RESUMEN
BACKGROUND: Muscarinic or 5-HT1A receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits. METHODS: Novel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT1A receptor agonist (F15599) alone or in combinations with VU0357017 (M1 receptor allosteric agonist), VU0152100 (M4 receptor positive allosteric modulator), and VU0238429 (M5 receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT1A receptors and the level of GAD65 in the frontal cortices (FCs) and hippocampi of the animals. RESULTS: F15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptors activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT1A expression in the hippocampi and decreased GAD65 levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained animals. No effects of the compounds were observed in untrained mice. CONCLUSION: Our results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptors activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptors activators reversed MK-801-induced 5-HT1A and GAD65 dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice.
Asunto(s)
Maleato de Dizocilpina , Serotonina , Ratones , Animales , Maleato de Dizocilpina/farmacología , Receptores Muscarínicos , Encéfalo , Colinérgicos/farmacología , Receptor de Serotonina 5-HT1ARESUMEN
The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer's disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were shown to be effective procognitive compounds, but little is known about their impact on eNOS expression and stability. Here, we investigated the influence of the acute and chronic administration of LY487379 or CDPPB (mGlu2 and mGlu5 PAMs), on eNOS expression in the mouse brain and the effect of the joint administration of the ligands with nitric oxide (NO) releasers, spermineNONOate or DETANONOate, in different combinations of doses, on MK-801- or scopolamine-induced amnesia in the novel object recognition (NOR) test. Our results indicate that both compounds provoked eNOS monomer formation, and CDPPB at a dose of 5 mg/kg exaggerated the effect of MK-801 or scopolamine. The coadministration of spermineNONOate or DETANONOate enhanced the antiamnesic effect of CDPPB or LY487379. The best activity was observed for ineffective or moderate dose combinations. The results indicate that treatment with mGluR2 and mGluR5 PAMs may be burdened with the risk of promoting eNOS uncoupling through the induction of dimer dissociation. Administration of the lowest possible doses of the compounds with NO⢠donors, which themselves have procognitive efficacy, may be proposed for the treatment of schizophrenia or AD.
Asunto(s)
Benzamidas , Disfunción Cognitiva , Maleato de Dizocilpina , Compuestos Nitrosos , Pirazoles , Piridinas , Sulfonamidas , Ratones , Animales , Maleato de Dizocilpina/farmacología , Óxido Nítrico/farmacología , Escopolamina/farmacología , Óxido Nítrico Sintasa de Tipo III , Disfunción Cognitiva/tratamiento farmacológico , Encéfalo , Regulación AlostéricaRESUMEN
The Morris water maze (MWM) is regarded as one of the most popular tests for detecting spatial memory in rodents. Long-term potentiation and cGMP synthesis seem to be among the crucial factors involved in this type of learning. Muscarinic (M1, M4, and M5 receptors) and metabotropic glutamate (mGlu) receptors are important targets in the search for antipsychotic drugs with the potency to treat cognitive disabilities associated with the disorder. Here, we show that muscarinic receptor activators (VU0357017, VU0152100, and VU0238429) and an mGlu2 receptor activator, LY487379, dose-dependently prevented the development of cognitive disorders as a result of MK-801 administration in the MWM. The dose-ranges of the compounds were as follows: VU0357017, 0.25, 0.5, and 1 mg/kg; VU0152100, 0.05, 0.25, and 1 mg/kg; VU0238429, 1, 5, and 20 mg/kg; and LY487379, 0.5, 3, and 5 mg/kg. The co-administration of LY487379 with each of the individual muscarinic receptor ligands showed no synergistic effect, which contradicts the results obtained earlier in the novel object recognition (NOR) test. MWM learning resulted in increased cGMP synthesis, both in the cortex and hippocampi, when compared to that in intact animals, which was prevented by MK-801 administration. The investigated compounds at the highest doses reversed this MK-801-induced effect. Neither the procedure nor the treatment resulted in changes in GluN2B-NMDA expression.
Asunto(s)
Maleato de Dizocilpina , Receptores de Glutamato Metabotrópico , Animales , Maleato de Dizocilpina/farmacología , Receptores de Glutamato Metabotrópico/metabolismo , Ácido Glutámico , N-Metilaspartato , Prueba del Laberinto Acuático de Morris , Receptores MuscarínicosRESUMEN
Accumulating evidence indicates that early adverse life experiences may be involved in the pathogenesis of Alzheimer's disease (AD). Prenatal stress (PS) can affect brain maturation and neuroimmune and metabolic interactions, leading to age-dependent cognitive deficits in offspring. However, a multi-faceted cause-and-effect impact of PS on the development of cognitive deficits in the process of physiological ageing and in the APPNL-F/NL-F mouse model of Alzheimer's disease has not yet been evaluated. We have identified age-dependent cognitive learning and memory deficits using male C57BL/6 J (wild type, WT) and the knock-in APPNL-F/NL-F (KI) aged 12, 15, and 18 months. An increase in the Aß42/Aß40 ratio and mouse ApoE levels in the hippocampus and frontal cortex preceded the onset of cognitive deficits in the KI mice. Moreover, dysfunction in insulin signaling, including increased IRS-1 serine phosphorylation in both brain areas and the tyrosine phosphorylation deficit in the frontal cortex, suggested age-dependent insulin/IGF-1 resistance. Resistance was reflected by disturbances in mTOR or ERK1/2 kinase phosphorylation and excessive pro-inflammatory (TNF-α, IL-6, and IL-23) status in the KI mice. Importantly, our study has provided insights into the higher vulnerability to PS-induced exacerbation of age-dependent cognitive deficits and biochemical dysfunction in KI mice than in WT animals. We anticipate our study will lead to future investigation of a multi-faceted cause-and-effect relationship between stress during neurodevelopment and the onset of AD pathology, distinguishing it from changes in the course of dementia during normal ageing.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Femenino , Embarazo , Masculino , Ratones , Animales , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Insulina , Ratones Transgénicos , Ratones Endogámicos C57BL , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismoRESUMEN
Learning and memory deficits accompany numerous brain dysfunctions, including schizophrenia and Alzheimer's disease (AD), and many studies point to the role of nitric oxide (NO) in these processes. The present investigations constitute the follow-up of our previous research, in which we investigated the activity of NO releasers and a selective inhibitor of neuronal NO synthase (nNOS) to prevent short-term memory deficits in novel object recognition and T-maze. Here, the ability of the compounds to prevent the induction of long-term memory deficits by MK-801 or scopolamine administration was investigated. The Morris Water Maze test, a reliable and valid test of spatial learning and memory, was used, in which escape latency in the acquisition phase and nine different parameters in the retention phase were measured. A fast NO releaser (spermine NONOate), a slow NO releaser (DETA NONOate), and a nNOS inhibitor, N(ω)-propyl-L-arginine (NPLA), were used. The compounds were administered i.p. at a dose range of 0.05-0.5 mg/kg. All compounds prevented learning deficits in the acquisition phase and reversed reference memory deficits in the retention phase of the scopolamine-treated mice. Spermine NONOate was the least effective. In contrast, the drugs poorly antagonised MK-801-induced deficits, and only the administration of DETA NONOate induced some improvements in the retention trial.
RESUMEN
Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3H)-one (A9-7, ALX-171, mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment.
Asunto(s)
Antipsicóticos , Quinazolinonas , Receptores de Glutamato Metabotrópico , Esquizofrenia , Animales , Humanos , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Maleato de Dizocilpina , Quinazolinonas/farmacología , Quinazolinonas/uso terapéutico , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Diseño de FármacosRESUMEN
The mGlu7 receptor belongs to the III group of metabotropic glutamatergic (mGlu) receptors and physiologically serves as an "emergency" receptor that is activated by high, almost pathological, glutamate concentrations. Of all mGlu receptors, this receptor is most highly expressed in the brain. Additionally, relatively intense expression of the receptor was found at the periphery, for example in the bowels or in the reproductive system of male mice, but this review will be focused predominantly on its role in the brain. In the CNS, the receptor is expressed presynaptically, in the center of the synaptic cleft, at the terminals of both excitatory glutamatergic and inhibitory GABAergic neurons. Thus, it may regulate the release of both glutamate and GABA. Schizophrenia is thought to develop as a consequence of a disturbed glutamatergic-GABAergic balance in different parts of the brain. Thus, the mGlu7 receptor may be involved in the pathophysiology of schizophrenia and consequently constitute the target for antipsychotic drug discovery. In this review, we summarize the available data about mGlu7 receptor ligands and their activity in animal models of schizophrenia. At present, only a few ligands are available, and negative allosteric modulators (NAMs) appear to exert antipsychotic-like efficacy, indicating that the inhibition of the receptor could constitute a promising target in the search for novel drugs. Additionally, the data concerning the expression of the receptor in the CNS and putative mechanisms by which its inhibition may contribute to the treatment of schizophrenia will be discussed. Finally, the polymorphisms of genes encoding the receptor in schizophrenic patients will also be provided.
Asunto(s)
Antipsicóticos , Receptores de Glutamato Metabotrópico , Esquizofrenia , Animales , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Ácido Glutámico , Ligandos , Masculino , Ratones , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismoRESUMEN
Nitric oxide is a small gaseous molecule that plays important roles in the majority of biological functions. Impairments of NO-related pathways contribute to the majority of neurological disorders, such as Alzheimer's disease (AD), and mental disorders, such as schizophrenia. Cognitive decline is one of the most serious impairments accompanying both AD and schizophrenia. In the present study, the activities of NO donors, slow (spermine NONOate) or fast (DETANONOate) releasers, and selective inhibitor of neuronal nitric oxide synthase N(ω)-propyl-l-arginine (NPLA) were investigated in pharmacological models of schizophrenia and AD. Cognitive impairments were induced by administration of MK-801 or scopolamine and were measured in novel object recognition (NOR) and Y-maze tests. The compounds were investigated at doses of 0.05-0.5 mg/kg. The dose-dependent effectiveness of all the compounds was observed in the NOR test, while only the highest doses of spermine NONOate and NPLA were active in the Y-maze test. DETANONOate was not active in the Y-maze test. The impact of the investigated compounds on motor coordination was tested at doses of 0.5 and 1 mg/kg. Only NPLA at a dose of 1 mg/kg slightly disturbed motor coordination in animals.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Donantes de Óxido Nítrico/uso terapéutico , Óxido Nítrico/metabolismo , Nootrópicos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Enfermedad de Alzheimer/inducido químicamente , Animales , Arginina/análogos & derivados , Arginina/uso terapéutico , Disfunción Cognitiva/inducido químicamente , Maleato de Dizocilpina , Inhibidores Enzimáticos/uso terapéutico , Masculino , Ratones , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo I/antagonistas & inhibidores , Compuestos Nitrosos/uso terapéutico , Prueba de Campo Abierto/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Esquizofrenia/inducido químicamente , Escopolamina , Espermina/análogos & derivados , Espermina/uso terapéuticoRESUMEN
MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or chronic administration of either compound. The present experiments were performed to study the nitric oxide (NO)-related mechanisms underlying memory dysfunction induced by acute or chronic (14 days) administration of MK-801 (0.3 mg/kg, i.p.) or scopolamine (1 mg/kg, i.p.). The levels of L-arginine and its derivatives, L-citrulline, L-glutamate, L-glutamine and L-ornithine, were measured. The expression of constitutive nitric oxide synthases (cNOS), dimethylaminohydrolase (DDAH1) and protein arginine N-methyltransferases (PMRTs) 1 and 5 was evaluated, and the impact of the studied tool compounds on cGMP production and NMDA receptors was measured. The studies were performed in both the cortex and hippocampus of mice. S-nitrosylation of selected proteins, such as GLT-1, APP and tau, was also investigated. Our results indicate that the availability of L-arginine decreased after chronic administration of MK-801 or scopolamine, as both the amino acid itself as well as its level in proportion to its derivatives (SDMA and NMMA) were decreased. Additionally, among all three methylamines, SDMA was the most abundant in the brain (~70%). Administration of either compound impaired eNOS-derived NO production, increasing the monomer levels, and had no significant impact on nNOS. Both compounds elevated DDAH1 expression, and slight decreases in PMRT1 and PMRT5 in the cortex after scopolamine (acute) and MK-801 (chronic) administration were observed in the PFC, respectively. Administration of MK-801 induced a decrease in the cGMP level in the hippocampus, accompanied by decreased NMDA expression, while increased cGMP production and decreased NMDA receptor expression were observed after scopolamine administration. Chronic MK-801 and scopolamine administration affected S-nitrosylation of GLT-1 transport protein. Our results indicate that the analyzed tool compounds used in pharmacological models of schizophrenia or AD induce changes in NO-related pathways in the brain structures involved in cognition. To some extent, the changes resemble those observed in human samples.
Asunto(s)
Corteza Cerebral/metabolismo , Maleato de Dizocilpina/efectos adversos , Antagonistas de Aminoácidos Excitadores/efectos adversos , Hipocampo/metabolismo , Trastornos de la Memoria , Óxido Nítrico/metabolismo , Escopolamina/efectos adversos , Animales , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Ratones , Escopolamina/farmacologíaRESUMEN
Brain ischemia is one of the leading causes of disability and mortality worldwide. Nitric oxide (NOâ¢), a molecule that is involved in the regulation of proper blood flow, vasodilation, neuronal and glial activity constitutes the crucial factor that contributes to the development of pathological changes after stroke. One of the early consequences of a sudden interruption in the cerebral blood flow is the massive production of reactive oxygen and nitrogen species (ROS/RNS) in neurons due to NO⢠synthase uncoupling, which leads to neurotoxicity. Progression of apoptotic or necrotic neuronal damage activates reactive astrocytes and attracts microglia or lymphocytes to migrate to place of inflammation. Those inflammatory cells start to produce large amounts of inflammatory proteins, including pathological, inducible form of NOS (iNOS), which generates nitrosative stress that further contributes to brain tissue damage, forming vicious circle of detrimental processes in the late stage of ischemia. S-nitrosylation, hypoxia-inducible factor 1α (HIF-1α) and HIF-1α-dependent genes activated in reactive astrocytes play essential roles in this process. The review summarizes the roles of NOâ¢-dependent pathways in the early and late aftermath of stroke and treatments based on the stimulation or inhibition of particular NO⢠synthases and the stabilization of HIF-1α activity.
Asunto(s)
Isquemia Encefálica/patología , Hipoxia Encefálica/patología , Óxido Nítrico/metabolismo , Animales , Apoptosis , Progresión de la Enfermedad , Depuradores de Radicales Libres , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación , Isquemia , Linfocitos/metabolismo , Necrosis , Neuronas/metabolismo , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Estrés Oxidativo , Especies de Nitrógeno Reactivo , Especies Reactivas de OxígenoRESUMEN
Recent studies revealed that the activation of serotonergic 5-HT1A and muscarinic M1, M4, or M5 receptors prevent MK-801-induced cognitive impairments in animal models. In the present study, the effectiveness of the simultaneous activation of 5-HT1A and muscarinic receptors at preventing MK-801-induced cognitive deficits in novel object recognition (NOR) or Y-maze tests was investigated. Activators of 5-HT1A (F15599), M1 (VU0357017), M4 (VU0152100), or M5 (VU0238429) receptors administered at top doses for seven days reversed MK-801-induced deficits in the NOR test, similar to the simultaneous administration of subeffective doses of F15599 (0.05 mg/kg) with VU0357017 (0.15 mg/kg), VU0152100 (0.05 mg/kg), or VU0238429 (1 mg/kg). The compounds did not prevent the MK-801-induced impairment when administered acutely. Their activity was less evident in the Y-maze. Pharmacokinetic studies revealed high brain penetration of F15599 (brain/plasma ratio 620%), which was detected in the frontal cortex (FC) up to 2 h after administration. Decreases in the brain penetration properties of the compounds were observed after acute administration of the combinations, which might have influenced behavioral responses. This negative effect on brain penetration was not observed when the compounds were administered repeatedly. Based on our results, prolonged administration of a 5-HT1A activator with muscarinic receptor ligands may be effective at reversing cognitive decline related to schizophrenia, and the FC may play a critical role in this interaction.
Asunto(s)
Colinérgicos/farmacología , Disfunción Cognitiva/tratamiento farmacológico , Corteza Prefrontal/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Agonistas de Receptores de Serotonina/farmacología , Animales , Benzamidas/farmacocinética , Benzamidas/farmacología , Benzamidas/uso terapéutico , Barrera Hematoencefálica/metabolismo , Colinérgicos/farmacocinética , Colinérgicos/uso terapéutico , Disfunción Cognitiva/etiología , Maleato de Dizocilpina/toxicidad , Masculino , Aprendizaje por Laberinto , Ratones , Piperidinas/farmacocinética , Piperidinas/farmacología , Piperidinas/uso terapéutico , Corteza Prefrontal/metabolismo , Piridinas/farmacocinética , Piridinas/farmacología , Piridinas/uso terapéutico , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Receptores Muscarínicos/metabolismo , Receptores de Serotonina/metabolismo , Esquizofrenia/complicaciones , Agonistas de Receptores de Serotonina/farmacocinética , Agonistas de Receptores de Serotonina/uso terapéutico , Tiofenos/farmacocinética , Tiofenos/farmacología , Tiofenos/uso terapéuticoRESUMEN
A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.
Asunto(s)
Antipsicóticos/farmacología , Inhibidores de Captación de Dopamina/farmacología , Indoles/farmacología , Nootrópicos/farmacología , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Triptaminas/farmacología , Animales , Antipsicóticos/síntesis química , Familia 2 del Citocromo P450/metabolismo , Modelos Animales de Enfermedad , Inhibidores de Captación de Dopamina/síntesis química , Células Hep G2 , Humanos , Indoles/síntesis química , Ligandos , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/fisiopatología , Ratones , Modelos Moleculares , Estructura Molecular , Nootrópicos/síntesis química , Unión Proteica , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/metabolismo , Trastornos Psicóticos/fisiopatología , Receptores de Dopamina D2/metabolismo , Receptores de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Relación Estructura-Actividad , Triptaminas/síntesis químicaRESUMEN
The olfactory bulbectomized (OBX) rat model is a well-established model of depression in which antidepressant drugs reverse deficits in the passive avoidance test 14 days after administration. Recently, the olfactory bulbectomized rat model has been proposed to be a model of Alzheimer's disease (AD), and the available data indicate similarities between the changes that typically occur in AD and those observed in OBX animals. In the present study, the occurrence of neurochemical impairments related to AD were investigated 8 months after OB ablation. The expression of the nitric oxide synthases eNOS and nNOS, receptor for advanced glycation endproducts (RAGEs) and dimethylarginine dimethylaminohydrolase (DDAH1) in the prefrontal cortices (PFCs), hippocampi and striata of olfactory bulbectomized and sham-operated rats was evaluated. Subsequently, the impact of the administration of a positive allosteric modulator of the mGlu5 receptor, CDPPB (14 days, 2.5 or 5 mg/kg), on OBX-related changes was assessed. OB ablation induced typical deficits in passive avoidance. Significant aberrations in the expression of both isoforms of NOS were observed in the hippocampus and striatum, and the expression of DDAH1 was increased in the PFCs of OBX animals. CDPPB at a dose of 5 mg/kg ameliorated cognitive impairment in the passive avoidance test and partially reversed the changes in eNOS and nNOS expression induced by the lesion. The results of this study confirm that some of the neurochemical changes observed in OBX animals may resemble those associated with AD pathology and that activation of the mGlu5 receptor may partially counteract these pathological alterations.
Asunto(s)
Disfunción Cognitiva/metabolismo , Receptor del Glutamato Metabotropico 5/metabolismo , Enfermedad de Alzheimer/fisiopatología , Amidohidrolasas/metabolismo , Animales , Antidepresivos/metabolismo , Benzamidas/farmacología , Encéfalo/metabolismo , Disfunción Cognitiva/fisiopatología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Masculino , Sistema Nervioso/química , Óxido Nítrico Sintasa/metabolismo , Bulbo Olfatorio/fisiología , Corteza Prefrontal/metabolismo , Pirazoles/farmacología , Ratas , Ratas Sprague-Dawley , Receptor para Productos Finales de Glicación Avanzada/metabolismo , Receptor del Glutamato Metabotropico 5/efectos de los fármacosRESUMEN
Schizophrenia is a mental disorder that affects approximately 1-2% of the population and develops in early adulthood. The disease is characterized by positive, negative, and cognitive symptoms. A large percentage of patients with schizophrenia have a treatment-resistant disease, and the risk of developing adverse effects is high. Many researchers have attempted to introduce new antipsychotic drugs to the clinic, but most of these treatments failed, and the diversity of schizophrenic symptoms is one of the causes of disappointing results. The present review summarizes the results of our latest papers, showing that the simultaneous activation of two receptors with sub-effective doses of their ligands induces similar effects as the highest dose of each compound alone. The treatments were focused on inhibiting the increased glutamate release responsible for schizophrenia arousal, without interacting with dopamine (D2) receptors. Ligands activating metabotropic receptors for glutamate, GABAB or muscarinic receptors were used, and the compounds were administered in several different combinations. Some combinations reversed all schizophrenia-related deficits in animal models, but others were active only in select models of schizophrenia symptoms (i.e., cognitive or negative symptoms).
Asunto(s)
Antipsicóticos/uso terapéutico , Antagonistas Muscarínicos/uso terapéutico , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores Muscarínicos/metabolismo , Esquizofrenia/tratamiento farmacológico , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Combinación de Medicamentos , Descubrimiento de Drogas , Humanos , Receptores de Glutamato Metabotrópico/metabolismoRESUMEN
Cinnabarinic acid (CA) is a kynurenine metabolite that activates mGlu4 metabotropic glutamate receptors. Using a highly sensitive ultra-performance liquid chromatography/tandem mass spectrometry (UPLC/MS-MS) method, we found that CA is present in trace amounts in human brain tissue. CA levels were largely reduced in the prefrontal cortex (PFC) of individuals affected by schizophrenia. This reduction did not correlate with age, sex, duration of the disease, and duration and type of antipsychotic medication and might, therefore, represent a trait of schizophrenia. Interestingly, systemic treatment with low doses of CA (<1 mg/kg, i.p.) showed robust efficacy in several behavioral tests useful to study antipsychotic-like activity in mice and rats and attenuated MK-801-evoked glutamate release. CA failed to display antipsychotic-like activity and inhibit excitatory synaptic transmission in mice lacking mGlu4 receptors. These findings suggest that CA is a potent endogenous antipsychotic-like molecule and reduced CA levels in the PFC might contribute to the pathophysiology of schizophrenia.
Asunto(s)
Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Fenómenos Electrofisiológicos/efectos de los fármacos , Quinurenina/metabolismo , Oxazinas/metabolismo , Oxazinas/farmacología , Corteza Prefrontal/metabolismo , Receptores de Glutamato Metabotrópico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Adulto , Animales , Antipsicóticos/administración & dosificación , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Oxazinas/administración & dosificación , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/deficiencia , Bancos de TejidosRESUMEN
The activity of an allosteric agonist of muscarinic M1 receptor, VU0357017, and a positive allosteric modulator (PAM) of M5 receptor, VU0238429, were investigated alone or in combination with the mGlu2 receptor PAM, LY487379 using the following behavioural tests: prepulse inhibition (PPI), novel object recognition (NOR), and spatial delayed alternation (SDA). VU0357017 (10 and 20 mg/kg) and VU0238429 (5 and 10 mg/kg) reversed deficits in PPI while VU0238429 (2.5 and 5 mg/kg) was effective in SDA. The simultaneous administration of subeffective doses of M1 or M5 activators (5, 1, or 0.25 mg/kg) with LY487379 (0.5 mg/kg) induced the same effect as that observed for the active dose of each compound. Selective M1 or M5 receptor blockers antagonized the effect exerted by these combinations, and pharmacokinetic studies confirmed independent transport through the blood-brain barrier. The expression of both receptors (M1 and M5) was established in brain structures involved in cognition (neocortex, hippocampus, and entorhinal cortex) in both the rat and the mouse brains by immunofluorescence staining. Specifically, double neuronal staining of mGlu2-M1 and mGlu2-M5 receptors was observed in many areas of the rat brain, while the number of double-stained mGlu2-M1 receptors was moderate in the mouse brain with no mGlu2-M5 colocalization. Finally, the combined administration of subeffective doses of the compounds did not alter prolactin levels or motor coordination, in contrast to the compounds given alone at the highest dose or in combination with standard neuroleptics.
Asunto(s)
Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Maleato de Dizocilpina/toxicidad , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M5/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Antagonistas de Aminoácidos Excitadores/toxicidad , Masculino , Ratones , Piridinas/farmacología , Ratas , Ratas Wistar , Receptor Muscarínico M1/agonistas , Receptor Muscarínico M5/agonistas , Receptores de Glutamato Metabotrópico/agonistas , Sulfonamidas/farmacologíaRESUMEN
Negative and cognitive symptoms of schizophrenia contribute to an impaired social and professional life for schizophrenic patients, and in most cases, these symptoms are treatment resistant. Therefore, identification of new treatment strategies is sorely needed. Metabotropic glutamate receptors (mGlu) and muscarinic (M) receptors for acetylcholine have been considered promising targets for novel antipsychotics. Among them, mGlu2 and M4 subtypes seem to be of particular importance. In the present study, the effect of mutual activation of mGlu2 and M4 receptors was assessed in MK-801-based animal models of negative and cognitive symptoms of schizophrenia, that is, social interaction and novel object recognition tests. Low sub-effective doses of LY487379 (0.5 mg/kg), a positive allosteric activator of the mGlu2 receptor, and VU152100 (0.25-0.5 mg/kg), a positive allosteric modulator of the M4 receptor, were simultaneously administered in the aforementioned tests. Combined administration of these compounds prevented MK-801-induced disturbances in social interactions and object recognition when acutely administered 30 min before MK-801. Prolonged (7 days) administration of these compounds resulted in the loss of effectiveness in preventing MK-801-induced disruptions in the novel object recognition test but not in the social interaction test. In the next set of experiments, MK-801 (0.3 mg/kg) was administered for seven consecutive days, and the activity of the compounds was investigated on day eight, during which time MK-801 was not administered. In this model, based on prolonged MK-801 administration, the effectiveness of the compounds to treat MK-801-induced disruptions was evident at low doses which were ineffective in preventing the behavioural disturbances induced by an acute MK-801 injection. Combined administration of the compounds did not exert better efficacy than each compound given alone. Pharmacokinetic analysis confirmed a lack of possible drug-drug interactions after combined administration of LY487379 and VU152100. Our data show that modulation of M4 and mGlu2 receptors may potentially be beneficial in the treatment of negative and cognitive symptoms of schizophrenia.
Asunto(s)
Antipsicóticos/uso terapéutico , Benzamidas/uso terapéutico , Memoria a Corto Plazo/efectos de los fármacos , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Conducta Social , Sulfonamidas/uso terapéutico , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacología , Benzamidas/administración & dosificación , Benzamidas/farmacología , Maleato de Dizocilpina/toxicidad , Quimioterapia Combinada , Agonistas de Aminoácidos Excitadores/administración & dosificación , Agonistas de Aminoácidos Excitadores/farmacología , Agonistas de Aminoácidos Excitadores/uso terapéutico , Antagonistas de Aminoácidos Excitadores/toxicidad , Masculino , Ratones , Pirazoles/administración & dosificación , Pirazoles/farmacología , Piridinas/administración & dosificación , Piridinas/farmacología , Receptor Muscarínico M4/efectos de los fármacos , Receptores de Glutamato , Esquizofrenia/etiología , Sulfonamidas/administración & dosificación , Sulfonamidas/farmacologíaRESUMEN
Recent preclinical studies point to muscarinic and GABAB receptors as novel therapeutic targets for the treatment of schizophrenia. This study was aimed to assess the role of muscarinic and GABAB receptor interactions in animal models of schizophrenia, using positive allosteric modulators (PAMs) of GABAB receptor (GS39783), muscarinic M4 (VU0152100) and M5 (VU0238429) receptor, and partial allosteric agonist of M1 receptor (VU0357017). DOI-induced head twitches, social interaction and novel object recognition tests were used as the models of schizophrenia. Analyses of DOI-induced increases in sEPSCs (spontaneous excitatory postsynaptic currents) were performed as complementary experiments to the DOI-induced head twitch studies. Haloperidol-induced catalepsy and the rotarod test were used to examine the adverse effects of the drugs. All three activators of muscarinic receptors were active in DOI-induced head twitches. When administered together with GS39783 in subeffective doses, only the co-administration of VU0152100 and GS39783 was effective. The combination also reduced the frequency but not the amplitude of DOI-induced sEPSCs. Neither VU0357017 nor VU0238429 were active in social interaction test when given alone, and also the combination of VU0152100 and GS39783 failed to reverse MK-801-induced deficits observed in this test. All muscarinic activators when administered alone or in combination with GS39783 reversed the MK-801-induced disruption of memory in the novel object recognition test, and their actions were blocked by specific antagonists. None of the tested compounds or their combinations influenced the motor coordination of the animals. The compounds had no effect on haloperidol-induced catalepsy and did not induce catalepsy when administered alone. Pharmacokinetic analysis confirmed lack of possible drug-drug interactions after combined administration of GS39783 with VU0357017 or VU0152100; however, when the drug was co-administered with VU0238429 its ability to pass the blood-brain barrier slightly decreased, suggesting potential drug-drug interactions. Our data show that modulation of cholinergic and GABAergic systems can potentially be beneficial in the treatment of the positive and cognitive symptoms of schizophrenia without inducing the adverse effects typical for presently used antipsychotics.
Asunto(s)
Antipsicóticos/farmacología , Neurotransmisores/farmacología , Receptores de GABA-B/metabolismo , Receptores Muscarínicos/metabolismo , Esquizofrenia/tratamiento farmacológico , Regulación Alostérica , Animales , Antipsicóticos/farmacocinética , Benzamidas/farmacocinética , Benzamidas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ciclopentanos/farmacocinética , Ciclopentanos/farmacología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Indoles/farmacocinética , Indoles/farmacología , Masculino , Ratones , Neurotransmisores/farmacocinética , Piridinas/farmacocinética , Piridinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Esquizofrenia/metabolismo , Tiofenos/farmacocinética , Tiofenos/farmacologíaRESUMEN
Close structural analogues of 5-carboxamidotryptamine (5-CT) based on the newly discovered indole-imidazole scaffold were synthesized and evaluated to search for a 5-HT7 receptor agonist of higher selectivity. In vitro drug-likeness studies and in vivo pharmacological evaluation of potent and selective low-basicity 5-HT7 receptor agonists, previously published 7 (3-(1-ethyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide, AH-494) and 13 (3-(1-methyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide), have supported their usefulness as pharmacological tools. Comprehensive in vitro comparison studies between 7, 13 and the commonly used 5-CT showed their very similar ADMET properties. Compound 7 at 1 mg kg-1 reversed MK-801-induced disruption in novel object recognition in mice and alleviated stress-induced hyperthermia (SIH) at high doses. Taking into account both in vitro and in vivo data, 7 and 13 may be considered as alternatives to 5-CT as pharmacological tools with important additional benefit associated with their low-basicity: high selectivity over 5-HT1AR.
RESUMEN
The data concerning antipsychotic-like activity of negative allosteric modulators (NAMs)/antagonists of mGlu7 receptors are limited. The only available ligands for this receptor are MMPIP and ADX71743. In the present studies, we used stable cell line expressing mGlu7 receptor and it was shown that both compounds dose-dependently potentiated forskolin elevated cAMP concentration in the T-REx 293 cells, showing their inverse agonist properties. Subsequently, pharmacokinetic studies were performed. Both compounds were given intraperitoneally (i.p.) at the dose of 10 mg/kg and reached Cmax 0.25-0.5 h after administration, and then they declined rapidly, ADX71743 being almost undetectable 2 h after administration, while the concentration of MMPIP was still observed, suggesting that the concentration of MMPIP was more stable. Finally, we investigated the role of both mGlu7 receptor NAMs in animal models of schizophrenia. Behavioral tests commonly used in antipsychotic drug discovery were conducted. Both tested compounds dose-dependently inhibited MK-801-induced hyperactivity (MMPIP at 15 mg/kg; ADX at 5 and 15 mg/kg) and DOI-induced head twitches (MMPIP at 5, 10, 15 mg/kg; ADX at 2.5, 5, 10 mg/kg). Moreover, the same effects were noticed in novel object recognition test, where MMPIP (5, 10, 15 mg/kg) and ADX71743 (1, 5, 15 mg/kg) reversed MK-801-induced disturbances. In the social interaction test, antipsychotic activity was observed only for ADX71743 (5, 15 mg/kg). ADX71743 at the dose 2.5 mg/kg reversed MK-801-induced disruption in prepulse inhibition while MMPIP at 10 mg/kg reversed MK-801-induced disruption in spatial delayed alternation. The present studies showed that mGlu7 receptor may be considered as a putative target for antipsychotic drugs, though more studies are needed due to limited number of available ligands.