RESUMEN
A facile and practical method for the synthesis of fused tricyclic pyrazolo[5,1-a]isoquinolines has been realized via the reactions of enaminones, hydrazine hydrochloride, and internal alkynes. By means of Rh catalysis, the extraordinary high-order bond functionalization, including the transformation of aryl C-H, ketone CâO, and alkenyl C-N bonds in the enaminones, marks the major feature of the cascade reactions. The results disclose the individual advantage of enaminones in the design of novel and efficient synthetic methods.
RESUMEN
By using readily available enaminones, aryl hydrazine hydrochlorides, and alkynes as starting materials, the chemo-selective three-component synthesis of atropisomeric N-(o-alkenylaryl) pyrazoles has been efficiently accessed with rhodium catalysis. Unlike Satoh-Miura reaction leading to the alkyne-based C-H benzannulation by using prior prepared N-phenyl pyrazoles and alkynes as substrates, this three-component protocol displays unprecedented selectivity of C-H alkenylation by blocking the second round metal alkenylation with the key protonation step in the presence of acids.
Asunto(s)
Rodio , Estructura Molecular , Pirazoles , Alquinos , CatálisisRESUMEN
The synthesis of N-naphthyl pyrazoles has been realized by the direct three-component reactions of enaminones, aryl hydrazine hydrochlorides and internal alkynes via Rh(III) catalysis. The synthetic reactions employing simple substrates lead to simultaneous construction of dual cyclic moieties, including a pyrazole ring and a phenyl ring, via sequential formation of two C-N and three C-C bonds.
RESUMEN
Memantine is a moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that stabilizes cognitive, functional, and behavioral decline in patients with moderate to severe Alzheimer's disease (AD). In AD, the extracellular deposition of fibrillogenic amyloid-beta peptides (Abeta) occurs as a result of aberrant processing of the full-length Abeta precursor protein (APP). Memantine protects neurons from the neurotoxic effects of Abeta and improves cognition in transgenic mice with high brain levels of Abeta. However, it is unknown how memantine protects cells against neurodegeneration and affects APP processing and Abeta production. We report the effects of memantine in three different systems. In human neuroblastoma cells, memantine, at therapeutically relevant concentrations (1-4 muM), decreased levels of secreted APP and Abeta(1-40). Levels of the potentially amylodogenic Abeta(1-42) were undetectable in these cells. In primary rat cortical neuronal cultures, memantine treatment lowered Abeta(1-42) secretion. At the concentrations used, memantine treatment was not toxic to neuroblastoma or primary cultures and increased cell viability and/or metabolic activity under certain conditions. In APP/presenilin-1 (PS1) transgenic mice exhibiting high brain levels of Abeta(1-42), oral dosing of memantine (20 mg/kg/day for 8 days) produced a plasma drug concentration of 0.96 microM and significantly reduced the cortical levels of soluble Abeta(1-42). The ratio of Abeta(1-40)/Abeta(1-42) increased in treated mice, suggesting effects on the gamma-secretase complex. Thus, memantine reduces the levels of Abeta peptides at therapeutic concentrations and may inhibit the accumulation of fibrillogenic Abeta in mammalian brains. Memantine's ability to preserve neuronal cells against neurodegeneration, to increase metabolic activity, and to lower Abeta level has therapeutic implications for neurodegenerative disorders.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Encéfalo/efectos de los fármacos , Memantina/administración & dosificación , Neuronas/efectos de los fármacos , Precursor de Proteína beta-Amiloide/genética , Animales , Western Blotting , Encéfalo/metabolismo , Línea Celular , Células Cultivadas , Medios de Cultivo Condicionados , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Humanos , Memantina/sangre , Ratones , Ratones Transgénicos , Neuronas/citología , Neuronas/metabolismo , Fármacos Neuroprotectores/administración & dosificación , RatasRESUMEN
The sporadic nature of Alzheimer's disease (AD) argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead (Pb) during brain development predetermined the expression and regulation of the amyloid precursor protein (APP) and its amyloidogenic beta-amyloid (Abeta) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (beta-site APP cleaving enzyme 1)] as well as their transcriptional regulator (Sp1) were elevated in aged (23-year-old) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD.
Asunto(s)
Envejecimiento , Enfermedad de Alzheimer , Exposición a Riesgos Ambientales , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Plomo/toxicidad , Factores de Edad , Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/fisiopatología , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides/análisis , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Células Cultivadas , Corteza Cerebral , Modelos Animales de Enfermedad , Embrión de Mamíferos , Epigénesis Genética , Femenino , Inmunoglobulinas/metabolismo , Macaca fascicularis , Ratones , Ratones Endogámicos C57BL , Neuronas , Fragmentos de Péptidos/análisisRESUMEN
One of the main hallmarks of Alzheimer's disease (AD) is the brain deposition of senile plaques made up of toxic amyloid beta-peptide (Abeta), which is derived from a larger protein called the beta-amyloid precursor protein (APP). Both APP processing and cholinesterase activity are affected in the AD brain, but, yet, cholinesterase inhibitors (ChEI) remain the primary Food and Drug Administration approved drugs for AD within the United States. Herein, we evaluated the effects of two clinically relevant drugs on the APP pathway, which is presumably involved in AD pathogenesis. Specifically, we compared the actions of the classical ChEI physostigmine (PHY) and its analog phenserine (PHE) on neuronal cell viability, on IC50 and on levels of different amyloid proteins. Interestingly, these drugs share the same chemical backbone, inhibit acetylcholinesterase with similar potency, but differentially affect APP processing. PHE treatment decreased levels of APP in the human neuroblastoma cells (p=0.009) whereas PHY showed a similar but less-pronounced trend, which did not attain statistical significance. PHE treatment significantly decreased levels of Abeta in human neuroblastoma cells (p=0.02) whereas PHY showed no significant change under the same conditions. The divergent actions of these two structurally related drugs on the amyloid pathway indicate that the mechanisms underpinning the cholinergic and the amyloid-lowering properties for this class of drugs are independent of each other.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides/metabolismo , Carbamatos , Inhibidores de la Colinesterasa , Fisostigmina/análogos & derivados , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Butirilcolinesterasa/metabolismo , Carbamatos/química , Carbamatos/metabolismo , Carbamatos/uso terapéutico , Línea Celular , Supervivencia Celular , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/metabolismo , Inhibidores de la Colinesterasa/uso terapéutico , Humanos , Indoles/química , Indoles/metabolismo , Indoles/uso terapéutico , Estructura Molecular , Neuronas/citología , Neuronas/metabolismo , Fisostigmina/química , Fisostigmina/metabolismo , Fisostigmina/uso terapéutico , Pirroles/química , Pirroles/metabolismo , Pirroles/uso terapéuticoRESUMEN
Inflammatory and oxidative events are up-regulated in the brain of AD patients. It has been reported that in animal models of AD, exposure to aluminum (Al) or copper (Cu) enhanced oxidative events and accumulation of amyloid beta (Abeta) peptides. The present study was designed to evaluate the effect of a 3-month exposure of mice to copper sulfate (8 microM), aluminum lactate (10 or 100 microM), or a combination of the salts. Results suggest that although Al or Cu may independently initiate inflammatory or oxidative events, they may function cooperatively to increase APP levels.
Asunto(s)
Aluminio/toxicidad , Encéfalo/efectos de los fármacos , Cobre/toxicidad , Inflamación/inducido químicamente , Abastecimiento de Agua/análisis , Enfermedad de Alzheimer/etiología , Péptidos beta-Amiloides/análisis , Precursor de Proteína beta-Amiloide/análisis , Animales , Encéfalo/metabolismo , Interleucina-1/biosíntesis , Interleucina-4/biosíntesis , Peroxidación de Lípido , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Oxidación-Reducción , Factor de Necrosis Tumoral alfa/biosíntesis , Abastecimiento de Agua/normasRESUMEN
Autism is characterized by restricted, repetitive behaviors and impairment in socialization and communication. Although no neuropathologic substrate underlying autism has been found, the findings of brain overgrowth via neuroimaging studies and increased levels of brain-derived neurotrophic factor (BDNF) in neuropathologic and blood studies favor an anabolic state. We examined acetylcholinesterase, plasma neuronal proteins, secreted beta-amyloid precursor protein (APP), and amyloid-beta 40 and amyloid-beta 42 peptides in children with and without autism. Children with severe autism and aggression expressed secreted beta-amyloid precursor protein at two or more times the levels of children without autism and up to four times more than children with mild autism. There was a trend for children with autism to show higher levels of secreted beta-amyloid precursor protein and nonamyloidogenic secreted beta-amyloid precursor protein and lower levels of amyloid-beta 40 compared with controls. This favors an increased alpha-secretase pathway in autism (anabolic), opposite to what is seen in Alzheimer disease. Additionally, a complex relationship between age, acetylcholinesterase, and plasma neuronal markers was found.
Asunto(s)
Acetilcolinesterasa/sangre , Péptidos beta-Amiloides/sangre , Precursor de Proteína beta-Amiloide/sangre , Trastorno Autístico/sangre , Fragmentos de Péptidos/sangre , Adolescente , Agresión , Trastorno Autístico/psicología , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Masculino , Índice de Severidad de la EnfermedadRESUMEN
The aging brain shows selective neurochemical changes involving several neural cell populations. Increased brain metal levels have been associated with normal aging and a variety of diseases, including Alzheimer's disease (AD). Melatonin levels are decreased in aging, particularly in AD subjects. The loss of melatonin, which is synthesized by the pineal gland, together with the degeneration of cholinergic neurons of the basal forebrain and the deposition of aggregated proteins, such as the amyloid beta peptides (Abeta), are believed to contribute to the development of cognitive symptoms of dementia. Aging and its variants, such as AD, should be viewed as the result of multiple "hits," including alterations in the levels of Abeta, metals, cholinesterase enzymes, and neuronal gene expression. Herein, we present evidence in support of this theory, based on several studies. We discuss melatonin's neuroprotective function, which plays an important role in aging, prolongation of life span, and health in the aged individual. It interacts with metals and, in some cases, neutralizes their toxic effects. Dietary supplementation of melatonin restores its age-related loss. In mice, an elevated brain melatonin significantly reduced levels of potentially toxic Abeta peptides. Thus, compensation of melatonin loss in aging by dietary supplementation could well be beneficial in terms of reducing metal-induced toxicity, lipid peroxidation, and losses in cholinergic signaling. We propose that certain cholinesterase inhibitors and the NMDA partial antagonist memantine, which are FDA-approved drugs for AD and useful to boost central nervous system functioning, can be made more effective by their combination with melatonin or other neuroprotectants. Herein, we highlight studies elucidating the role of the amyloid pathway, metals, melatonin, and the cholinergic system in the context of aging and AD. Finally, melatonin is present in edible plants and walnuts, and consuming foodstuffs containing melatonin would be beneficial by enhancing the antioxidative capacity of the organisms.
Asunto(s)
Envejecimiento/fisiología , Amiloide/fisiología , Colinesterasas/fisiología , Melatonina/fisiología , Metales/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/fisiología , Animales , Fenómenos Fisiológicos Celulares , Humanos , Membranas Mitocondriales/fisiología , Dolor/fisiopatología , Columna Vertebral/fisiopatologíaRESUMEN
Melatonin is a hormone secreted by the pineal gland, mostly in the dark period of the light/dark cycle, with corresponding fluctuations reflected in the plasma melatonin levels. This hormone plays a critical role in the regulation of various neural and endocrine processes that are synchronized with daily change in photoperiod. Abnormal melatonin levels are associated with metabolic disturbances and other disorders. Melatonin potentially plays an important role in aging, prolongation of life span, and health in the aged individual. It may exert a beneficial action on neurodegenerative conditions in those with debilitating diseases. It interacts with metals and, in some cases, neutralizes their toxic effects. Levels of melatonin decrease with aging in mice. Its dietary supplementation has recently been shown to result in a significant rise in levels of endogenous melatonin in serum as well as all other tissue samples tested. The effects of dietary melatonin have been studied in the brain of mice with regard to nitric oxide synthase, synaptic proteins, and amyloid beta peptides (Abeta), which are involved in amyloid deposition and plaque formation in Alzheimer's disease (AD). Melatonin supplementation has no significant effect on cerebral cortical levels of nitric oxide synthase or synaptic proteins, such as synaptophysin and SNAP-25. Notably, however, elevated brain melatonin levels resulted in a significant reduction in levels of toxic cortical Abeta of both 40- and 42-amino-acid forms. Taken together, these results suggest that dietary melatonin supplementation may slow the neurodegenerative changes associated with brain aging and that the depletion of melatonin in the brain of aging mice may, in part, account for this adverse change.
Asunto(s)
Envejecimiento/fisiología , Expresión Génica/fisiología , Melatonina/metabolismo , Metales , Enfermedades Neurodegenerativas/metabolismo , Envejecimiento/efectos de los fármacos , Animales , Suplementos Dietéticos , Interacciones Farmacológicas , Expresión Génica/efectos de los fármacos , Humanos , Melatonina/uso terapéutico , Metales/toxicidad , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/etiologíaRESUMEN
Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid beta-peptide (Abeta), a proteolytic fragment of amyloid beta precursor protein (APP), aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe Abeta-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and Abeta. Phenserine is dose-limited in animals by its cholinergic actions; its cholinergically inactive enantiomer, posiphen (+)-[phenserine], was assessed. In cultured human neuroblastoma cells, posiphen, like phenserine, dose- and time-dependently lowered APP and Abeta levels by reducing the APP synthesis rate. This action translated to an in vivo system. Posiphen administration to mice (7.5-75 mg/kg daily, 21 consecutive days) significantly decreased levels of total APP (tissue mass-adjusted) in a dose-dependent manner. Abeta40 and Abeta42 levels were significantly lowered by posiphen (> or =15 mg/kg) compared with controls. The activities of alpha-, beta-, and gamma-secretases were assessed in the same brain samples, and beta-secretase activity was significantly reduced. Posiphen, like phenserine, can lower Abeta via multiple mechanisms and represents an interesting drug candidate for AD treatment.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/análisis , Inhibidores de la Colinesterasa/farmacología , Fisostigmina/análogos & derivados , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/análisis , Precursor de Proteína beta-Amiloide/genética , Animales , Línea Celular Tumoral , Corteza Cerebral/química , Corteza Cerebral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Fisostigmina/farmacología , ARN Mensajero/análisis , EstereoisomerismoRESUMEN
A wealth of independent research with transgenic mice, antibodies, and vaccines has pointed to a causative role of the amyloid-beta peptide (A beta) in Alzheimer's disease (AD). Based on these and earlier associative studies, A beta represents a promising target for development of therapeutics focused on AD disease progression. Interestingly, a cholinesterase inhibitor currently in clinical trials, phenserine, has been shown to inhibit production of both amyloid precursor protein (APP) and A beta. We have shown that this inhibition occurs at the post-transcriptional level with a specific blocking of the synthesis of APP relative to total protein synthesis (Shaw et al., 2001). However, the dose of phenserine necessary to block APP production is far higher than that needed to elicit its anticholinesterase activity, and it is these latter actions that are dose limiting in vivo. The focus of this study was to screen 144 analogs of phenserine to identify additional small molecules that inhibit APP protein synthesis, and thereby A beta production, without possessing potent acetylcholinesterase (AChE) inhibitory activity. An enzyme-linked immunosorbent assay was used to identify analogs capable of suppressing APP production following treatment of human neuroblastoma cells with 20 muM of compound. Eight analogs were capable of dose dependently reducing APP and A beta production without causing cell toxicity in further studies. Several of these analogs had little to no AChE activities. Translation of APP and A beta actions to mice was demonstrated with one agent. They thus represent interesting lead molecules for assessment in animal models, to define their tolerance and utility as potential AD therapeutics.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/antagonistas & inhibidores , Precursor de Proteína beta-Amiloide/biosíntesis , Fármacos Neuroprotectores/farmacología , Fisostigmina/análogos & derivados , Animales , Western Blotting , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Evaluación Preclínica de Medicamentos , Ensayo de Inmunoadsorción Enzimática , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/biosíntesis , Fisostigmina/química , Fisostigmina/farmacología , ARN Mensajero/análisis , ARN Mensajero/biosíntesis , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Like acetylcholinesterase, butyrylcholinesterase (BChE) inactivates the neurotransmitter acetylcholine (ACh) and is hence a viable therapeutic target in Alzheimer's disease, which is characterized by a cholinergic deficit. Potent, reversible, and brain-targeted BChE inhibitors (cymserine analogs) were developed based on binding domain structures to help elucidate the role of this enzyme in the central nervous system. In rats, cymserine analogs caused long-term inhibition of brain BChE and elevated extracellular ACh levels, without inhibitory effects on acetylcholinesterase. In rat brain slices, selective BChE inhibition augmented long-term potentiation. These compounds also improved the cognitive performance (maze navigation) of aged rats. In cultured human SK-N-SH neuroblastoma cells, intra- and extracellular beta-amyloid precursor protein, and secreted beta-amyloid peptide levels were reduced without affecting cell viability. Treatment of transgenic mice that overexpressed human mutant amyloid precursor protein also resulted in lower beta-amyloid peptide brain levels than controls. Selective, reversible inhibition of brain BChE may represent a treatment for Alzheimer's disease, improving cognition and modulating neuropathological markers of the disease.
Asunto(s)
Acetilcolina/metabolismo , Enfermedad de Alzheimer/enzimología , Péptidos beta-Amiloides/metabolismo , Encéfalo/efectos de los fármacos , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/farmacología , Aprendizaje/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/enzimología , Encéfalo/metabolismo , Inhibidores de la Colinesterasa/administración & dosificación , Relación Dosis-Respuesta a Droga , Hipocampo/efectos de los fármacos , Hipocampo/enzimología , Humanos , Masculino , Ratones , Ratones Transgénicos , Neuroblastoma/tratamiento farmacológico , Neuroblastoma/enzimología , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Ratas Wistar , Serina/administración & dosificación , Serina/análogos & derivados , Serina/farmacología , Células Tumorales CultivadasRESUMEN
Melatonin levels decrease with aging in mice. Dietary supplementation with melatonin has recently been shown to result in a significant rise in levels of endogenous melatonin in the serum and all other tissue samples tested. Herein, the effects of dietary melatonin on brain levels of nitric oxide synthase, synaptic proteins and amyloid beta-peptides (Abeta) were determined in mice. Melatonin supplementation did not significantly change cerebral cortical levels of nitric oxide synthase or synaptic proteins such as synaptophysin and SNAP-25. Increased brain melatonin concentrations however, led to a significant reduction in levels of toxic cortical Abeta of both short and long forms which are involved in amyloid depositions and plaque formation in Alzheimer's diseases. Thus, melatonin supplementation may retard neurodegenerative changes associated with brain aging. Depletion of melatonin in the brain of aging mice may in part account for this adverse change.
Asunto(s)
Péptidos beta-Amiloides/metabolismo , Antioxidantes/farmacología , Corteza Cerebral/efectos de los fármacos , Melatonina/administración & dosificación , Fragmentos de Péptidos/metabolismo , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Animales , Western Blotting , Corteza Cerebral/metabolismo , Suplementos Dietéticos , Melatonina/sangre , Ratones , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/prevención & control , Óxido Nítrico Sintasa/metabolismoRESUMEN
Glucagon-like peptide-1(7-36)-amide (GLP-1) is an endogenous insulinotropic peptide that is secreted from the gastrointestinal tract in response to food. It enhances pancreatic islet beta-cell proliferation and glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. GLP-1 receptors, which are coupled to the cyclic AMP second messenger pathway, are expressed throughout the brains of rodents and humans. It was recently reported that GLP-1 and exendin-4, a naturally occurring, more stable analogue of GLP-1 that binds at the GLP-1 receptor, possess neurotrophic properties and can protect neurons against glutamate-induced apoptosis. We report here that GLP-1 can reduce the levels of amyloid-beta peptide (Abeta) in the brain in vivo and can reduce levels of amyloid precursor protein (APP) in cultured neuronal cells. Moreover, GLP-1 and exendin-4 protect cultured hippocampal neurons against death induced by Abeta and iron, an oxidative insult. Collectively, these data suggest that GLP-1 can modify APP processing and protect against oxidative injury, two actions that suggest a novel therapeutic target for intervention in Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Muerte Celular/efectos de los fármacos , Glucagón/farmacología , Hipocampo/efectos de los fármacos , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Fragmentos de Péptidos/farmacología , Precursores de Proteínas/farmacología , Ponzoñas , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/biosíntesis , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/farmacología , Precursor de Proteína beta-Amiloide/efectos de los fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Muerte Celular/fisiología , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Exenatida , Feto , Glucagón/uso terapéutico , Péptido 1 Similar al Glucagón , Hipocampo/metabolismo , Hipocampo/fisiopatología , Hierro/metabolismo , Hierro/farmacología , Masculino , Ratones , Ratones Endogámicos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Células PC12 , Fragmentos de Péptidos/biosíntesis , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/uso terapéutico , Péptidos/farmacología , Péptidos/uso terapéutico , Precursores de Proteínas/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
The insulinotropic hormone glucagon-like peptide-1 (7-36)-amide (GLP-1) has potent effects on glucose-dependent insulin secretion, insulin gene expression, and pancreatic islet cell formation and is presently in clinical trials as a therapy for type 2 diabetes mellitus. We report on the effects of GLP-1 and two of its long-acting analogs, exendin-4 and exendin-4 WOT, on neuronal proliferation and differentiation, and on the metabolism of two neuronal proteins in the rat pheochromocytoma (PC12) cell line, which has been shown to express the GLP-1 receptor. We observed that GLP-1 and exendin-4 induced neurite outgrowth in a manner similar to nerve growth factor (NGF), which was reversed by coincubation with the selective GLP-1 receptor antagonist exendin (9-39). Furthermore, exendin-4 could promote NGF-initiated differentiation and may rescue degenerating cells after NGF-mediated withdrawal. These effects were induced in the absence of cellular dysfunction and toxicity as quantitatively measured by 3-(4,5-cimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and lactate dehydrogenase assays, respectively. Our findings suggest that such peptides may be used in reversing or halting the neurodegenerative process observed in neurodegenerative diseases, such as the peripheral neuropathy associated with type 2 diabetes mellitus and Alzheimer's and Parkinson's diseases. Due to its novel twin action, GLP-1 and exendin-4 have therapeutic potential for the treatment of diabetic peripheral neuropathy and these central nervous system disorders.