RESUMO
Alzheimer's disease (AD) is a complex neurodegenerative process, also considered a metabolic condition due to alterations in glucose metabolism and insulin signaling pathways in the brain, which share similarities with diabetes. This study aimed to investigate the therapeutic effects of benfotiamine (BFT), a vitamin B1 analog, in the early stages of the neurodegenerative process in a sporadic model of Alzheimer's-like disease induced by intracerebroventricular injection of streptozotocin (STZ). Supplementation with 150 mg/kg of BFT for 7 days reversed the cognitive impairment in short- and long-term memories caused by STZ in rodents. We attribute these effects to BFT's ability to modulate glucose transporters type 1 and 3 (GLUT1 and GLUT3) in the hippocampus, inhibit GSK3 activity in the hippocampus, and modulate the insulin signaling in the hippocampus and entorhinal cortex, as well as reduce the activation of apoptotic pathways (BAX) in the hippocampus. Therefore, BFT emerges as a promising and accessible intervention in the initial treatment of conditions similar to AD.
Assuntos
Doença de Alzheimer , Modelos Animais de Doenças , Hipocampo , Insulina , Transdução de Sinais , Estreptozocina , Tiamina , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Masculino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Tiamina/farmacologia , Tiamina/análogos & derivados , Tiamina/uso terapêutico , Ratos , Cognição/efeitos dos fármacos , Ratos Wistar , Aprendizagem em Labirinto/efeitos dos fármacosRESUMO
BACKGROUND: Around two-thirds of patients with Alzheimer's disease (AD) are women, which could be related to the depletion of female sexual hormones at menopause. The replacement of these hormones with hormone therapy (HT) to possibly decrease AD risk or treat AD patients has generated conflicting results in the literature. OBJECTIVE: Our aim was to systematically review the relationship between HT use in postmenopausal women with AD and the risk of developing or treating AD symptoms. DATA SOURCES: The PubMed, LILACS, Scopus, Scielo, and Web of Science databases were searched from January 1994 to December 2020 using the descriptors 'Alzheimer Disease OR Alzheimer's Disease' and 'Hormone Replacement Therapy OR Estrogen Replacement Therapy'. STUDY SELECTION: Observational and controlled clinical trials including postmenopausal women diagnosed with AD and evaluating HT efficacy were eligible for inclusion. DATA EXTRACTION: Extracted data comprise study design, covariates, inclusion criteria for sample selection, AD diagnosis criteria, biases, HT regimen, and cognitive measurement tools used. RESULTS: Overall, 25 studies were selected. Among the 14 observational studies, 8 reported an improvement in cognitive function and a decrease in AD risk, especially in younger postmenopausal women. Five observational studies did not demonstrate any association between HT and AD, and one study reported an increase in AD risk, regardless of time of HT initiation. Of the 11 controlled clinical trials included, 7 showed an amelioration in cognitive function after HT. The remaining 4 trials saw no difference between HT and control. CONCLUSION: Both observational and controlled clinical trials had methodological issues and discrepancies in inclusion criteria and HT protocols. These inconsistencies made it difficult to establish an association between HT and AD.
Assuntos
Doença de Alzheimer , Doença de Alzheimer/tratamento farmacológico , Terapia de Reposição de Estrogênios , Feminino , Hormônios , Humanos , Menopausa , Pós-MenopausaRESUMO
The cannabinoid system has the ability to modulate cellular and molecular mechanisms, including excitotoxicity, oxidative stress, apoptosis, and inflammation, acting as a neuroprotective agent, by its relationship with signaling pathways associated to the control of cell proliferation, differentiation, and survival. Recent reports have raised new perspectives on the possible role of cannabinoid system in neurodegenerative diseases like Alzheimer disease's (AD). AD is a neurodegenerative disorder characterized by the presence of amyloid plaques, neurofibrillary tangles, neuronal death, and progressive cognitive loss, which could be caused by energy metabolism impairment, changes in insulin signaling, chronic oxidative stress, neuroinflammation, Tau hyperphosphorylation, and Aß deposition in the brain. Thus, we investigated the presumptive protective effect of the cannabinoid type 1 (CB1)-selective receptor agonist arachidonyl-2'-chloroethylamide (ACEA) against streptozotocin (STZ) exposure stimuli in an in vitro neuronal model (Neuro-2a neuroblastoma cells) and in vivo model (intracerebroventricular STZ injection), experimental models of sporadic AD. Our results demonstrated that ACEA treatment reversed cognitive impairment and increased activity of Akt and ERK triggered by STZ, and increased IR expression and increased the anti-apoptotic proteins levels, Bcl-2. In the in vitro model, ACEA was able to rescue cells from STZ-triggered death and modulated the NO release by STZ. Our study has demonstrated a participation of the cannabinoid system in cellular survival, involving the CB1 receptor, which occurs by positive regulation of the anti-apoptotic proteins, suggesting the participation of this system in neurodegenerative processes. Our data suggest that the cannabinoid system is an interesting therapeutic target for the treatment of neurodegenerative diseases.
Assuntos
Ácidos Araquidônicos/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Receptor CB1 de Canabinoide/agonistas , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Transtornos Cognitivos/metabolismo , Masculino , Camundongos , Degeneração Neural/tratamento farmacológico , Degeneração Neural/metabolismo , Óxido Nítrico/metabolismo , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , EstreptozocinaRESUMO
Neurodegeneration is the result of progressive destruction of neurons in the central nervous system, with unknown causes and pathological mechanisms not yet fully elucidated. Several factors contribute to neurodegenerative processes, including neuroinflammation, accumulation of neurotoxic factors, and misfolded proteins in the lumen of the endoplasmic reticulum (ER). Endocannabinoid signaling has been pointed out as an important modulatory system in several neurodegeneration-related processes, inhibiting the inflammatory response and increasing neuronal survival. Thus, we investigated the presumptive protective effect of the selective cannabinoid type 1 (CB1) receptor agonist arachidonyl-2'-chloroethylamide (ACEA) against inflammatory (lipopolysaccharide, LPS) and ER stress (tunicamycin) stimuli in an in vitro neuronal model (Neuro-2a neuroblastoma cells). Cell viability analysis revealed that ACEA was able to protect against cell death induced by LPS and tunicamycin. This neuroprotective effect occurs via the CB1 receptor in the inflammation process and via the transient receptor potential of vanilloid type-1 (TRPV1) channel in ER stress. Furthermore, the immunoblotting analyses indicated that the neuroprotective effect of ACEA seems to involve the modulation of eukaryotic initiation factor 2 (eIF2α), transcription factor C/EBP homologous protein (CHOP), and caspase 12, as well as the survival/death p44/42 MAPK, ERK1/2-related signaling pathways. Together, these data suggest that the endocannabinoid system is a potential therapeutic target in neurodegenerative processes, especially in ER-related neurodegenerative diseases.
Assuntos
Apoptose/efeitos dos fármacos , Ácidos Araquidônicos/farmacologia , Endocanabinoides/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Fármacos NeuroprotetoresRESUMO
The endocannabinoid system has been implicated in several neurobiological processes, including neurodegeneration, neuroprotection and neuronal plasticity. The CB1 cannabinoid receptors are abundantly expressed in the basal ganglia, the circuitry that is mostly affected in Parkinson's Disease (PD). Some studies show variation of CB1 expression in basal ganglia in different animal models of PD, however the results are quite controversial, due to the differences in the procedures employed to induce the parkinsonism and the periods analyzed after the lesion. The present study evaluated the CB1 expression in four basal ganglia structures, namely striatum, external globus pallidus (EGP), internal globus pallidus (IGP) and substantia nigra pars reticulata (SNpr) of rats 1, 5, 10, 20, and 60 days after unilateral intrastriatal 6-hydroxydopamine injections, that causes retrograde dopaminergic degeneration. We also investigated tyrosine hydroxylase (TH), parvalbumin, calbindin and glutamic acid decarboxylase (GAD) expression to verify the status of dopaminergic and GABAergic systems. We observed a structure-specific modulation of CB1 expression at different periods after lesions. In general, there were no changes in the striatum, decreased CB1 in IGP and SNpr and increased CB1 in EGP, but this increase was not sustained over time. No changes in GAD and parvalbumin expression were observed in basal ganglia, whereas TH levels were decreased and the calbindin increased in striatum in short periods after lesion. We believe that the structure-specific variation of CB1 in basal ganglia in the 6-hydroxydopamine PD model could be related to a compensatory process involving the GABAergic transmission, which is impaired due to the lack of dopamine. Our data, therefore, suggest that the changes of CB1 and calbindin expression may represent a plasticity process in this PD model.
Assuntos
Gânglios da Base/metabolismo , Globo Pálido/metabolismo , Neostriado/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Substância Negra/metabolismo , Animais , Calbindinas/metabolismo , Immunoblotting , Imuno-Histoquímica , Masculino , Oxidopamina , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Ratos , Ratos Wistar , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Neurodegenerative disorders are undoubtedly an increasing problem in the health sciences, given the increase of life expectancy and occasional vicious life style. Despite the fact that the mechanisms of such diseases are far from being completely understood, a large number of studies that derive from both the basic science and clinical approaches have contributed substantial data in that direction. In this review, it is discussed several frontiers of basic research on Parkinson´s and Alzheimer´s diseases, in which research groups from three departments of the Institute of Biomedical Sciences of the University of São Paulo have been involved in a multidisciplinary effort. The main focus of the review involves the animal models that have been developed to study cellular and molecular aspects of those neurodegenerative diseases, including oxidative stress, insulin signaling and proteomic analyses, among others. We anticipate that this review will help the group determine future directions of joint research in the field and, more importantly, set the level of cooperation we plan to develop in collaboration with colleagues of the Nucleus for Applied Neuroscience Research that are mostly involved with clinical research in the same field.
Os transtornos neurodegenerativos são, sem dúvida, um problema crescente nas ciências da saúde, dado o aumento da expectativa de vida e de estilos de vida pouco saudáveis. Embora os mecanismos de tais doenças ainda estejam longe de ser esclarecidos, vários estudos que derivam tanto da ciência básica quanto de abordagens clínicas contribuíram nessa direção. Na presente revisão, são discutidas linhas de frente da pesquisa básica sobre as doenças de Parkinson e Alzheimer, em que grupos de pesquisas de três departamentos do Instituto de Ciências Biomédicas da Universidade de São Paulo estão envolvidos em um esforço multidisciplinar. O foco principal desta revisão envolve os modelos animais desenvolvidos para se estudar os aspectos celulares e moleculares daquelas doenças neurodegenerativas, incluindo o estresse oxidativo, a sinalização da insulina e as análises proteômicas, dentre outros. Antecipamos que esta revisão irá auxiliar o grupo a determinar as futuras direções da pesquisa conjunta nessa área e, o mais importante, estabelecer o nível de cooperação que planejamos desenvolver juntamente com colegas do Núcleo de Apoio à Pesquisa em Neurociência Aplicada que estão envolvidos com pesquisa clínica na mesma área.
Assuntos
Animais , Humanos , Doença de Alzheimer/metabolismo , Doença de Parkinson/metabolismo , Doença de Alzheimer/etiologia , Biomarcadores/análise , Encéfalo/patologia , Modelos Animais de Doenças , Exercício Físico/fisiologia , NADPH Oxidases/metabolismo , Estresse Oxidativo/fisiologia , Doença de Parkinson/etiologia , Peptídeos/análise , ProteômicaRESUMO
The aim of the present study was to evaluate the behavioral patterns associated with autism and the prevalence of these behaviors in males and females, to verify whether our model of lipopolysaccharide (LPS) administration represents an experimental model of autism. For this, we prenatally exposed Wistar rats to LPS (100 µg/kg, intraperitoneally, on gestational day 9.5), which mimics infection by gram-negative bacteria. Furthermore, because the exact mechanisms by which autism develops are still unknown, we investigated the neurological mechanisms that might underlie the behavioral alterations that were observed. Because we previously had demonstrated that prenatal LPS decreases striatal dopamine (DA) and metabolite levels, the striatal dopaminergic system (tyrosine hydroxylase [TH] and DA receptors D1a and D2) and glial cells (astrocytes and microglia) were analyzed by using immunohistochemistry, immunoblotting, and real-time PCR. Our results show that prenatal LPS exposure impaired communication (ultrasonic vocalizations) in male pups and learning and memory (T-maze spontaneous alternation) in male adults, as well as inducing repetitive/restricted behavior, but did not change social interactions in either infancy (play behavior) or adulthood in females. Moreover, although the expression of DA receptors was unchanged, the experimental animals exhibited reduced striatal TH levels, indicating that reduced DA synthesis impaired the striatal dopaminergic system. The expression of glial cell markers was not increased, which suggests that prenatal LPS did not induce permanent neuroinflammation in the striatum. Together with our previous finding of social impairments in males, the present findings demonstrate that prenatal LPS induced autism-like effects and also a hypoactivation of the dopaminergic system.
Assuntos
Transtorno Autístico/induzido quimicamente , Transtorno Autístico/psicologia , Comportamento Animal/efeitos dos fármacos , Dopamina/fisiologia , Lipopolissacarídeos/toxicidade , Efeitos Tardios da Exposição Pré-Natal/psicologia , Animais , Feminino , Imuno-Histoquímica , Relações Interpessoais , Deficiências da Aprendizagem/induzido quimicamente , Deficiências da Aprendizagem/psicologia , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/psicologia , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Jogos e Brinquedos , Gravidez , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Receptores Dopaminérgicos/biossíntese , Tirosina 3-Mono-Oxigenase/biossíntese , Vocalização AnimalRESUMO
Neurodegenerative disorders are undoubtedly an increasing problem in the health sciences, given the increase of life expectancy and occasional vicious life style. Despite the fact that the mechanisms of such diseases are far from being completely understood, a large number of studies that derive from both the basic science and clinical approaches have contributed substantial data in that direction. In this review, it is discussed several frontiers of basic research on Parkinson's and Alzheimer's diseases, in which research groups from three departments of the Institute of Biomedical Sciences of the University of São Paulo have been involved in a multidisciplinary effort. The main focus of the review involves the animal models that have been developed to study cellular and molecular aspects of those neurodegenerative diseases, including oxidative stress, insulin signaling and proteomic analyses, among others. We anticipate that this review will help the group determine future directions of joint research in the field and, more importantly, set the level of cooperation we plan to develop in collaboration with colleagues of the Nucleus for Applied Neuroscience Research that are mostly involved with clinical research in the same field.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Parkinson/metabolismo , Doença de Alzheimer/etiologia , Animais , Biomarcadores/análise , Encéfalo/patologia , Modelos Animais de Doenças , Exercício Físico/fisiologia , Humanos , NADPH Oxidases/metabolismo , Estresse Oxidativo/fisiologia , Doença de Parkinson/etiologia , Peptídeos/análise , ProteômicaRESUMO
Aging can lead to cognitive, affective, learning, memory and motor deficits. Since the cerebellum and glutamatergic neurotransmission are involved in several of those functions, the present work aimed at studying the expression of AMPA and NMDA glutamate receptor subunits in the chick cerebellum during aging. Young (30 days old) and aged (ca. 4 years old) chickens (Gallus gallus) were used in order to evaluate the expression of GluR1, GluR2/3 and NR1 subunits. The cerebella of young and aged chickens were subjected to immunohistochemical and immunoblotting techniques. Numbers of GluR1, GluR2/3 and NR1-positive cells and optical density of the immunoblotting data were analyzed and submitted to statistical analysis using ANOVA and the Bonferroni post hoc test. Mean density of Purkinje cells stained for Giemsa, GluR1, GluR2/3 and NR1 in the cerebellum all showed a statistically significant decrease in aged animals when compared to the young animals (Giemsa, P<0.01; GluRs and NR1, P<0.03). However, the ratio of GluR1 and GluR2/3-positive Purkinje cells in relation the total number of Purkinje cells found in each time point decreased with aging (ca. 10%), whereas the ratio of NR1-positive cells increased (ca. 9%). The immunoblotting data showed a significant decrease of GluR1 (ca. 66%) and GluR2/3 (ca. 55%) protein expression with aging, but did not reveal changes for NR1. Our data suggest that aging can lead to differential changes in the pattern of expression of glutamate receptor subunits, which can underlie at least part of the cognitive and motor disorders found in aged animals.
Assuntos
Envelhecimento/metabolismo , Proteínas Aviárias/metabolismo , Cerebelo/metabolismo , Células de Purkinje/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Envelhecimento/patologia , Animais , Contagem de Células , Cerebelo/patologia , Galinhas , Immunoblotting , Imuno-Histoquímica , Células de Purkinje/patologia , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
The endocannabinoid system has been implicated in several neurobiological processes, including neurodegeneration and neuroprotection. The aim of this study was to evaluate the effects of unilateral retinal ablation on the expression of the cannabinoid receptor subtype 1 (CB(1)) at both protein and mRNA levels in the optic tectum of the adult chick brain. After different survival times postlesion (2-30 days), the chick brains were subjected to immunohistochemical, immunoblotting, and real-time PCR procedures to evaluate CB(1) expression. TUNEL and Fluoro-Jade B were used to verify the possible occurrence of cell death, and immunostaining for the microtubule-associated protein MAP-2 was performed to verify possible dendritic remodeling after lesions. No cell death could be observed in the deafferented tectum, at least up to 30 days postlesion, although Fluoro-Jade B could reveal degenerating axons and terminals. Retinal ablation seems to generate an increase of CB(1) protein in the optic tectum and other retinorecipient visual areas, which paralleled an increase in MAP-2 staining. On the other hand, CB(1) mRNA levels were not changed after retinal ablation. Our results reveal that CB(1) expression in visual structures of the adult chick brain may be negatively regulated by the retinal innervation. The increase of CB(1) receptor expression observed after retinal removal indicates that these receptors are not presynaptic in retinal axons projecting to the tectum and suggests a role of the cannabinoid system in plasticity processes ensuing after lesions.