Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 488
Filtrar
1.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(8): 889-893, 2021 Aug 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-34565735

RESUMO

The prevalence of abnormal glucose and lipid metabolism and its relevant diseases has increased year by year, and it has become a problem that threatens human health. Therefore, finding a more effective way to prevent and treat diseases related to abnormal glucose and lipid metabolism has become an urgent public problem. Agmatine is a polyamine substance which widely presents in mammals.It is a metabolite produced by decarboxylation of L-arginine under the action of arginine decarboxylase, hence also known as decarboxylated arginine. Its biological effects have been confirmed. Previous studies have shown that agmatine possesses anti-diabetic effects in diabetic animals. Agmatine not only increases the insulin secretion form ß-pancreatic cells to inhibit the hyperglycemia, but also attenuates insulin resistance in rats. Agmatine also plays a positive role in lipid metabolism disorders and related diseases by modulating lipid metabolism and fatty acid oxidation.


Assuntos
Agmatina , Agmatina/farmacologia , Animais , Arginina/metabolismo , Glicolipídeos , Metabolismo dos Lipídeos , Ratos
2.
Neurochem Res ; 46(8): 1933-1940, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33914233

RESUMO

Agmatine, an endogenous derivative of arginine, has been found to be effective in treating idiopathic pain, convulsion, stress-mediated behavior, and attenuate the withdrawal symptoms of drugs like morphine. In the early stages of ischemic brain injury in animals, exogenous agmatine treatment was found to be neuroprotective. Agmatine is also considered as a putative neurotransmitter and is still an experimental drug. Chemically, agmatine is called agmatine 1-(4-aminobutyl guanidine). Crystallographic study data show that positively-charged guanidine can bind to the protein containing Gly and Asp residues, and the amino group can interact with the complimentary sites of Glu and Ser. In this study, we blocked the amino end of the agmatine by conjugating it with FITC, but the guanidine end was unchanged. We compared the neuroprotective function of the agmatine and agmatine-FITC by treating them in neurons after excitotoxic stimulation. We found that even the amino end blocked neuronal viability in the excitotoxic condition, by NMDA treatment for 1 h, was increased by agmatine-FITC, which was similar to that of agmatine. We also found that the agmatine-FITC treatment reduced the expression of nitric oxide production in NMDA-treated cells. This study suggests that even if the amino end of agmatine is blocked, it can perform its neuroprotective function.


Assuntos
Agmatina/farmacologia , Neurônios/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Agmatina/química , Animais , Células Cultivadas , Córtex Cerebral/citologia , Feminino , Feto/citologia , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/farmacologia , Camundongos Endogâmicos ICR , N-Metilaspartato/toxicidade , Fármacos Neuroprotetores/química , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo
3.
Neurosci Lett ; 753: 135881, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33838255

RESUMO

Essential tremor (ET) is one of the most prevalent movement disorders and the most common cause of abnormal tremors. However, it cannot be treated efficiently with the currently available pharmacotherapy options. The pathophysiology of harmaline-induced tremor, most commonly used model of ET, involves various neurotransmitter systems including glutamate as well as ion channels. Agmatine, an endogenous neuromodulator, interacts with various glutamate receptor subtypes and ion channels, which have been associated with its' beneficial effects on several neurological disorders. The current study aims to assess the effect of agmatine on the harmaline model of ET. Two separate groups of male rats were injected either with saline or agmatine (40 mg/kg) 30 min prior to single intraperitoneal injection of harmaline (20 mg/kg). The percent duration, intensity and frequency of tremor and locomotor activity were evaluated by a custom-built tremor and locomotion analysis system. Pretreatment with agmatine reduced the percent tremor duration and intensity of tremor induced by harmaline, without affecting the tremor frequency. However, it did not affect the decreased spontaneous locomotor activity due to harmaline. This pattern of ameliorating effects of agmatine on harmaline-induced tremor provide the first evidence for being considered as a treatment option for ET.


Assuntos
Agmatina/farmacologia , Tremor Essencial/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Agmatina/uso terapêutico , Animais , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estimulantes do Sistema Nervoso Central/toxicidade , Modelos Animais de Doenças , Tremor Essencial/induzido quimicamente , Tremor Essencial/diagnóstico , Harmalina/administração & dosagem , Harmalina/toxicidade , Humanos , Masculino , Fármacos Neuroprotetores/uso terapêutico , Ratos , Índice de Gravidade de Doença
4.
J Physiol Biochem ; 77(2): 305-320, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33635523

RESUMO

Diabetic retinopathy (DR) is the most common diabetic neurovascular complication, and the leading cause of preventable blindness among working-age individuals. Recently, agmatine, the endogenous decarboxylated L-arginine, has gained attention as a pleiotropic agent that modulates the diabetes-associated decline in quality of life, and exhibited varied protective biological effects. Diabetes was induced by a single streptozotocin (STZ, 50 mg/kg, i.p.) injection. When diabetes was verified, the animals were randomly allocated into three groups (16 rat each); diabetic, agmatine-treated diabetic (1 mg/kg, daily, for 12 weeks), and control group. Blood glucose homeostasis, retinal redox status, apoptotic parameters, nitric oxide synthase (NOS), nitric oxide (NO), vascular endothelial growth factor (VEGF), glutamate, glutamine, glutamine synthase (GS) activity, nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), and mitogen-activated protein kinase (MAPKs) pathways were assayed biochemically. Retinal vascular permeability was measured. Retinal morphology was evaluated by hematoxylin and eosin staining. Retinal N-methyl-D-aspartic acid receptor1 (NMDAR1) and glutamate aspartate transporter (GLAST) mRNA were quantified. Glucose transporter 1, pro-caspase3, and glial fibrillary acidic protein (GFAP) expression were quantified by immunohistochemistry. Chronic agmatine treatment abrogated STZ-induced retinal neurodegeneration features including gliosis, and neuronal apoptosis, restored retinal vascular permeability, mostly through antioxidant, anti-apoptotic capacity, abolishing glutamate excitotoxicity, modulating the activity of NMDARs, MAPKs/NFκB, and NOS/NO pathways. By restoring the molecular and functional background of retinal neurovascular homeostatic balance, agmatine would be appropriate therapeutic option acting upstream of the DR, impeding its progression.


Assuntos
Agmatina/farmacologia , Antioxidantes/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Hipoglicemiantes/farmacologia , Fármacos Neuroprotetores/farmacologia , Retina/efeitos dos fármacos , Animais , Glicemia/metabolismo , Caspase 3/genética , Caspase 3/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/induzido quimicamente , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Transportador 1 de Aminoácido Excitatório/genética , Transportador 1 de Aminoácido Excitatório/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Glutamato-Amônia Ligase/genética , Glutamato-Amônia Ligase/metabolismo , Ácido Glutâmico/metabolismo , Masculino , NF-kappa B/genética , NF-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo I/metabolismo , Estresse Oxidativo , Ratos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Retina/metabolismo , Retina/patologia , Estreptozocina/administração & dosagem , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
5.
Eur J Pharmacol ; 892: 173739, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33220274

RESUMO

3-Hydroxy-3-methyl-glutaryl-co-enzyme-A (HMG-CoA) reductase inhibitors (statins) are popularly used for the treatment of obesity and hypercholesterolemia with established safety profile. Statins exhibits a wide range of neurobehavioral effects in addition to their peripheral actions, and may be beneficial in treatment of psychiatric conditions. Present study investigated the role of agmatine and imidazoline receptors in antidepressant-like effect of statins in mouse forced swimming test (FST). The antidepressant-like effect of atorvastatin (5 mg/kg, p.o.) and simvastatin (10 mg/kg, p.o.) was potentiated by pretreatment with agmatine (5 mg/kg, i.p.) as well as the drugs known to increase endogenous agmatine levels in brain viz., L-arginine (40 µg/mouse, i.c.v.), an agmatine biosynthetic precursor; arcaine (50 µg/mouse, i.c.v), agmatinase inhibitor; and aminoguanidine (6.5 µg/mouse, i.c.v.), a diamine oxidase inhibitor. Further, both the statins increased agmatine levels within hippocampus and prefrontal cortex. Conversely, prior administration of I1 receptor antagonist, efaroxan (1 mg/kg, i.p.) and I2 receptor antagonist, idazoxan (0.25 mg/kg, i.p.) blocked the antidepressant-like effect of statins and their synergistic combination with agmatine. These results demonstrate the involvement of agmatine and imidazoline receptors in antidepressant-like effect of statins and suggest as a potential therapeutic target for the treatment of depressive disorders.


Assuntos
Agmatina/metabolismo , Antidepressivos/farmacologia , Atorvastatina/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Depressão/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Sinvastatina/farmacologia , Agmatina/farmacologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Depressão/metabolismo , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Quimioterapia Combinada , Receptores de Imidazolinas/efeitos dos fármacos , Receptores de Imidazolinas/metabolismo , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Natação
6.
Neurosci Lett ; 740: 135447, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127446

RESUMO

Alzheimer's disease is an age related progressive neurodegenerative disorder characterized by decline in cognitive functions, such as memory loss and behavioural abnormalities. The present study sought to assess alterations in agmatine metabolism in the beta-amyloid (Aß1-42) Alzheimer's disease mouse model. Aß1-42 injected mice showed impairment of cognitive functioning as evidenced by increased working and reference memory errors in radial arm maze (RAM). This cognitive impairment was associated with a reduction in the agmatine levels and elevation in its degrading enzyme, agmatinase, whereas reduced immunocontent was observed in its synthesizing enzyme arginine decarboxylase expression within hippocampus and prefrontal cortex. Chronic agmatine treatment and its endogenous modulation by l-arginine, or arcaine or aminoguanidine prevented the learning and memory impairment induced by single intracranial Aß1-42 peptide injection. In conclusion, the present study suggests the importance of the endogenous agmatinergic system in ß-amyloid induced memory impairment in mice.


Assuntos
Agmatina/metabolismo , Agmatina/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides , Transtornos da Memória/metabolismo , Fragmentos de Peptídeos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/psicologia , Animais , Carboxiliases/biossíntese , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Hipocampo/enzimologia , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Camundongos , Córtex Pré-Frontal/enzimologia , Desempenho Psicomotor/efeitos dos fármacos , Ureo-Hidrolases/metabolismo
7.
Brain Res ; 1747: 147045, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32758481

RESUMO

Epidemiological studies indicated that mood disorders like depression and anxiety are highly prevalent in type-II diabetes mellitus (T2DM). However, the neurobiological mechanisms underlying the relationship between T2DM and depression have yet to be identified. Thus, understanding the neural mechanisms that mediate the co-morbidity of depression and type-II diabetes mellitus may unlock new pharmacological treatments for this condition. The present study investigated the role of the agmatinergic system in T2DM induced depression using forced swim test (FST) and anxiety in the elevated plus-maze (EPM)in rats. T2DM was induced by the combination of high-fat diet (HFD) and streptozotocin (STZ) injection and confirmed by high blood glucose levels. After 12 weeks, HFD fed and STZ injected rats exhibited depression-like behaviors and anxiety. It was associated with increased expression of pro-inflammatory cytokines like IL-6 and TNF-α, and reduced BDNF immunocontent in the hippocampal tissues. The T2DM-induced depression, anxiety, and neuroinflammatory markers were significantly inhibited by agmatine (10-20 mg/kg, i.p.), by once-daily administration during 9th to 12th week of the protocol. Agmatine levels were significantly reduced in the hippocampus of T2DM rats as compared to the normal fed (NF) control animals. In conclusion, the present study suggests the importance of endogenous agmatine in T2DM induced anxiety and depressive-like behavior in rats. The data projects agmatine as a potential therapeutic target for T2DM-associated depression, anxiety, and comorbidities.


Assuntos
Agmatina/farmacologia , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Agmatina/uso terapêutico , Animais , Ansiolíticos/farmacologia , Ansiolíticos/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Ansiedade/etiologia , Ansiedade/metabolismo , Citocinas/metabolismo , Depressão/etiologia , Depressão/metabolismo , Diabetes Mellitus Experimental/metabolismo , Dieta Hiperlipídica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley
8.
Exp Neurol ; 333: 113398, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32659382

RESUMO

We investigated the ability of agmatine to potentiate the antidepressant-like and synaptic effects of ketamine in mice. Agmatine (0.1 and 1 mg/kg, p.o.) and ketamine (1 and 10 mg/kg, i.p.) produced an antidepressant-like effect in the tail suspension test. The combination of agmatine (0.01 mg/kg, p.o.) and ketamine (0.1 mg/kg, i.p.), at subthreshold doses, produced an antidepressant-like effect 1 h, 24 h and 7d after treatment. Western blot analysis from prefrontal cortex tissue showed that the combined treatment, after 1 h, increased p70S6K and GluA1, and reduced synapsin 1 phosphorylation. Additionally, after 24 h, Akt, p70S6K, GluA1, and synapsin 1 phosphorylation; and PSD95 immunocontent increased (which persisted for up to 7d). Dendritic architecture analysis of the prefrontal cortex revealed that the combined treatment improved dendritic arbor complexity (after 24 h, up to 7d), and increased spine density (after 1 h, up to 24 h). Morphometric analysis revealed a filopodia-shaped dendrite spine upregulation after 1 h. A predominance of stubby, mushroom, branched and filopodia; and a reduction in thin protrusions were observed after 24 h. Finally, mushroom-shaped dendritic spines predominance increased after 7d. Agmatine potentiated ketamine's antidepressant, and dendritic arbors and spines remodeling effects in a time-dependent manner. Our data indicate Akt/p70S6K signaling as a likely target for these effects.


Assuntos
Agmatina/farmacologia , Antidepressivos/farmacologia , Dendritos/efeitos dos fármacos , Espinhas Dendríticas/efeitos dos fármacos , Ketamina/farmacologia , Proteína Oncogênica v-akt/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Dendritos/ultraestrutura , Espinhas Dendríticas/ultraestrutura , Sinergismo Farmacológico , Elevação dos Membros Posteriores , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos
9.
Behav Brain Res ; 392: 112692, 2020 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-32479847

RESUMO

Numerous studies have investigated the role of agmatine in the central nervous system and indicated neuroprotective properties. In addition to its potent antioxidant effects, agmatine is an endogenous neuromodulator and has wide spectrum molecular actions on different receptor subtypes (NMDA, Imidazoline 1-2, alpha-2 adrenoreceptor, 5-HT2a, 5-HT3) and cellular signaling pathways (MAPK, PKA, NO, BDNF). Although the neuroprotective effects of agmatine demonstrated in experimental Parkinson's disease model, the effects of agmatine with the aspect of neuroplasticity and possible signaling mechanisms behind agmatine actions have not been investigated. Herein, in this study, we investigated the role of the of agmatine on rotenone-induced Parkinson's disease model. Agmatine at the dose of 100 mg/kg i.p., was mitigated oxidative damage and alleviated motor impairments which were the results of the rotenone insult. Additionally, agmatine decreased neuronal loss, tyrosine hydroxylase immunoreactivity and increased cREB, BDNF and ERK1/2 expression in the striatum, which are crucial neuroplasticity elements of striatal integrity. Taken together, the present study expands the knowledge of molecular mechanisms behind neuroprotective actions of agmatine in Parkinson's disease, and as far as we have known, this is the first study to delineate agmatine treated activation of cellular pathways which are important elements in neuronal cell survival.


Assuntos
Agmatina/farmacologia , Doença de Parkinson/tratamento farmacológico , Agmatina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Corpo Estriado/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/metabolismo , Ratos , Ratos Sprague-Dawley , Rotenona/farmacologia , Transdução de Sinais/efeitos dos fármacos
10.
Pharmacol Biochem Behav ; 196: 172976, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32598984

RESUMO

Agmatine is a biogenic amine synthesized following decarboxylation of L-arginine by the enzyme arginine decarboxylase and exhibits favourable outcome in neurodegenerative disorders. Present study was designed to examine the relationship between agmatine and the imidazoline receptors in memory deficits induced by Aß1-42 peptide in mice. Mice were treated with single intracerebroventricular (i.c.v.) injection of Aß1-42 peptide (3 µg) and evaluated for learning and memory in Morris water maze (MWM) and subjected to Aß1-42, TNF-α and IL-6 and BDNF immunocontent analysis within the hippocampus. While the learning and memory impairment was evident in the mice subjected to MWM test following Aß1-42 peptide administration, there was a significant increase in Aß1-42, TNF-α and IL-6 and reduction in BDNF immunocontent within the hippocampus. Daily intraperitoneal (i.p.) treatment with agmatine (10 and 20 mg/kg); imidazoline I1 receptor agonist, moxonidine and imidazoline I2 receptor agonist, 2-BFI starting from day 8 to 27 post-Aß1-42 injection, significantly prevented the cognitive deficits and normalized the Aß1-42 peptide, IL-6, TNF-α and BDNF immunocontent in hippocampus. On the other hand, pre-treatment with imidazoline I1 receptor antagonist, efaroxan and imidazoline I2 receptor antagonist, BU 224 attenuated the effects of agmatine on learning and memory in MWM, IL-6, TNF-α and BDNF content. In conclusion, the present study provides functional evidence for the involvement of the imidazoline receptors in agmatine induced reversal of Aß1-42 induced memory deficits in mice. The data projects agmatine and imidazoline receptor agonists as a potential therapeutic target for the treatment of AD.


Assuntos
Agmatina/uso terapêutico , Peptídeos beta-Amiloides/fisiologia , Receptores de Imidazolinas/agonistas , Receptores de Imidazolinas/antagonistas & inibidores , Transtornos da Memória/tratamento farmacológico , Fragmentos de Peptídeos/fisiologia , Agmatina/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Transtornos da Memória/etiologia , Camundongos , Aprendizagem Espacial/efeitos dos fármacos
11.
Neurotoxicology ; 80: 1-11, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32522471

RESUMO

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder characterized by abnormal accumulation of extracellular ß-amyloid (Aß) plaques and neuronal damage. The present study investigated the effect of chronic intra-hippocampal agmatine administration on ß-Amyloid (Aß) induced memory impairment in mice. Aß1-42 peptide injected mice demonstrated impairment of cognitive abilities evaluated as reference memory error and working memory error in radial arm maze (RAM) and decreased exploration time for novel object as well as recognition index in novel object recognition (NOR) test along with elevation in Aß1-42 peptide, ß-Site APP cleaving enzyme 1 (BACE 1), microtubule-associated protein tau (MAPt), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and reduction in neprilysin and brain derived neurotrophic factor (BDNF) immunocontent within hippocampus and prefrontal cortex. Importantly, this was associated with a reduction in the agmatine levels following Aß1-42 peptide administration. Chronic administration of agmatine from day 8-27, prevented the memory impairment in mice and normalized the neurochemical alteration within prefrontal cortex and hippocampus induced by Aß1-42 peptide administration. However, it did not modulate the amyloid precursor protein and BACE expression. This study suggests that agmatine improves learning and memory impairment possibly through the down regulation of neuroinflammatory pathways in AD.


Assuntos
Agmatina/farmacologia , Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hipocampo/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Transtornos da Memória/prevenção & controle , Memória/efeitos dos fármacos , Nootrópicos/farmacologia , Agmatina/metabolismo , Peptídeos beta-Amiloides , Animais , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Teste de Campo Aberto/efeitos dos fármacos , Fragmentos de Peptídeos , Transdução de Sinais
12.
Naunyn Schmiedebergs Arch Pharmacol ; 393(10): 1931-1939, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32447465

RESUMO

Considering the involvement of GABAergic system in the action of the fast-acting antidepressant ketamine, and that agmatine may exert an antidepressant-like effect through mechanisms similar to ketamine, the purpose of the present study was to evaluate the involvement of GABAA and GABAB receptors in the antidepressant-like effect of agmatine. The administration of muscimol (0.1 mg/kg, i.p., GABAA receptor agonist) or diazepam (0.05 mg/kg, p.o., GABAA receptor positive allosteric modulator) at doses that caused no effect in the tail suspension test (TST) combined with a subeffective dose of agmatine (0.0001 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST. In another set of experiments, the administration of baclofen (1 mg/kg, i.p., GABAB receptor agonist) abolished the reduction of immobility time in the TST elicited by agmatine (0.1 mg/kg, p.o., active dose). In another cohort of animals, treatment with NMDA (0.1 pmol/site, i.c.v.) prevented the antidepressant-like effect of the combined administration of agmatine and muscimol as well as ketamine and muscimol in the TST. Results suggest that the effect of agmatine in the TST may involve an activation of GABAA receptors dependent on NMDA receptor inhibition, similar to ketamine, as well as modulation of GABAB receptors.


Assuntos
Agmatina/uso terapêutico , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Neurônios GABAérgicos/efeitos dos fármacos , Receptores de GABA/fisiologia , Agmatina/farmacologia , Animais , Antidepressivos/farmacologia , Depressão/psicologia , Feminino , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Neurônios GABAérgicos/fisiologia , Elevação dos Membros Posteriores/efeitos adversos , Elevação dos Membros Posteriores/psicologia , Camundongos , Ácido gama-Aminobutírico/fisiologia
13.
Neurotox Res ; 38(2): 319-329, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32399718

RESUMO

Chronic treatment with agmatine, similarly to fluoxetine, may cause antidepressant-like effects mediated, at least in part, by the modulation of hippocampal plasticity. However, the ability of chronic treatment with agmatine to cause antidepressant-like effects associated with the modulation of mammalian target of rapamycin (mTOR) signaling pathway and protection against neuronal death remains to be established. In this study, we investigated the effects of agmatine (0.1 mg/kg, p.o.) and the conventional antidepressant fluoxetine (10 mg/kg, p.o.) treatment on the levels of phosphorylated mTOR (p-mTOR), neuronal death, and overall volume in the hippocampal dentate gyrus (DG) of mice exposed to chronic corticosterone (20 mg/kg, p.o.) treatment for 21 days, a model of stress and depressive-like behavior. Chronic corticosterone treatment increased cell death in the sub-granular zone (SGZ) of the DG, as assessed by Fluoro-Jade B labeling. Agmatine, similarly to fluoxetine, was capable of reversing this alteration in the entire DG, an effect more evident in the ventral portion of the hippocampus. Additionally, reduced phosphorylation of mTOR (Ser2448), a pro-survival protein that is active when phosphorylated at Ser2448, was observed in the whole hippocampal DG in corticosterone-treated mice, an effect not observed in agmatine or fluoxetine-treated mice. Chronic exposure to corticosterone caused a significant reduction in overall hippocampal volume, although no alterations were observed between the groups with regards to DG volume. Altogether, the results indicate that agmatine, similar to fluoxetine, was able to counteract corticosterone-induced impairment on mTOR signaling and cell death in hippocampal DG.


Assuntos
Agmatina/farmacologia , Anti-Inflamatórios/toxicidade , Corticosterona/toxicidade , Hipocampo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Serina-Treonina Quinases TOR/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Giro Denteado/citologia , Giro Denteado/efeitos dos fármacos , Fluoxetina/farmacologia , Hipocampo/metabolismo , Camundongos , Inibidores de Captação de Serotonina/farmacologia , Serina-Treonina Quinases TOR/metabolismo
14.
Brain Res Bull ; 160: 56-64, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32344125

RESUMO

Extensive clinical and experimental studies established that depression and mood disorders are highly prevalent neuropsychiatric conditions in Alzheimer's disease (AD). However, its neurochemical basis is not clearly understood. Thus, understanding the neural mechanisms involved in mediating the co-morbidity of depression and AD may be crucial in exploring new pharmacological treatments for this condition. The present study investigated the role of the agmatinergic system in ß-amyloid (Aßß1-42) peptide-induced depression using forced swim test (FST) in mice. Following the 28th days of its administration, Aß1-42 peptide produced depression-like behavior in mice as evidenced by increased immobility time in FST and increased expression of pro-inflammatory cytokines like IL-6 and TNF-α compared to the control animals. The Aß1-42 peptide-induced depression and neuroinflammatory markers were significantly inhibited by agmatine -, moxonidine, 2-BFI and l-arginine by once-daily administration during day 8-27 of the protocol. The antidepressant-like effect of agmatine in Aß1-42 peptide in mice was potentiated by imidazoline receptor I1 agonist, moxonidine and imidazoline receptor I2 agonist 2-BFI at their sub-effective doses. On the other hand, it was completely blocked by imidazoline receptor I1 antagonist, efaroxan and imidazoline receptor I2 antagonist, idazoxan Also, agmatine levels were significantly reduced in brain samples of ß-amyloid injected mice as compared to the control animals. In conclusion, the present study suggests the importance of endogenous agmatinergic system and imidazoline receptors system in ß-amyloid induced a depressive-like behavior in mice. The data projects agmatine as a potential therapeutic target for the AD-associated depression and comorbidities.


Assuntos
Agmatina/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Mediadores da Inflamação/antagonistas & inibidores , Agmatina/farmacologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/toxicidade , Animais , Depressão/metabolismo , Depressão/psicologia , Hipocampo/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Fragmentos de Peptídeos/toxicidade
15.
J Mater Chem B ; 8(12): 2418-2430, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32115589

RESUMO

Bioreducible cationic polymers have gained considerable attention in gene delivery due to their low cytotoxicity and high efficiency. In the present work, we reported a cationic polymer, poly(disulfide-l-lysine)-g-agmatine (denoted as SSL-AG), and evaluated its ability to transfer pEGFP-ZNF580 plasmid (pZNF580) into human umbilical vein endothelial cells (HUVECs). This SSL-AG polymeric carrier efficiently condensed pZNF580 into positively charged particles (<200 nm) through electrostatic interaction. This carrier also exhibited excellent buffering capacity in the physiological environment, good pDNA protection against enzymatic degradation and rapid pDNA release in a highly reducing environment mainly because of the responsive cleavage of disulfide bonds in the polymer backbone. The hemolysis assay and in vitro cytotoxicity assay suggested that the SSL-AG carrier and corresponding gene complexes possessed both good hemocompatibility and great cell viability in HUVECs. The cellular uptake of the SSL-AG/Cy5-oligonucleotide group was 3.6 times that of the poly(l-lysine)/Cy5-oligonucleotide group, and its mean fluorescence intensity value was even higher than that of the PEI 25 kDa/Cy5-oligonucleotide group. Further, the intracellular trafficking results demonstrated that the SSL-AG/Cy5-oligonucleotide complexes exhibited a high nucleus co-localization rate (CLR) value (36.0 ± 2.8%, 3.4 times that of the poly (l-lysine)/Cy5-oligonucleotide group, 1.6 times that of the poly(disulfide-l-lysine)-g-butylenediamine/Cy5-oligonucleotide group) at 24 h, while the endo/lysosomal CLR value was relatively low. This suggested that SSL-AG successfully delivered plasmid into HUVECs with high cellular uptake, rapid endosomal escape and efficient nuclear accumulation owing to the structural advantages of the bioreducible and agmatine groups. In vitro transfection assay also verified the enhanced transfection efficiency in the SSL-AG/pZNF580 group. Furthermore, the results of CCK-8, cell migration and in vitro/vivo angiogenesis assays revealed that pZNF580 delivered by SSL-AG could effectively enhance the proliferation, migration and vascularization of HUVECs. In a word, the SSL-AG polymer has great potential as a safe and efficient gene carrier for gene therapy.


Assuntos
Agmatina/química , Técnicas de Transferência de Genes , Polilisina/química , Agmatina/síntese química , Agmatina/farmacologia , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Camundongos , Tamanho da Partícula , Polilisina/síntese química , Polilisina/farmacologia , Propriedades de Superfície
16.
Transplantation ; 104(9): 1906-1916, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32032294

RESUMO

BACKGROUND: Liver ischemia reperfusion injury (LIRI) is a common problem during surgical procedures of the liver. It causes severe inflammatory responses and cell death, eventually leading to serious liver damage. Agmatine (AGM) is an endogenous polyamine with analgesic, anti-inflammatory, and antiapoptotic effects. However, it is still unknown whether AGM can protect the liver from damage caused by LIRI. METHODS: For the in vivo experiments, a mouse model of partial warm hepatic ischemia reperfusion was established using C57BL/6J mice and then serum transaminase concentrations were analyzed. Histopathology was used to evaluate the degree of liver injury and quantitative real-time PCR was used to measure the amount of inflammatory cytokines. For the in vitro experiments, a cellular model of cobalt chloride (CoCl2)-induced hypoxia was established using AML12 cells. Flow cytometry was performed to measure the apoptosis levels. Western blotting analysis was conducted to measure the levels of proteins involved in apoptosis and Wnt/ß-catenin signaling. We also chose 2 inhibitors of the Wnt/ß-catenin signaling to elucidate the relationship between AGM and the Wnt/ß-catenin signaling. RESULTS: AGM showed protective effects against LIRI-induced liver damage, inflammatory responses, and cell apoptosis along with alleviation of CoCl2-induced hepatocyte injury. AGM activated the Wnt/ß-catenin signaling pathway during LIRI and CoCl2-induced hepatocyte injury; however, when the Wnt/ß-catenin pathway was inhibited, the protective effects of AGM declined. CONCLUSIONS: AGM showed protective effects against LIRI by activating the Wnt/ß-catenin signaling pathway.


Assuntos
Agmatina/farmacologia , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Via de Sinalização Wnt/efeitos dos fármacos , beta Catenina/fisiologia , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
17.
Curr Clin Pharmacol ; 15(3): 251-264, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31622210

RESUMO

AIM: Endogenous agmatine has a significant role in learning and memory processes as a neurotransmitter. Various studies described the physiological role of endogenous agmatine in learning and memory of multiple cognitive tasks suggesting elevated levels of agmatine during the learning process in the rat brain. Dietary intake of choline showed correlation with cognitive functions in human subjects and treatment with choline supplements validated the ability to diminish learning and cognitive impairment dementias. METHODS: 36 Albino rats were equally divided into three groups previously: a) control-water, b) Test I - AlCl3 (100 mg/Kg body weight), and c) Test II - Forced swim stress (FSS) for 14 days. On the next day of AlCl3 and FSS last administration, animals were allocated into further three groups and received the following treatments: a. water was given orally to the control group, b. Agmatine (100 mg/Kg Body Weight) group, and c. Choline (100 mg/Kg Body Weight) group for the next 14 days. Behaviors were assessed in Light/Dark Box, Open Field, Novel Object Recognition Test (NOR), T Maze Test, and Morris Water Maze Test. RESULTS: Animals administered with agmatine demonstrated increased time spent in bright areas of light/dark box and square crossed while improved spatial memory in Morris water maze and T maze test and enhanced discrimination of novel object in NOR were observed in learning and memory paradigms along with choline. CONCLUSION: The present study determines that agmatine at the dose of (100 mg/kg body weight) attenuates memory and cognitive impairment in comparison with choline supplements.


Assuntos
Agmatina/farmacologia , Colina/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Estresse Psicológico/tratamento farmacológico , Agmatina/administração & dosagem , Animais , Colina/administração & dosagem , Aprendizagem por Discriminação/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Ratos , Ratos Wistar , Estresse Psicológico/psicologia , Natação
18.
Amino Acids ; 52(2): 181-197, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30915570

RESUMO

Agmatine, a natural polyamine produced from arginine by arginine decarboxylase, was first discovered in 1910, but its physiological significance was disregarded for a century. The recent rediscovery of agmatine as an endogenous ligand for α2-adrenergic and imidazoline receptors in the mammalian brain suggests that this amine may be a promising therapeutic agent for treating a broad spectrum of central nervous system-associated diseases. In the past two decades, numerous preclinical and several clinical studies have demonstrated its pleiotropic modulatory functions on various molecular targets related to neurotransmission, nitric oxide synthesis, glucose metabolism, polyamine metabolism, and carnitine biosynthesis, indicating potential for therapeutic applications and use as a nutraceutical to improve quality of life. An enzymatic activity of arginine decarboxylase which produces agmatine from arginine was low in mammals, suggesting that a large portion of the agmatine is supplemented from diets and gut microbiota. In the present review, we focus on and concisely summarize the beneficial effects of agmatine for treating depression, anxiety, neuropathic pain, cognitive decline and learning impairment, dependence on drugs, and metabolic diseases (diabetes and obesity), since these fields have been intensively investigated. We also briefly discuss agmatine content in foodstuffs, and a simple approach for enhancing agmatine production using the filamentous fungus Aspergillus oryzae, widely used for the production of various Asian fermented foods.


Assuntos
Agmatina/metabolismo , Aspergillus oryzae/metabolismo , Suplementos Nutricionais/análise , Agmatina/farmacologia , Animais , Depressão/tratamento farmacológico , Humanos , Doenças Metabólicas/tratamento farmacológico , Neuralgia/tratamento farmacológico
19.
Crit Care Med ; 48(1): e40-e47, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634234

RESUMO

OBJECTIVES: The knowledge that agmatine is found in the human body has existed for several years; however, its role in sepsis has not yet been studied. In the present study, we investigate the role of agmatine in the progression and treatment of sepsis. DESIGN: Clinical/laboratory investigations. SETTING: Medical centers/University-based research laboratory. SUBJECTS: Elective ICU patients with severe sepsis and healthy volunteers; C57BL/6 mice weighing 18-22 g. INTERVENTIONS: Serum agmatine level and its associations with inflammatory markers were assessed in patients with sepsis. Agmatine was administered intraperitoneally to mice before a lipopolysaccharide challenge. Human peripheral blood mononuclear cells and murine macrophages were pretreated with agmatine followed by lipopolysaccharide stimulation. MEASUREMENTS AND MAIN RESULTS: Serum agmatine levels were significantly decreased in patients with sepsis and lipopolysaccharide-induced mice, and correlated with Acute Physiology and Chronic Health Evaluation II score, procalcitonin, tumor necrosis factor-α, and interleukin-6 levels. In a therapeutic experiment, exogenous agmatine attenuated the cytokine production of peripheral blood mononuclear cells from patients with sepsis and healthy controls. Agmatine also exerted a significant beneficial effect in the inflammatory response and organ damage and reduced the death rate in lipopolysaccharide-induced mice. Imidazoline I2 receptor agonist 2-benzofuran-2-yl blocked the pharmacological action of agmatine; whereas, other imidazoline receptor ligands did not. Furthermore, agmatine significantly impaired the inflammatory response by inactivating nuclear factor-κB, but not protein 38 mitogen-activated protein kinase, c-Jun N-terminal kinase, extracellular signal-regulated kinase, and inducible nitric oxide synthase signaling in macrophages. Activation of imidazoline I2 receptor or knockdown of ribosomal S6 kinase 2 counteracted the effects of agmatine on phosphorylation and degradation of inhibitor of nuclear factor-κBα. CONCLUSIONS: Endogenous agmatine metabolism correlated with the progression of sepsis. Supplemental exogenous agmatine could ameliorate the lipopolysaccharide-induced systemic inflammatory responses and multiple organ injuries through the imidazoline I2 receptor-ribosomal S6 kinase 2-nuclear factor-κB pathway. Agmatine could be used as both a clinical biomarker and a promising pharmaconutrient in patients with severe sepsis.


Assuntos
Agmatina/uso terapêutico , Receptores de Imidazolinas/fisiologia , NF-kappa B/fisiologia , Proteínas Quinases S6 Ribossômicas 90-kDa/fisiologia , Sepse/tratamento farmacológico , Transdução de Sinais/fisiologia , Agmatina/farmacologia , Animais , Células Cultivadas , Progressão da Doença , Humanos , Receptores de Imidazolinas/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 90-kDa/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
20.
Sci Rep ; 9(1): 12669, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481723

RESUMO

Agmatine (decarboxylated arginine) exerts numerous central nervous system (CNS) dependent pharmacological effects and may potentially modulate altered neurochemistry seen in neurological disorders. In preclinical studies, injection has been the predominant route of systemic administration. However, a significant translational step would be the use of oral agmatine treatment at therapeutic doses and better understanding of L-arginine metabolic profiles in the CNS post-treatment. The present study systematically investigated the tolerability, safety and brain-plasma neurochemistry following daily oral agmatine sulfate treatment (via gavage) to wild-type (WT) mice up to 900 mg/kg for one week (Experiment 1) or WT and APPswe/PS1ΔE9 transgenic (Tg) mice at 300 mg/kg for fifteen weeks (Experiment 2). Agmatine treatment in both experiments was well tolerated with no marked behavioural impairments, and gross necropsy and organ histology revealed no pathological alterations after 15-week dosing. Moreover, oral treatment increased agmatine levels in the hippocampus and plasma of WT mice (Experiment 1), and in 6 brain regions examined (but not plasma) of WT and Tg mice (Experiment 2), at 30 minutes or 24 hours post-treatment respectively. This study provides fundamental pre-clinical evidence that daily oral delivery of agmatine sulfate to both WT and Tg mice is safe and well tolerated. Exogenous agmatine passes through the blood brain barrier and accumulates in the brain to a greater extent in Tg mice. Furthermore exogenous agmatine has differential actions in the brain and periphery, and its effect on brain putrescine appears to be dependent on the time post-treatment.


Assuntos
Agmatina/farmacologia , Encéfalo/efeitos dos fármacos , Administração Oral , Agmatina/sangue , Precursor de Proteína beta-Amiloide/genética , Animais , Arginina/sangue , Arginina/metabolismo , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Hipocampo/química , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...