RESUMO
Objective. Agmatine, decarboxylated arginine, was shown in preclinical studies to exert efficacious neuroprotection by interacting with multiple molecular targets. This study was designed to ascertain safety and efficacy of dietary agmatine sulfate in herniated lumbar disc-associated radiculopathy. Study Design. First, an open-label dose escalation study was performed to assess the safety and side-effects of agmatine sulfate. In the follow-up study, participants diagnosed with herniated lumbar disc-associated radiculopathy were randomly assigned to receive either placebo or agmatine sulfate in a double-blind fashion. Methods. Participants in the first study were recruited consecutively into four cohorts who took the following escalating regimens: 1.335 g/day agmatine sulfate for 10 days, 2.670 g/day for 10 days, 3.560 g/day for 10 days, and 3.560 g/day for 21 days. Participants in the follow-up study were assigned to receive either placebo or agmatine sulfate, 2.670 g/day for 14 days. Primary outcome measures were pain using the visual analog scale, the McGill pain questionnaire and the Oswestry disability index, sensorimotor deficits, and health-related quality of life using the 36-item short form (SF-36) questionnaire. Secondary outcomes included other treatment options, and safety and tolerability assessment. Results. Safety parameters were within normal values in all participants of the first study. Three participants in the highest dose cohort had mild-to-moderate diarrhea and mild nausea during treatment, which disappeared upon treatment cessation. No other events were observed. In the follow-up study, 51 participants were randomly enrolled in the agmatine group and 48 in the placebo. Continuous improvement of symptoms occurred in both groups, but was more pronounced in the agmatine (analyzed n = 31) as compared with the placebo group (n = 30). Expressed as percent of baseline values, significantly enhanced improvement in average pain measures and in quality of life scores occurred after treatment in the agmatine group (26.7% and 70.8%, respectively) as compared with placebo (6.0% [P = 0.05] and 20.0% [P = 0.05], respectively). No treatment-related adverse events were noted. Conclusions. Dietary agmatine sulfate is safe and efficacious treatment for alleviating pain and improving quality of life in lumbar disc-associated radiculopathy. Study Registration. ClinicalTrials.gov Protocol Registration System Identifier: NCT00405041.
Assuntos
Agmatina/uso terapêutico , Deslocamento do Disco Intervertebral/complicações , Radiculopatia/tratamento farmacológico , Adulto , Idoso , Agmatina/administração & dosagem , Agmatina/efeitos adversos , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Vértebras Lombares/patologia , Masculino , Pessoa de Meia-Idade , Força Muscular/efeitos dos fármacos , Medição da Dor , Radiculopatia/etiologia , Sensação/efeitos dos fármacosRESUMO
The study is based on the premise that the enzyme lysyl oxidase (LO), which catalyzes the crosslinking of extracellular matrix (ECM) proteins, participates in ECM modulation and senile plaque formation in Alzheimer's disease (AD). Experiments on hippocampal samples indicate that LO activity is increased (about 30%) in AD, but also in non-Alzheimer's dementia, as compared to controls with unrelated diseases. Immunohistochemistry with specific LO antibody indicates localization in blood vessel walls and in plaque-like structures. The number of LO-positive plaque-like structures in AD was over two-fold higher as compared to both non-Alzheimer's dementia and control groups. The findings lead us to suggest that active LO molecules in the ECM may be associated with plaque formation.
Assuntos
Doença de Alzheimer/enzimologia , Artérias Cerebrais/enzimologia , Matriz Extracelular/metabolismo , Hipocampo/enzimologia , Placa Amiloide/enzimologia , Proteína-Lisina 6-Oxidase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Biomarcadores/metabolismo , Artérias Cerebrais/fisiopatologia , Cromossomos Humanos Par 5/genética , Feminino , Predisposição Genética para Doença/genética , Hipocampo/fisiopatologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Placa Amiloide/patologia , Proteína-Lisina 6-Oxidase/genética , Regulação para Cima/fisiologiaRESUMO
UNLABELLED: Recent findings indicate that rapid and transient changes in polyamine metabolism, termed the polyamine-stress-response, may occur repeatedly in the brain after chronic intermittent stress. Here, we sought to examine the effects of chronic intermittent restraint stress, or of daily intraperitoneal dexamethasone injections on polyamine concentrations in the hippocampus of adult male C57BL/6 mice. Additionally, we studied the effects of alpha-difluoromethylornithine, an irreversible ornithine decarboxylase inhibitor, on stress-induced changes in polyamines and on behavioral reactivity to novelty stress measured in an open-field arena. As previously observed, following a single stress episode putrescine concentration increased transiently, but the polyamines spermidine and spermine remained unchanged. Following chronic restraint stress, putrescine concentration was increased after each daily stress episode with the largest increase observed after the 4th episode, while spermidine was increased just after the 2nd and 4th episodes and spermine only after the 4th daily episode. In contrast, all polyamine concentrations were increased after 10 injections of either dexamethasone or vehicle (0.9% NaCl). A 14-day course of alpha-difluoromethylornithine treatment resulted in a complete putrescine depletion and over 50% reduction in polyamines, and led to changes in open field activity indicative of altered emotional behavior. CONCLUSIONS: (a) while putrescine concentration increases in the hippocampus after each restraint stress episode, spermidine and spermine undergo a delayed but transient increase; (b) in contrast, chronic dexamethasone treatment may lead to a permanent increase in the concentrations of all polyamines and; (c) chronic alpha-difluoromethylornithine treatment reduces brain polyamine concentrations and modulates emotional reactivity to novelty stress. The study indicates that the brain polyamine-stress-response is a dynamic process that varies with the type, intensity and length of stressful stimuli, and implicates this response as an adaptive mechanism in the reaction to stressors.
Assuntos
Comportamento Animal/fisiologia , Poliaminas Biogênicas/metabolismo , Encéfalo/metabolismo , Estresse Fisiológico/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Poliaminas Biogênicas/antagonistas & inibidores , Poliaminas Biogênicas/biossíntese , Encéfalo/efeitos dos fármacos , Dexametasona/administração & dosagem , Eflornitina/administração & dosagem , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Inibidores da Ornitina Descarboxilase , Restrição Física , Cloreto de Sódio/administração & dosagem , Estresse Fisiológico/induzido quimicamente , Estresse Fisiológico/psicologiaRESUMO
Based on previous studies which suggest that blood polyamines fluctuate during the menstrual cycle, the present study was set to determine whether plasma concentrations of the polyamine spermine show menstrual cycle-associated changes and if so, how these changes relate to phasic variations in other female hormones. Blood samples were collected from a group of 9 healthy women of various ages at 5 defined periods during their menstrual cycle including 1 woman on oral contraceptives. Spermine concentrations were determined in plasma acid extracts by reversed-phase high performance liquid chromatography method. Plasma estradiol, LH and FSH were measured by microparticle enzyme immunoassay using an automatic analyzer. Spermine concentrations, 104.4 +/- 12.2 nmol/ml at 1-3 day of the cycle, were increased transiently with a peak (263.8 +/- 22.1 nmol/ml) at 8-10 day and declined to 85.4 +/- 29.8 nmol/ml by 21-23 day of the cycle. The peak spermine concentrations coincided with the first increase in plasma estrogen levels. The individual variations in the temporal profile of spermine concentrations were of similar magnitude as individual differences in other female hormones. We conclude that: a) Plasma spermine concentrations undergo distinct cyclic alterations during the menstrual cycle with peak concentrations coinciding with the first estradiol increase, and b) Peak plasma spermine concentrations occur during the follicular phase, just prior to ovulation, during the period of rapid endometrial growth.
Assuntos
Ciclo Menstrual/sangue , Espermina/sangue , Adulto , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Técnicas Imunoenzimáticas , Hormônio Luteinizante/sangueRESUMO
There is presently a great interest in the therapeutic potential of agmatine, decarboxylated arginine, for various diseases. Recent clinical studies have already shown that oral agmatine sulfate given for up to 3 weeks provides a safe and, as compared with current therapeutics, more effective treatment for neuropathic pain. These studies have ushered in the use of dietary agmatine as a nutraceutical. However, in view of information paucity, assessment of long-term safety of oral agmatine treatment is now clearly required. The authors of this report undertook to assess their own health status during ongoing consumption of a high daily dosage of oral agmatine over a period of 4-5 years. A daily dose of 2.67 g agmatine sulfate was encapsulated in gelatin capsules; the regimen consists of six capsules daily, each containing 445 mg, three in the morning and three in the evening after meals. Clinical follow-up consists of periodic physical examinations and laboratory blood and urine analyses. All measurements thus far remain within normal values and good general health status is sustained throughout the study period, up to 5 years. This case study shows for the first time that the recommended high dosage of agmatine may be consumed for at least 5 years without evidence of any adverse effects. These initial findings are highly important as they provide significant evidence for the extended long-term safety of a high daily dosage of dietary agmatine--a cardinal advantage for its utility as a nutraceutical.
Assuntos
Agmatina/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Segurança , Administração Oral , Agmatina/administração & dosagem , Agmatina/uso terapêutico , Dieta , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Neuralgia/tratamento farmacológico , Fatores de TempoRESUMO
Agmatine, decarboxylated arginine, exerts beneficial effects in various experimental disease models. Clinical trials indicate the safety and effectiveness of short-term (up to 21 days) high dose regimens of oral agmatine sulfate, but longer term studies are lacking. This pilot study undertook to assess the safety of a longer term high dosage oral agmatine sulfate in laboratory rats. Adult Wistar rats consumed 5.3 g/l agmatine sulfate in their drinking water for 95 days, a regimen estimated to result in a daily dosage of absorbed agmatine of about 100mg/kg. Animals' body weight, water consumption and blood pressure were periodically measured, and general cage behavior, fur appearance, urination and feces appearance monitored. These parameters were also determined at 20 days after treatment cessation (day 115). On days 95 and 115, animals were euthanized for gross necropsy assessment. Agmatine-treated rats showed slight, but significant reductions in body weight and blood pressure, and reduced water consumption during treatment, which recovered completely within 20 days after treatment cessation. Otherwise, no abnormal behaviors or organ pathologies were observed. These findings are first to suggest apparent safety of sub-chronic high dosage dietary agmatine sulfate in laboratory rats, thus lending further support to the therapeutic applications of agmatine.
Assuntos
Agmatina/análogos & derivados , Agmatina/efeitos adversos , Administração Oral , Agmatina/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Feminino , Masculino , Projetos Piloto , Ratos , Ratos Wistar , Testes de Toxicidade SubcrônicaRESUMO
Agmatine (decarboxylated arginine) has been known as a natural product for over 100 years, but its biosynthesis in humans was left unexplored owing to long-standing controversy. Only recently has the demonstration of agmatine biosynthesis in mammals revived research, indicating its exceptional modulatory action at multiple molecular targets, including neurotransmitter systems, nitric oxide (NO) synthesis and polyamine metabolism, thus providing bases for broad therapeutic applications. This timely review, a concerted effort by 16 independent research groups, draws attention to the substantial preclinical and initial clinical evidence, and highlights challenges and opportunities, for the use of agmatine in treating a spectrum of complex diseases with unmet therapeutic needs, including diabetes mellitus, neurotrauma and neurodegenerative diseases, opioid addiction, mood disorders, cognitive disorders and cancer.
Assuntos
Agmatina/uso terapêutico , Descoberta de Drogas , Agmatina/química , Agmatina/história , Agmatina/metabolismo , Agmatina/farmacologia , Animais , Descoberta de Drogas/história , História do Século XX , História do Século XXI , Humanos , Transdução de Sinais/efeitos dos fármacos , Distribuição TecidualRESUMO
Lithium, the most prevalent treatment for manic-depressive illness, might have a neuroprotective effect after brain injury. In culture, lithium can exert neurotoxic effects associated with reduction in polyamine synthesis but neuroprotective effects as cultured neurons mature. Cumulative evidence suggests that lithium may exert some of its effects on neurons indirectly, by initially acting on glial cells. We used rat cerebellar cultures to ascertain the effects of lithium on ornithine decarboxylase (ODC) activity, the enzyme catalyzing the first step in polyamine synthesis, and to compare effects of lithium with those of the ODC inhibitor alpha-difluoromethylornithine (DFMO) on neuron survival and glial growth. Switching cultures from high (25 mM) to low (5 mM) KCl concentrations served as the traumatic neuronal insult. The results indicate the following. 1) Whereas high depolarizing KCl concentration enhances neuron survival, it inhibits astroglial growth. 2) Lithium (LiCl; 1-5 mM) enhances neuronal survival but inhibits astroglial growth. 3) Lithium treatment leads to reduced ODC activity. 4) DFMO enhances neuron survival but inhibits astroglial growth. 5) Lithium and DFMO lead to transformation of astroglia from epithelioid (flat) to process-bearing morphology and to increased numbers of microglia. 6) Combined lithium plus DFMO treatment is cytolethal to both neurons and glia in culture. In conclusion, lithium treatment results in growth retardation and altered cell morphology of cultured astroglia and increased microglia proliferation, and these effects may be associated with inhibition of polyamine synthesis. This implies that direct effects on astrocytes and microglia may contribute to the effects of lithium on neurons.
Assuntos
Astrócitos/citologia , Divisão Celular/efeitos dos fármacos , Cerebelo/citologia , Cloreto de Lítio/farmacologia , Microglia/citologia , Animais , Astrócitos/efeitos dos fármacos , Técnicas de Cultura de Células , Sobrevivência Celular , Cerebelo/efeitos dos fármacos , Ácido Edético/farmacologia , Eflornitina/farmacologia , Inibidores Enzimáticos/farmacologia , Microglia/efeitos dos fármacos , Inibidores da Ornitina Descarboxilase , RatosRESUMO
Agmatine treatment is known to exert neuroprotective effects in several models of neurotoxic and ischemic brain and spinal cord injuries. Here we sought to find out whether agmatine treatment would also prove to be neuroprotective in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson's disease. Concomitant daily treatment (intraperitoneal injections) with agmatine (100 mg/kg for 5 days) and MPTP (40 mg/kg for 2 days) exacerbated MPTP-related toxicity as evidenced by a larger reduction in dopamine uptake into striatal synaptosomes (42.4% as compared to 58.3% of control, respectively). In contrast, agmatine treatment commencing after MPTP, produced partial protection (31%) against MPTP dopaminergic toxicity. The findings implicate agmatine in mechanisms regulating MPTP neurotoxicity, but underscore the characteristic neuroprotective efficacy of agmatine when applied after the insult.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Agmatina/farmacologia , Corpo Estriado/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Corpo Estriado/enzimologia , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monoaminoxidase/metabolismo , Óxido Nítrico Sintase/metabolismo , Doença de Parkinson/etiologia , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
The rate of nerve regeneration is a critical determinant of the degree of functional recovery after injury. Here, we sought to determine whether treatment with the neuroprotective compound, agmatine, with or without nerve reconstruction utilizing a regional autogenous vein graft would accelerate the rate of facial nerve regeneration. Experiments compared the following seven groups of adult male rats: (A) Intact untreated controls. (B) Sham operation with interruption of the nerve blood supply (controls). (C) Transection of the mandibular branch of the facial nerve (generating a gap of 3 mm) followed by saline treatment. (D) Nerve transection with unsutured autogenous vein (external jugular) graft reconstruction plus saline treatment. (E) Nerve transection with sutured vein graft approximation (coaptation of the proximal and distal nerve stumps) plus saline. (F) Nerve transection with sutured vein graft followed by agmatine treatment (four daily intraperitoneal injections of 100 mg/kg agmatine sulfate). (G) Nerve transection with unsutured vein graft followed by agmatine treatment. Functional recovery, as assessed by grading vibrissae movements and by recording nerve conduction velocity and numbers of regenerated axons, indicated that either vein reconstruction or agmatine treatment resulted in accelerated and more complete recovery as compared with controls. But best results were observed in animals that underwent combined treatment, i.e., vein reconstruction plus agmatine injection. We conclude that agmatine treatment can accelerate facial nerve regeneration and that agmatine treatment together with autogenous vein graft offers an advantageous alternative to other facial nerve reconstruction procedures.
Assuntos
Agmatina/uso terapêutico , Traumatismos do Nervo Facial/tratamento farmacológico , Traumatismos do Nervo Facial/cirurgia , Recuperação de Função Fisiológica/efeitos dos fármacos , Transplante Autólogo/métodos , Veias/transplante , Análise de Variância , Animais , Modelos Animais de Doenças , Estimulação Elétrica/métodos , Traumatismos do Nervo Facial/fisiopatologia , Imuno-Histoquímica/métodos , Masculino , Condução Nervosa/fisiologia , Proteínas de Neurofilamentos/metabolismo , Ratos , Ratos Sprague-Dawley , Tempo de Reação/fisiologia , Tempo de Reação/efeitos da radiação , Recuperação de Função Fisiológica/fisiologia , Fatores de Tempo , Resultado do Tratamento , Vibrissas/fisiologiaRESUMO
An early transient increase in brain polyamine (PA) metabolism, termed the PA-stress-response (PSR), is a common reaction to stressful stimuli, including physical, emotional, and hormonal stressors, with a magnitude related to the stress intensity. In the extreme, traumatic injury can result in an incomplete PSR, with persistent accumulation of putrescine and eventual reduction in the concentrations of the higher polyamines (PAs), spermidine and spermine. Chronic intermittent application of stressors causes a recurrence of the brain PSR, but, in contrast, it leads to habituation of the response in the periphery (liver). Severe continuous stress, however, may lead to accumulation of brain PAs. Long-term inhibition of PA synthesis depletes brain PAs and can result in altered emotional reactivity to stressors. Furthermore, the brain PSR, in contrast to the periphery, can be blocked by a long-term, but not by short-term, treatment with lithium, the most efficacious treatment of manic-depressive illness. The brain PSR is developmentally regulated, and the switch to the mature pattern coincides with the cessation of the "stress hyporesponsive period" in the hypothalamic-pituitary-adrenocortical (HPA) system. In contrast to the brain and liver, the PSR in the adrenal and thymus is down-regulated by acute stressors. Transient up-regulation of the PSR, as in the brain and liver, is implicated in cell survival while its down-regulation is implicated in cell death. Taken together, the findings indicate that the PSR is a dynamic process that varies with the type, intensity, and duration of stressors, and implicate this response as an adaptive mechanism in the reaction to stressful events. Under persistent stressful conditions, however, the PSR may be maladaptive as may be reflected by PA accumulation. This raises the hypothesis that proper regulation of brain PSR may be critical for neuronal function and for an appropriate behavioral response to stressors.