#39;ac&eacute;tylcholine, l&#39;acide arachidonique (AA), pr&eacute;c&eacute;demment a &eacute;t&eacute; signal&eacute; pour fonctionner comme un inhibiteur r&eacute;versible de r&eacute;troaction de la mAChR. Afin de d&eacute;terminer si les effets de l&#39;AA sur la liaison &agrave; la mAChR sous-type sp&eacute;cifique et si AA inhibe la liaison du ligand d&#39;autres G protein-coupled receptors (RCPG), les effets de l&#39;AA sur la liaison du ligand pour les sous-types mAChR (M1, M2, M3, M4 et M5) et le r&eacute;cepteur opio&iuml;de micro, r&eacute;cepteurs b&ecirc;ta2-adr&eacute;nergiques (b&ecirc;ta2-AR), le r&eacute;cepteur 5-hydroxytryptamine (5-dB) et les r&eacute;cepteurs nicotiniques ont &eacute;t&eacute; examin&eacute;s. AA a &eacute;t&eacute; trouv&eacute; pour inhiber la liaison du ligand &agrave; tous les sous-types de mAChR, &agrave; la b&ecirc;ta2-AR, la 5-dB et pour le r&eacute;cepteur micro-opio&iuml;de. Cependant, AA n&#39;inhibe pas la liaison du ligand au r&eacute;cepteur nicotinique, m&ecirc;me &agrave; des concentrations &eacute;lev&eacute;es d&#39;AA. Ainsi, AA inhibe plusieurs types des RCPG, avec 50 % d&#39;inhibition se produisant &agrave; la maman de 3-25, tandis que le r&eacute;cepteur nicotinique, un non-RCPG, demeure inchang&eacute;e. Il faut poursuivre les recherches afin de d&eacute;terminer le m&eacute;canisme par lequel AA inhibe la fonction GPCR.

Inhibition de la liaison du ligand pour les r&eacute;cepteurs coupl&eacute;s aux prot&eacute;ines G par l&#39;acide arachidonique.

Acido arachidonico (AA), rilasciato in risposta alla stimolazione (mAChR) recettori muscarinici dell&#39;acetilcolina, in precedenza &egrave; stato segnalato per funzionare come un inibitore reversibile feedback del mAChR. Per determinare se gli effetti di AA associazione per il mAChR sono sottotipo specifico e se AA inibisce il legame ligando con altre proteine recettori accoppiati G (GPCR), gli effetti di AA su Associazione ligando per i sottotipi di mAChR (M1, M2, M3, M4 e M5) e il micro-oppioidi recettore, recettori beta2-adrenergici (beta2-AR), sono stati esaminati, recettore 5-idrossitriptamina (5-HTR) e recettori nicotinici. AA &egrave; stato trovato per inibire il legame ligando per tutti i sottotipi di mAChR, beta2-AR, 5-HTR e il recettore di micro-oppioidi. Tuttavia, AA non inibisce legame del ligando al recettore nicotinico, anche a concentrazioni elevate di AA. Cos&igrave;, AA inibisce diversi tipi di GPCR, con inibizione del 50% che si verificano a mamma 3-25, mentre il recettore nicotinico, un non-GPCR, rimane inalterato. Sono necessarie ulteriori ricerche per determinare il meccanismo mediante il quale AA inibisce la funzione GPCR.

Inibizione del legame ligando di recettori accoppiati a proteine G di acido arachidonico.

&Aacute;cido araquid&oacute;nico (AA), aparecido en respuesta a la estimulaci&oacute;n de receptores (mAChR) muscar&iacute;nico, previamente se ha divulgado para funcionar como un inhibidor reversible de la regeneraci&oacute;n de la mAChR. Para determinar si los efectos de AA en Uni&oacute;n a la mAChR subtipo espec&iacute;fico y si AA inhibe ligando a otros G prote&iacute;na-junt&oacute; los receptores (GPCRs), los efectos de AA en el ligando para los subtipos de mAChR (M1, M2, M3, M4 y M5) y el micro-opioid receptor, receptor beta2-adren&eacute;rgico (beta2-AR), el receptor 5-Hidroxitriptamina (5-HTR) y los receptores nicot&iacute;nicos fueron examinados. AA fue encontrado para inhibir ligando todos los subtipos de mAChR, beta2-AR, el reactor de 5 y el receptor del micro-opioide. No obstante, AA no inhibe ligando al receptor nicot&iacute;nico, incluso a altas concentraciones de AA. Por lo tanto, AA inhibe varios tipos de GPCRs, con 50% de inhibici&oacute;n que ocurren en la momia 3-25, mientras que los receptores nicot&iacute;nicos, un no-GPCR, permanece invariable. Se necesitan m&aacute;s investigaciones para determinar el mecanismo por el cual AA inhibe la funci&oacute;n GPCR.

Inhibici&oacute;n de ligando de receptores acoplados a prote&iacute;na de G de &aacute;cido araquid&oacute;nico.

Intranasal administration is emerging as a reliable and non-invasive method to bypass the blood-brain barrier and deliver drugs to the brain. This approach has been primarily used to explore therapeutic avenues for neurological diseases. However, intranasal administration could also be used to create animal models of brain disease. Beta-amyloid peptide (AÎ²) accumulation is a key feature of Alzheimer's disease (AD), and the most common models of AD are transgenic mice expressing mutant human genes linked to familial AD. An alternative model of amyloidosis utilizes intracerebroventricular infusion of thiorphan or phosphoramidon to block the activity of key AÎ² degrading enzymes (NEP, NEP2) resulting in accumulation of AÎ². Here, we demonstrate that intranasal administration of phosphoramidon produces significantly elevated cerebral AÎ² levels in wild-type mice. Furthermore, intranasal phosphoramidon administration in double knockout mice lacking NEP and NEP2 also showed increased levels of AÎ²(40). These data show that intranasal delivery of drugs can be used to model AD and suggest that other phosphoramidon-sensitive peptidases are degrading AÎ² in NEP/NEP2-deficient mice.

Intranasal phosphoramidon increases beta-amyloid levels in wild-type and NEP/NEP2-deficient mice.

Administration intranasale est en train de devenir une m&eacute;thode fiable et non invasive pour contourner la barri&egrave;re h&eacute;mato - enc&eacute;phalique et lib&eacute;rer des m&eacute;dicaments du cerveau. Cette approche a d&#39;abord &eacute;t&eacute; utilis&eacute;e pour explorer des avenues th&eacute;rapeutiques pour les maladies neurologiques. Toutefois, l&#39;administration intranasale pourrait &eacute;galement servir &agrave; cr&eacute;er des mod&egrave;les animaux de cancer du cerveau. Accumulation du peptide b&ecirc;ta-amylo&iuml;de (A&szlig;) est un &eacute;l&eacute;ment cl&eacute; de la maladie d&#39;Alzheimer (ma), et les mod&egrave;les les plus courants des AD sont des souris transg&eacute;niques exprimant des g&egrave;nes humains mutants li&eacute;s &agrave; AD familial. Un mod&egrave;le alternatif de l&#39;amylose utilise une perfusion intrac&eacute;r&eacute;broventriculaire de thiorphan ou phosphoramidon pour bloquer l&#39;activit&eacute; des enzymes d&eacute;gradants A&beta; cl&eacute;s (NEP, NEP2) ce qui entra&icirc;ne l&#39;accumulation de b&ecirc;ta-amylo&iuml;des. Ici, nous d&eacute;montrons que l&#39;administration intranasale de phosphoramidon produit significativement &eacute;lev&eacute;s les niveaux de b&ecirc;ta-amylo&iuml;des c&eacute;r&eacute;brales chez les souris de type sauvage. En outre, administration intranasale phosphoramidon en double les souris knock-out manque NEP et NEP2 aussi a montr&eacute; des niveaux accrus de A&beta;(40). Ces donn&eacute;es montrent qu&#39;intranasale de m&eacute;dicaments peut &ecirc;tre utilis&eacute; pour mod&eacute;liser des AD et sugg&egrave;rent qu&#39;autres peptidases phosphoramidon sensibles sont d&eacute;gradants A&beta; dans souris NEP/NEP2-d&eacute;ficientes.

Phosphoramidon intranasale augmente les niveaux de b&ecirc;ta-amylo&iuml;de dans le type sauvage et souris NEP/NEP2-d&eacute;ficientes.

Somministrazione intranasale sta emergendo come un metodo affidabile e non invasivo per aggirare la barriera sangue - cervello e fornire i farmaci al cervello. Questo approccio &egrave; stato utilizzato principalmente per esplorare vie terapeutiche per le malattie neurologiche. Tuttavia, somministrazione intranasale potrebbe essere utilizzato anche per creare modelli animali di malattia del cervello. Accumulo del peptide beta-amiloide (A&beta;) &egrave; una caratteristica fondamentale della malattia di Alzheimer (AD), e i pi&ugrave; comuni modelli di annuncio sono topi transgenici che esprimono geni umani mutanti legati al familiare AD. Un modello alternativo di amiloidosi utilizza intracerebroventricular infusione di thiorphan o phosphoramidon di bloccare l&#39;attivit&agrave; di A&beta; degradanti enzimi chiave (NEP, NEP2) con conseguente accumulo di A&beta;. Qui, ci dimostrano che la somministrazione intranasale di phosphoramidon produce livelli A&beta; cerebrali significativamente elevati nei topi wild-type. Inoltre, la somministrazione intranasale phosphoramidon double topi knockout difettare NEP e NEP2 anche ha mostrato aumento dei livelli di A&beta;(40). Questi dati mostrano che intranasale consegna dei farmaci pu&ograve; essere utilizzato per modellare AD e suggeriscono che altre peptidasi phosphoramidon-sensibili sono degradanti A&beta; in mouse NEP/NEP2-carenti.

Phosphoramidon intranasale aumenta i livelli di beta-amiloide nel wild-type e mouse NEP/NEP2-carenti.

La administraci&oacute;n intranasal se perfila como un m&eacute;todo fiable y no invasivo para eludir la barrera hemato - encef&aacute;lica y administrar medicamentos al cerebro. Este enfoque se ha utilizado principalmente para explorar v&iacute;as terap&eacute;uticas para enfermedades neurol&oacute;gicas. Sin embargo, la administraci&oacute;n intranasal tambi&eacute;n podr&iacute;a utilizarse para crear modelos animales de enfermedad cerebral. Acumulaci&oacute;n del p&eacute;ptido beta-amiloide (A&szlig;) es una caracter&iacute;stica clave de la enfermedad de Alzheimer (EA), y los modelos m&aacute;s comunes de la EA son ratones transg&eacute;nicos que expresaban genes humanos mutantes ligados a AD familiar. Un modelo alternativo de amiloidosis utiliza infusi&oacute;n intracerebroventricular de tiorfano o fosforamidon para bloquear la actividad de enzimas degradantes claves A&beta; (NEP, NEP2) lo que resulta en acumulaci&oacute;n de A&szlig;. Aqu&iacute;, demostramos que la administraci&oacute;n intranasal de fosforamidon produce niveles significativamente elevados de A&szlig; cerebrales en ratones de tipo salvaje. Adem&aacute;s, la administraci&oacute;n intranasal fosforamidon en doble ratones knockout que carecen de NEP y NEP2 tambi&eacute;n demostr&oacute; aumento en los niveles de A&beta;(40). Estos datos demuestran que entrega intranasal de drogas puede utilizarse para modelo AD y sugieren que otras peptidasas fosforamidon sensibles son degradantes A&beta; en ratones NEP/NEP2-deficientes.

Fosforamidon intranasal aumenta los niveles de beta-amiloide en el tipo salvaje y ratones NEP/NEP2-deficientes.

Intranasal delivery has been shown to target peptide therapeutics to the central nervous system (CNS) of animal models and induce specific neurological responses. In an investigation into the pathways by which intranasal administration delivers insulin to the CNS, this study has focused on the direct delivery of insulin from the olfactory mucosa to the olfactory bulbs via the olfactory nerve pathway.

Intranasal delivery of insulin via the olfactory nerve pathway.

Intranasale s&#39;est av&eacute;r&eacute; d&#39;une cible th&eacute;rapeutique de peptide au syst&egrave;me nerveux central (CNS) de mod&egrave;les animaux et induisent des r&eacute;ponses neurologiques sp&eacute;cifiques. Dans une enqu&ecirc;te sur les voies par lequel l&#39;administration intranasale offre l&#39;insuline dans le SNC, cette &eacute;tude a port&eacute; sur l&#39;offre directe d&#39;insuline de la muqueuse olfactive aux bulbes olfactifs via la voie du nerf olfactif.

Intranasale d&#39;insuline par la voie du nerf olfactif.

Consegna intranasale ha dimostrato therapeutics del peptide per il sistema nervoso centrale (CNS) di modelli animali di destinazione e di indurre risposte neurologiche specifiche. In un&#39;inchiesta i percorsi da cui somministrazione intranasale eroga insulina al CNS, questo studio si &egrave; concentrato sulla consegna diretta di insulina dalla mucosa olfattiva ai bulbi olfattivi attraverso il pathway del nervo olfattivo.

Article	Year
Inhibition of ligand binding to G protein-coupled receptors by arachidonic acid. Journal of molecular neuroscience : MN\| PubMed ID: 16186629	2005
Intranasal phosphoramidon increases beta-amyloid levels in wild-type and NEP/NEP2-deficient mice. Journal of molecular neuroscience : MN\| PubMed ID: 20941644	2011
Intranasal delivery of insulin via the olfactory nerve pathway. The Journal of pharmacy and pharmacology\| PubMed ID: 23146033	2012

Aleta L. Svitak

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