RESUMEN
The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel that is critical to many processes in the brain. Genome-wide association studies suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity are important for body weight homeostasis1. Here we report the engineering and preclinical development of a bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycaemia and dyslipidaemia in rodent models of metabolic disease. GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects neuroplasticity in the hypothalamus and brainstem. Importantly, targeting of MK-801 to GLP-1 receptor-expressing brain regions circumvents adverse physiological and behavioural effects associated with MK-801 monotherapy. In summary, our approach demonstrates the feasibility of using peptide-mediated targeting to achieve cell-specific ionotropic receptor modulation and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for safe and effective obesity treatment.
Asunto(s)
Maleato de Dizocilpina , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Obesidad , Receptores de N-Metil-D-Aspartato , Animales , Humanos , Masculino , Ratones , Ratas , Tronco Encefálico/metabolismo , Tronco Encefálico/efectos de los fármacos , Modelos Animales de Enfermedad , Maleato de Dizocilpina/efectos adversos , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Dislipidemias/tratamiento farmacológico , Dislipidemias/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Receptor del Péptido 1 Similar al Glucagón/agonistas , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Ratones Endogámicos C57BL , Plasticidad Neuronal/efectos de los fármacos , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ratas Sprague-Dawley , Ratas Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidoresRESUMEN
Cannabidiol (CBD) is a promising neurological agent with potential beneficial effects on memory and cognitive function. The combination of CBD and topiramate in the treatment of some neurological diseases has been of great interest. Since Topiramate-induced memory loss is a major drawback of its clinical application and the overall effect of the combination of CBD and topiramate on memory is still unclear, here we investigated the effect of CBD on topiramate-induced memory loss and the underlying molecular mechanisms. A one trial step-through inhibitory test was used to evaluate memory consolidation in rats. Moreover, the role of N-methyl-D-aspartate receptors (NMDARs) in the combination of CBD and topiramate in memory consolidation was evaluated through the intra-CA1 administration of MK-801 and NMDA. Western blot analysis was used to evaluate variations in brain-derived neurotrophic factor (BDNF) and phosphorylated cyclic AMP response element-binding protein (pCREB)/CREB ratio in the prefrontal cortex (PFC) and hippocampus (HPC). While the intraperitoneal (i.p.) administration of topiramate (50, 75, and 100 mg/kg) significantly reduced inhibitory time latency, the i.p. administration of CBD (20 and 40 mg/kg) could effectively reverse these effects. Similarly, the sub-effective doses of NMDA plus CBD (10 mg/kg) could improve the topiramate-induced memory loss along with an enhancement in BDNF and pCREB expression in the PFC and HPC. Contrarily, the administration of sub-effective doses of the NMDAR antagonist (MK-801) diminished the protective effects of CBD (20 mg/kg) on topiramate-induced memory loss associated with decreased BDNF and pCREB levels in the PFC and HPC. These findings suggest that CBD can improve topiramate-induced memory impairment, partially by the NMDARs of the PFC and HPC, possibly regulated by the CREB/BDNF signaling pathway.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Cannabidiol , Ratas , Animales , Topiramato/uso terapéutico , Topiramato/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Maleato de Dizocilpina/metabolismo , N-Metilaspartato/metabolismo , Hipocampo/metabolismo , Transducción de Señal , Corteza Prefrontal/metabolismo , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Amnesia/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismoRESUMEN
BACKGROUND: NMDA receptors have a significant role in the development of opioid physical dependence. Evidence demonstrated that a drug of abuse enhances neuronal excitability in the Paraventricular Nucleus (PVT). The current research studied whether blocking NMDA receptors through the administration of MK801 in the PVT nucleus could affect the development of Morphine (Mor) dependence and hence the behavioral indices induced by morphine withdrawal in rats. METHODS: Male Wistar rats weighing 250-300 g were used. For induction of drug dependence, we injected Mor subcutaneously (s.c.) (6, 16, 26, 36, 46, 56, and 66 mg/kg, 2 ml/kg) at an interval of 24 hours for 7 days. Animals were divided into two groups in which the NMDA receptor antagonist, MK801 (20 mM in 0.1 ml), or its vehicle were applied into the PVT nucleus for 7 days before each Mor administration. On day 8, after injection of naloxone (Nal, 2.5 mg/kg, i.p.), withdrawal behaviors were checked for 25 min. RESULTS: The current results demonstrated that the blockade of the NMDA receptor in the PVT nucleus significantly increased withdrawal behaviors provoked by the application of Nal in morphinedependent (Mor-d) rats. CONCLUSION: We concluded that the NMDA receptor in the PVT nucleus changes the development of Mor dependence.
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Dependencia de Morfina , Trastornos Relacionados con Opioides , Síndrome de Abstinencia a Sustancias , Ratas , Masculino , Animales , Morfina/farmacología , Morfina/uso terapéutico , Naloxona/farmacología , Naloxona/uso terapéutico , Receptores de N-Metil-D-Aspartato/uso terapéutico , Narcóticos/farmacología , Narcóticos/uso terapéutico , Antagonistas de Narcóticos/farmacología , Antagonistas de Narcóticos/uso terapéutico , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Núcleos Talámicos de la Línea Media , Ratas Wistar , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Dependencia de Morfina/tratamiento farmacológicoRESUMEN
RATIONALE: The administration of NMDA receptor (NMDAR) antagonists constitutes a widely used model that produce both positive (e.g., hyperactivity) and negative (e.g., social withdrawal) symptoms relevant for schizophrenia in rodents. These effects can be reversed with the administration of atypical (second and third generation) antipsychotics. OBJECTIVES: In this study we combined the NMDAR-antagonist model with the Roman High-Avoidance (RHA) strain, a psychogenetically selected model of schizophrenia-relevant features. We also studied whether some atypical antipsychotic drugs (clozapine, ziprasidone, and aripiprazole) would be able to attenuate or reverse the behavioural alterations induced by MK801 and whether such effects might be dependent on the rat strain. METHODS: MK801 dose-response study was conducted in RHA and Roman Low-Avoidance (RLA) male rats. After that, the 0.15 mg/kg MK801 dose was selected to carry out pharmacological studies versus atypical antipsychotics. RESULTS: In the first experiment we establish that MK801 (dizocilpine), a NMDAR antagonist, produces dose-related hyperactivity and social withdrawal, which are more marked in RHA than RLA rats. The administration of the atypical antipsychotics clozapine (2.5 mg/kg) or ziprasidone (2.5 mg/kg) partially reversed or attenuated some of the social behaviour deficits and hyperactivity induced by the administration of MK801. Aripiprazole (3 mg/kg), a third-generation antipsychotic, reversed or attenuated the social preference deficit, the hyperactivity and the impairment of social latency induced by MK801. CONCLUSIONS: These results seem to be in line with previous studies with the NMDAR-antagonist model and add face (MK801-induced social withdrawal and hyperactivity) and predictive (attenuation of MK801-induced effects by atypical antipsychotics) validity to the RHA rat strain as a model of schizophrenia-relevant features.
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Antipsicóticos , Clozapina , Esquizofrenia , Masculino , Ratas , Animales , Antipsicóticos/uso terapéutico , Esquizofrenia/inducido químicamente , Esquizofrenia/tratamiento farmacológico , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Clozapina/uso terapéutico , Aripiprazol/uso terapéutico , Aislamiento SocialRESUMEN
Aberrant neurogenesis in the subventricular zone (SVZ) and hippocampus (HIP) contributes to schizophrenia pathogenesis. Haloperidol (HAL) and olanzapine (OLA), commonly prescribed antipsychotics for schizophrenia treatment, affect neurogenesis too. The effect of HAL and OLA on an mHippoE-2 cell line was studied in vitro where we measured the cell number and projection length. In vivo, we studied the gene expression of DCX, Sox2, BDNF, and NeuN in the SVZ and HIP in an MK-801-induced animal schizophrenia model. Cells were incubated with HAL, OLA, and MK-801 for 24, 48, and 72 h. Animals were injected for 6 days with saline or MK801 (0.5 mg/kg), and from the 7th day with either vehicle HAL (1 mg/kg) or OLA (2 mg/kg), for the next 7 days. In vitro, HAL and OLA dose/time-dependently suppressed cells' proliferation and shortened their projection length. HAL/OLA co-treatment with MK-801 for 24 h reversed HAL's/OLA's inhibitory effect. In vivo, HAL and OLA suppressed DCX and NeuN genes' expression in the HIP and SVZ. MK-801 decreased DCX and NeuN genes' expression in the HIP and OLA prevented this effect. The data suggest that subchronic HAL/OLA treatment can inhibit DCX and NeuN expression. In an MK-801 schizophrenia model, OLA reversed the MK-801 inhibitory effect on DCX and NeuN and HAL reversed the effect on DCX expression; however, only in the HIP.
Asunto(s)
Antipsicóticos , Esquizofrenia , Animales , Antipsicóticos/uso terapéutico , Benzodiazepinas , Proliferación Celular , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Haloperidol/farmacología , Haloperidol/uso terapéutico , Hipocampo , Olanzapina/farmacología , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genéticaRESUMEN
BACKGROUND: It has been well documented that social isolation stress (SIS) can induce posttraumatic stress disorder (PTSD)-like behavior in rodents, however, the underlying mechanism is remained misunderstood. In the current study, we aimed to elucidate the role of NO/NMDAR pathway in PTSD-like behavior through modulating of astrocyte activity and improvement of oxidative stress. METHODS: Male NMRI mice were used to evaluate the memory function by using Morris water maze (MWM) and fear memory extinction by using freezing response. We used MK-801 (NMDAR-antagonist), L-NNA (NOS-inhibitor), NMDA (NMDAR-agonist), and L-arginine (NO-agent) to find a proper treatment. Also, immunohistochemistry, RT-PCR, and oxidative stress assays were used to evaluate the levels of astrocytes and oxidative stress. We used five mice in each experimental task. RESULTS: Our results revealed that SIS could induce learning and memory dysfunction as well as impairment of fear memory extinction in MWM and freezing response tests, respectively. Also, we observed that combined treatment including blockage of NOS (by L-NNA, 0.5 mg/kg) and NMDAR (by MK-801, 0.001 mg/kg) at subeffective doses could result in improvement of both memory and fear memory. In addition, we observed that SIS significantly increases the GFAP expression and astrocyte activity, which results in significant imbalance in oxidative stress. Coadministration of MK-801 and L-NNA at subeffective doses not only decreases the expression of GFAP, but also regulates the oxidative stress imbalance CONCLUSION: Based on these results, it could be hypothesized that blockage of NO/NMDAR pathway might be a novel treatment for PTSD-like behavior in animals by inhibiting the astrocyte and regulating oxidative stress level.
Asunto(s)
Trastornos por Estrés Postraumático , Animales , Astrocitos/metabolismo , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Masculino , Ratones , Estrés Oxidativo , Receptores de N-Metil-D-Aspartato/metabolismo , Aislamiento Social , Trastornos por Estrés Postraumático/tratamiento farmacológico , Trastornos por Estrés Postraumático/metabolismoRESUMEN
Despite attenuating the positive symptoms, drugs currently used to treat schizophrenia frequently do not improve the negative symptoms and cognitive impairments. In addition, they show low tolerability, which has been associated with high rates of treatment discontinuation. Recent evidence suggests that the endocannabinoid system may be a target for schizophrenia treatment. The CB2 receptor modulates dopaminergic neurotransmission, which is abnormally enhanced in schizophrenia patients. Here, we aimed to evaluate whether HU-910, a selective CB2 receptor agonist, would reverse schizophrenia-related behavioral changes observed after the acute injections of amphetamine or the N-methyl-d-aspartate receptor (NMDAR) antagonist MK-801. We also investigated the effects of HU-910 in the memory impairment caused by repeated MK-801 administration. Finally, we tested whether HU-910 would produce the cannabinoid tetrad (catalepsy, hypolocomotion, hypothermia, and antinociception). In male C57BL/6 mice, the acute treatment with HU-910 (30 mg/kg) prevented the hyperlocomotion induced by acute MK-801. This effect was blocked by the CB2 receptor antagonist AM630 (1 mg/kg). On the contrary, HU-910 did not prevent the increased locomotor activity caused by acute amphetamine. The acute treatment with HU-910 (3, 10, and 30 mg/kg) also attenuated the impairments in the prepulse inhibition test induced by acute MK-801 and amphetamine. The repeated treatment with HU-910 attenuated the cognitive impairment caused by chronic administration of MK-801 in the novel object recognition test. Furthermore, HU-910 did not produce the cannabinoid tetrad. These results indicate that HU-910 produced antipsychotic-like effects and support further research on the potential therapeutic properties of this compound to treat schizophrenia.
Asunto(s)
Cannabinoides , Esquizofrenia , Animales , Compuestos Bicíclicos con Puentes , Cannabinoides/uso terapéutico , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Receptor Cannabinoide CB2 , Receptores de N-Metil-D-Aspartato , Roedores , Esquizofrenia/tratamiento farmacológicoRESUMEN
Psychomimetic behaviors manifest in adult rodents long after neonatal exposure to the noncompetitive NMDA receptor antagonist MK-801. In the present study, we used this neurodevelopmental model of schizophrenia to evaluate the therapeutic potential of positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) during adolescence. To this end, we randomly assigned male and female C57BL6 mouse littermates to one of three treatment groups: (i) neonatal and adolescent saline, (ii) neonatal MK-801 (0.25 mg/kg) and adolescent saline, and (iii) neonatal MK-801 and adolescent CDPPB (10 mg/kg), a positive allosteric modulator of mGluR5. When animals reached adulthood, a wide range of behavioral tests were conducted including sucrose preference, anxiety assessment in the elevated plus maze, and a series of food-reinforced operant procedures meant to assess motor activity, motivation, learning, and attention. Neonatal MK-801 exposure produced profound motor hyperactivity in both sexes and attenuated sucrose preference in males, effects that were reversed by CDPPB. MK-801 produced other deficits such as impaired set shifting or response inhibition deficits that were not reversed by CDPPB. Overall, female mice were more susceptible to MK-801's behavioral effects than males. These findings further support the use of neonatal MK-801 exposure as an animal model of schizophrenia and suggest that CDPPB can reverse the neurodevelopmental progression of some schizophrenia-like behaviors.
Asunto(s)
Maleato de Dizocilpina , Esquizofrenia , Animales , Benzamidas/farmacología , Benzamidas/uso terapéutico , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Femenino , Masculino , Ratones , Pirazoles/farmacología , Pirazoles/uso terapéutico , Esquizofrenia/inducido químicamente , Esquizofrenia/tratamiento farmacológicoRESUMEN
Psychological stress has been demonstrated to increase reports of pain in humans with pelvic pain of urologic origin. In rodent models, conditioning with acute footshock (AFS) has been demonstrated to increase measures of stress/anxiety as well as bladder hypersensitivity. The spinal neurochemical mechanisms of this pro-nociceptive process are unknown and so the present study administered antagonists for multiple receptors that have been associated with facilitatory mechanisms into the spinal intrathecal space. Bladder hypersensitivity was induced through use of an AFS paradigm in which female Sprague-Dawley rats received a 15-min intermittent shock treatment. Visceromotor responses (VMRs; abdominal muscle contractions) to air pressure-controlled urinary bladder distension (UBD) were used as nociceptive endpoints. Immediately following AFS treatments, rats were anesthetized (inhaled isoflurane, IP urethane) and surgically prepared. Pharmacological antagonists were administered via an intrathecal (IT) catheter onto the lumbosacral spinal cord and VMRs to graded UBD determined 15 min later. Administration of IT naloxone hydrochloride (10 µg) and IT phentolamine hydrochloride (10 µg) resulted in VMRs that were more robust than VMRs in rats that received AFS and IT normal saline whereas there was no significant effect of these drugs on VMRs in rats which underwent non-footshock procedures. In contrast, a low dose of the NMDA-receptor antagonist, MK-801 (30 µg), significantly reduced VMRs in rats made hypersensitive to UBD by AFS, but had no significant effect on rats that underwent non-footshock procedures. This study suggests that pro-nociceptive effects of AFS in otherwise healthy rats involve a spinal NMDA-linked mechanism. The effects of IT naloxone and IT phentolamine suggest the presence of inhibitory influences that are opioidergic and/or alpha-adrenergic and that are masked by the pro-nociceptive mechanisms. Other agents with no statistically significant effect on VMRs include methysergide (30 µg), ondansetron (10 µg), mecamylamine (50 µg), antalarmin (24 µg), aSVG30 (12 µg), and SSR149415 (50 µg).
Asunto(s)
Maleato de Dizocilpina/uso terapéutico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Médula Espinal/metabolismo , Vejiga Urinaria/metabolismo , Animales , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Femenino , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiopatología , Estrés Fisiológico , Vejiga Urinaria/fisiopatologíaRESUMEN
We previously generated an ischemic stroke in a zebrafish model using N2 gas perfusion; however, this model was an unsuitable drug screening system due to low throughput. In this study, we examined a zebrafish ischemic stroke model using an oxygen absorber to assess drug effects. Hypoxic exposure more than 2 h using the oxygen absorber significantly induced cell death in the brain and damage to the neuronal cells. To confirm the utility of the ischemic model induced by the oxygen absorber, we treated zebrafish with neuroprotective agents. MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, significantly suppressed cell death in the brain, and edaravone, a free radical scavenger, significantly reduced the number of dead cells. These results suggest that the activation of NMDA receptors and the production of reactive oxygen species induce neuronal cell damage in accordance with previous mammalian reports. We demonstrate the suitability of an ischemic stroke model in zebrafish larvae using the oxygen absorber, enabling a high throughput drug screening.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Maleato de Dizocilpina/uso terapéutico , Evaluación Preclínica de Medicamentos/métodos , Edaravona/uso terapéutico , Depuradores de Radicales Libres/uso terapéutico , Larva , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Pez Cebra , Animales , Encéfalo/patología , Isquemia Encefálica/etiología , Isquemia Encefálica/patología , Muerte Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Edaravona/farmacología , Depuradores de Radicales Libres/farmacología , Gases , Hipoxia/complicaciones , Hipoxia/patología , Neuronas/patología , NitrógenoRESUMEN
BACKGROUND: Osteoarthritis is currently one of the most common chronic diseases. As life expectancy increases, its prevalence and incidence are expected to rise. At present, more and more evidences prove the correlation between the complement system and osteoarthritis (OA). This study aims to investigate complement C5's influence on the effect of MK801 on osteoarthritis synovial fibroblasts (OA-SFs). METHODS: We used IL-1b to induce OA-SFs derived from mice to obtain OA-SFs. And we performed RT-PCR and Western Blot assays to evaluate the expression levels of associated mRNA and protein. The alteration of MAC expression on OA-SFs cell membrane was evaluated by immunofluorescence assay. The expression of related inflammatory factors of OA-SFs was evaluated by ELISA experiment. RESULTS: MK801 could significantly inhibit the expression of osteoarthritis (OA) marker factors, such as: membrane attack complex (MAC), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase-13 (MMP13). Meanwhile, MK801 can significantly inhibit the expression of complement C5 (C5) in OA-SFs. Immunofluorescence assay showed that MAC expression on OA-SFs cell membrane was significantly inhibited by MK801. The nucleo-plasmic separation experiment demonstrated that MK801 could significantly inhibit the activation of Nuclear factor-κB (NF-κB) signaling pathway in OA-SFs. Futhermore, koncking down the expression of C5 reversed the inhibition MK801 on the expression of OA-SFs inflammatory factors. CONCLUSIONS: These results illustrated two points: first, MK801 inhibited the generation of MAC and the release of inflammation factors in OA-SFs through C5; second: MK801 inhibited the activation of NF-κB signaling pathway in OA-SFs.
Asunto(s)
Complemento C5/metabolismo , Maleato de Dizocilpina/uso terapéutico , Fibroblastos/efectos de los fármacos , Osteoartritis/tratamiento farmacológico , Animales , Western Blotting , Células Cultivadas , Complejo de Ataque a Membrana del Sistema Complemento/antagonistas & inhibidores , Fibroblastos/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , FN-kappa B/metabolismo , Osteoartritis/metabolismo , Osteoartritis/patología , ARN Mensajero , Transducción de Señal , Líquido Sinovial/efectos de los fármacos , Líquido Sinovial/inmunología , Membrana Sinovial/citología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Glutamatergic neurotransmission dysfunction and the early involvement of the hippocampus have been proposed to be important aspects of the pathophysiology of schizophrenia. Here, we performed proteomic analysis of hippocampus postmortem samples from schizophrenia patients as well as neural cells-neurons and oligodendrocytes-treated with MK-801, an NMDA receptor antagonist. There were similarities in processes such as oxidative stress and apoptotic process when comparing hippocampus samples with MK-801-treated neurons, and in proteins synthesis when comparing hippocampus samples with MK-801-treated oligodendrocytes. This reveals that studying the effects of glutamatergic dysfunction in different neural cells can contribute to a better understanding of what it is observed in schizophrenia patients' postmortem brains.
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Hipocampo , Receptores de N-Metil-D-Aspartato , Esquizofrenia , Maleato de Dizocilpina/uso terapéutico , Hipocampo/metabolismo , Humanos , Neuronas , Oligodendroglía , Proteómica , Receptores de N-Metil-D-Aspartato/fisiología , Esquizofrenia/metabolismoRESUMEN
Cardiovascular-related accidents such as stroke are currently ranked as the second leading cause of death worldwide, and the risk of stroke increases dramatically with age. Aging results in structural and functional alterations of the oligodendrocytes which lead to loss of neuronal connectivity, cognitive deficits, and increased susceptibility to ischemic damage. Here, we have carried out proteomic profiling of MO3.13 oligodendrocyte cells following treatment with NMDA channel blocker MK-801 to increase our understanding of the mechanisms involved in brain aging, as well as those which render it more susceptible to ischemic damage. The main objective was to identify potential biomarkers which could be used to track disease or therapeutic effects.
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Envejecimiento/efectos de los fármacos , Maleato de Dizocilpina/uso terapéutico , Oligodendroglía/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Biomarcadores/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oligodendroglía/metabolismo , Proteómica/métodos , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Clozapine has remarkable efficacy on both negative and cognitive symptoms of schizophrenia due to its slight activation of NMDA receptor. In fact, much evidence to the contrary. NMDAR is a complex containing specific binding sites, which are regulated to improve negative symptoms and cognitive deficits associated with individuals affected by schizophrenia. PQQ is a powerful neuroprotectant that specifically binds with NMDA receptors in the brain to produce beneficial physiological and cognitive outcomes. The aim of this study was to enhance NMDAR function and improve cognitive ability in schizophrenia by PQQ combined with clozapine. METHODS: Rats were divided into four groups (n = 5) including control (saline), model (MK-801, 0.5 mg·kg- 1·d- 1), atypical antipsychotic (MK-801 (0.5 mg·kg- 1·d- 1) + Clozapine (1.0 mg·kg- 1·d- 1), and co-agonist NMDA receptor (MK-801 (0.5 mg·kg- 1·d- 1) + Clozapine (0.5 mg·kg- 1·d- 1) + PQQ (1.0 µg·kg- 1·d- 1) group. Each group of rats was injected subcutaneously every day for 6 weeks. Behavior test, including stereotyped behavior, locomotor hyperactivity, learning and memory, was performed. The Western blot assay was performed to analyze the expression of GSK-3ß, Akt, NMDAR1, and MGLUR in rat hippocampus. RESULTS: Results indicated that clozapine and PQQ combination therapy can improve MK801-induced schizophrenia behavior including stereotyped behavior, locomotor hyperactivity and cognitive impairment. Furthermore, we found that modulating NMDA receptors could ameliorate the memory impairments in Mk-801 induced schizophrenia rats by reducing the expression of NMDAR1 and MGLUR3, decreasing hippocampal tau hyperphosphorylation and inhibiting apoptosis through Akt /GSK-3ß signaling pathway. CONCLUSIONS: These findings suggest that combination therapy for enhancing NMDA receptors may be able to rescue cognition deficit in schizophrenia. More studies are needed to better elucidate these mechanisms.
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Antipsicóticos , Clozapina , Disfunción Cognitiva , Esquizofrenia , Animales , Antipsicóticos/uso terapéutico , Clozapina/farmacología , Clozapina/uso terapéutico , Cognición , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Glucógeno Sintasa Quinasa 3 beta , Humanos , Ratas , Receptores de N-Metil-D-Aspartato , Esquizofrenia/tratamiento farmacológicoRESUMEN
Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, presents a rapid and sustained antidepressant effect in clinical and preclinical studies. Regarding ketamine effects on anxiety, there is a widespread discordance among pre-clinical studies. To address this issue, the present study reviewed the literature (electronic database MEDLINE) to summarize the profile of ketamine effects in animal tests of anxiety/fear. We found that ketamine anxiety/fear-related effects may depend on the anxiety paradigm, schedule of ketamine administration and tested species. Moreover, there was no report of ketamine effects in animal tests of fear related to panic disorder (PD). Based on that finding, we evaluated if treatment with ketamine and another NMDA antagonist, MK-801, would induce acute and sustained (24 hours later) anxiolytic and/or panicolytic-like effects in animals exposed to the elevated T-maze (ETM). The ETM evaluates, in the same animal, conflict-evoked and fear behaviors, which are related, respectively, to generalized anxiety disorder and PD. Male Wistar rats were systemically treated with racemic ketamine (10, 30 and 80 mg/kg) or MK-801 (0.05 and 0.1 mg/kg) and tested in the ETM in the same day or 24 hours after their administration. Ketamine did not affect the behavioral tasks performed in the ETM acutely or 24 h later. MK-801 impaired inhibitory avoidance in the ETM only at 45 min post-injection, suggesting a rapid but not sustained anxiolytic-like effect. Altogether our results suggest that ketamine might have mixed effects in anxiety tests while it does not affect panic-related behaviors.
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Ansiedad/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Miedo/efectos de los fármacos , Miedo/psicología , Ketamina/uso terapéutico , Aprendizaje por Laberinto/efectos de los fármacos , Animales , Ansiedad/psicología , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Antagonistas de Aminoácidos Excitadores/farmacología , Miedo/fisiología , Ketamina/farmacología , Masculino , Aprendizaje por Laberinto/fisiología , Ratas , Ratas WistarRESUMEN
RATIONALE: Autism spectrum disorder (ASD), the fastest growing neurodevelopmental disorder, is characterized by social deficits, repetitive/stereotypic activity, and impaired verbal and nonverbal communication and is commonly diagnosed at early stages of life. Based on the excitatory-inhibitory imbalance theory of autism, some recent animal experiments have reported amelioration in autistic-like phenotypes in adult animals following acute treatment of NMDA antagonists. However, we suggested the neonatal period as a critical period for NMDA antagonist intervention. OBJECTIVES: This experiment was designed to determine the role of postnatal MK-801, an NMDA receptor blocker, in the prenatal valproic acid (VPA) rat model of ASD. METHODS: The model of autism was induced by subcutaneous administration of valproic acid (600 mg/kg) to pregnant rats at gestational day 12.5. The effects of MK-801 (0.03 mg/kg, from postnatal day 6-10) in correcting ASD-associated behaviors in male offspring were assessed by open-field, three-chambered social interaction tests. Moreover, the nociceptive threshold was measured by tail flick and hot plate. Behavioral tests were performed on PND 55-60. Nissl staining was performed to confirm the safety of 0.03 mg/kg MK-801 for the brain. RESULTS: We reported that MK-801 rescued social deficits, repetitive behaviors (self-grooming), anxiety-related behavior, and the low nociceptive threshold in the VPA-treated rats. Further, histological examination showed that there were no significant differences among all the groups in terms of the neuronal survival rate. CONCLUSIONS: Our results showed that postnatal low-dose MK-801 improved ASD-associated behaviors in the VPA-treated rats and that early exposure to NMDA antagonist resulted in permanent changes in adult behavior.
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Trastorno del Espectro Autista/tratamiento farmacológico , Maleato de Dizocilpina/uso terapéutico , Efectos Tardíos de la Exposición Prenatal/tratamiento farmacológico , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Conducta Social , Conducta Estereotipada/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Femenino , Masculino , Neuronas/efectos de los fármacos , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Ratas , Ácido ValproicoRESUMEN
The connection between the endocannabinoid system (ECS) and schizophrenia is supported by a large body of research. The ECS is composed of two types cannabinoid (CB: CB1 and CB2) receptors and their endogenous ligands, endocannabinoids. The best-known endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are intracellularly degraded by fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Thus, the function of ECS might be modulated in a direct way, through CB receptor ligands or indirectly by FAAH and MAGL inhibitors. We evaluated that the direct influence of ECS, using FAAH (URB 597) and MAGL (JZL 184) inhibitors, on the schizophrenia-like effects in mice. The behavioral schizophrenia-like symptoms were obtained in animals by using N-methyl D-aspartate (NMDA) receptor antagonists, MK-801. An acute administration of MK-801 (0.3 and 0.6 mg/kg) induced psychotic symptoms in rodents, manifested as the increase in locomotor activity, measured in actimeters, as well as the memory impairment, assessed in the passive avoidance (PA) task. We revealed that an acute administration of URB 597, at the dose of 0.3 mg/kg, attenuated MK-801 (0.6 mg/kg)-induced memory impairment. In turn, an acute administration of URB 597 at a higher dose (1 mg/kg) potentiated MK-801 (0.3 mg/kg)-induced memory impairment. Similarly, an acute administration of JZL 184 (20 and 40 mg/kg) intensified an amnestic effect of MK-801 (0.3 mg/kg). Moreover, an acute injection of JZL 184 (1 mg/kg) potentiated hyperlocomotion is provoked by MK-801 (0.3 and 0.6 mg/kg) administration. The present findings clearly indicate that ECS, through an indirect manner, modulates a variety of schizophrenia-like responses in mice.
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Amidohidrolasas/antagonistas & inhibidores , Cognición , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Amidohidrolasas/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Benzamidas/administración & dosificación , Benzamidas/farmacología , Benzamidas/uso terapéutico , Benzodioxoles/administración & dosificación , Benzodioxoles/farmacología , Benzodioxoles/uso terapéutico , Carbamatos/administración & dosificación , Carbamatos/farmacología , Carbamatos/uso terapéutico , Cognición/efectos de los fármacos , Maleato de Dizocilpina/administración & dosificación , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Inhibidores Enzimáticos/farmacología , Inyecciones , Masculino , Memoria/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Piperidinas/administración & dosificación , Piperidinas/farmacología , Piperidinas/uso terapéutico , Esquizofrenia/fisiopatologíaRESUMEN
Several studies have proposed cerebral malaria (CM) as a CD4+ and CD8+ T lymphocyte-mediated disease. However, there are no data regarding the recruitment and/or persistence of these cells in the CNS following the phase of infection resolution. Glutamate-mediate excitotoxicity has also been implicated in CM. Blockade of glutamate NMDA receptors by its noncompetitive antagonist MK801 modulates cytokine and neurotrophic factors expression preventing cognitive and depressive-like behavior in experimental CM. Herein, we aim to investigate the role of T lymphocytes in later outcomes in CM, and whether the protective role of MK801 is associated with T lymphocytes response.
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Malaria Cerebral/tratamiento farmacológico , Malaria Cerebral/inmunología , Plasmodium berghei/efectos de los fármacos , Plasmodium berghei/inmunología , Linfocitos T/inmunología , Animales , Maleato de Dizocilpina/farmacología , Maleato de Dizocilpina/uso terapéutico , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Femenino , Ratones , Ratones Endogámicos C57BL , Linfocitos T/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: Overstimulation of glutamate receptors, especially neuronal N-methyl-D-aspartate receptor (NMDAR), mediates excitatory neurotoxicity in multiple neurodegenerative diseases. However, the role of NMDAR in the regulation of Japanese encephalitis virus (JEV)-mediated neuropathogenesis remains undisclosed. The primary objective of this study was to understand the function of NMDAR to JEV-induced neuronal cell damage and inflammation in the central nervous system. METHODS: The effect of JEV-induced NMDAR activation on the progression of Japanese encephalitis was evaluated using the primary mouse neuron/glia cultures and a mouse model of JEV infection. A high-affinity NMDAR antagonist MK-801 was employed to block the activity of NMDAR both in vitro and in vivo. The subsequent impact of NMDAR blockade was assessed by examining the neuronal cell death, glutamate and inflammatory cytokine production, and JEV-induced mice mortality. RESULTS: JEV infection enhanced the activity of NMDAR which eventually led to increased neuronal cell damage. The data obtained from our in vitro and in vivo assays demonstrated that NMDAR blockade significantly abrogated the neuronal cell death and inflammatory response triggered by JEV infection. Moreover, administration of NMDAR antagonist protected the mice from JEV-induced lethality. CONCLUSION: NMDAR plays an imperative role in regulating the JEV-induced neuronal cell damage and neuroinflammation. Thus, NMDAR targeting may constitute a captivating approach to rein in Japanese encephalitis.
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Virus de la Encefalitis Japonesa (Especie)/patogenicidad , Encefalitis Japonesa/patología , Neuronas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animales , Anexina A5/metabolismo , Caspasa 3/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Maleato de Dizocilpina/uso terapéutico , Embrión de Mamíferos , Encefalitis Japonesa/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Neuroglía/patología , Neuronas/patología , Neuronas/virología , Fosfopiruvato Hidratasa/metabolismo , Fosforilación/efectos de los fármacosRESUMEN
BACKGROUND/AIMS: To investigate the effect of propofol on glucose metabolism in colorectal cancer cells and in an in vivo xenograft model. METHODS: Glucose metabolism was assessed by measuring the extracellular acidification rate in HT29 and SW480 colorectal cancer cells. Quantitative real-time PCR and western blot analyses were used to detect mRNA and protein levels, respectively. Intracellular calcium was assessed by using a Fluo-3 AM fluorescence kit. Micro-positron emission tomography/computed tomography (microPET/CT) imaging was used to analyze glucose metabolism in the tumors of the xenograft model. RESULTS: Propofol exposure induced a dose-dependent decrease of aerobic glycolysis in HT29 and SW480 colorectal cancer cells. MicroPET/CT indicated that propofol also inhibited 18F-FDG uptake in the xenograft model. In addition, hypoxia-inducible factor 1α (HIF1α) was also reduced by propofol dose-dependently. Propofol repressed the NMDAR-CAMKII-ERK pathway to inactivate HIF1α and therefore reduced glycolysis. CONCLUSION: Propofol inhibited aerobic glycolysis in colorectal cancer cells through the inactivation of the NMDAR-CAMKII-ERK pathway, which may facilitate a better understanding of the use of propofol in the clinical setting.