RESUMO
Attention deficit hyperactivity disorder (ADHAD) is a neurobehavioral disorder that affects children and adolescents with a high prevalence. Despite its prevalence and an unclear etiology, previous reports suggest that it is closely related to homocysteine metabolism. Male Sprague Dawley rats were administered with homocysteine from postnatal day (PD) 2 to PD 16. Locomotor activity was evaluated at 35 PD (prepuberal age) and 60 PD (adult age) before and after amphetamine administration. In rats evaluated at both ages, homocysteine induced hyperactivity, and the amphetamine administration reduced hyperactivity significantly at 35 PD, but not at 60 PD. In the social interaction test, homocysteine reduced the number of contacts and increased the latency to the first contact only in rats at 35 PD. Homocysteine also had an effect on short term memory at 35D and 60 PD and long-term memory at 60 PD. Morphological changes were found mainly in the shape of dendritic spines in the prefrontal cortex (PFC-3), dorsal hippocampus (CA1), dentate gyrus (DG) and nucleus accumbens (NAcc), in rats administered neonatally with homocysteine at both ages studied. In prepuberal and adult rats, there was an increase in dendritic length in DG and NAcc, respectively. The dendritic spine morphology also was altered at both ages, mainly decreasing the number of mushroom spines in NAcc and CA1 at 30 PD and in all the areas studied at 60 PD rats. Those areas are associated with the processes of attention, learning and memory that were studied, and those alterations are possibly related to changes observed in the behavioral tests. These behavioral and morphological changes in rats at 35 PD administered with homocysteine could be similar to changes found in children diagnosed with ADHD. Moreover, half to two thirds of children diagnosed with ADHD reach adulthood with this disorder. In this study we found similarities with ADHD, finding alterations in both rats at 35 PD and 60 PD. So, this may be proposed as an animal model to study this disorder present in children, adolescents and adults.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Animais , Espinhas Dendríticas , Modelos Animais de Doenças , Homocisteína/farmacologia , Masculino , Neurônios , Córtex Pré-Frontal , Ratos , Ratos Sprague-DawleyRESUMO
Neurodegenerative diseases called tauopathies, such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, and Parkinson's disease, among others, are characterized by the pathological processing and accumulation of tau protein. AD is the most prevalent neurodegenerative disease and is characterized by two lesions: neurofibrillary tangles (NFTs) and neuritic plaques. The presence of NFTs in the hippocampus and neocortex in early and advanced stages, respectively, correlates with the patient's cognitive deterioration. So far, no drugs can prevent, decrease, or limit neuronal death due to abnormal pathological tau accumulation. Among potential non-pharmacological treatments, physical exercise has been shown to stimulate the development of stem cells (SCs) and may be useful in early stages. However, this does not prevent neuronal death from the massive accumulation of NFTs. In recent years, SCs therapies have emerged as a promising tool to repopulate areas involved in cognition in neurodegenerative diseases. Unfortunately, protocols for SCs therapy are still being developed and the mechanism of action of such therapy remains unclear. In this review, we show the advances and limitations of SCs therapy. Finally, we provide a critical analysis of its clinical use for AD.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Células-Tronco/metabolismo , Proteínas tau/metabolismo , Doença de Alzheimer/patologia , Amiloide/metabolismo , Regulamentação Governamental , Hipocampo/patologia , Humanos , Neocórtex/patologiaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid ß-peptide (Aß) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aß vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aß deposits on the NVU and the blood-brain barrier (BBB) are unknown. In this study, we analyze different Aß species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aß and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aß species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aß in AD.
Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Astrócitos/patologia , Vasos Sanguíneos/patologia , Encéfalo/patologia , Microglia/patologia , Actinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Vasos Sanguíneos/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Estudos de Casos e Controles , Caspases/metabolismo , Humanos , Junções Íntimas/patologiaRESUMO
Chronic consumption of ß-sitosterol-ß-D-glucoside (BSSG), a neurotoxin contained in cycad seeds, leads to Parkinson's disease in humans and rodents. Here, we explored whether a single intranigral administration of BSSG triggers neuroinflammation and neurotoxic A1 reactive astrocytes besides dopaminergic neurodegeneration. We injected 6 µg BSSG/1 µL DMSO or vehicle into the left substantia nigra and immunostained with antibodies against tyrosine hydroxylase (TH) together with markers of microglia (OX42), astrocytes (GFAP, S100ß, C3), and leukocytes (CD45). We also measured nitric oxide (NO), lipid peroxidation (LPX), and proinflammatory cytokines (TNF-α, IL-1ß, IL-6). The Evans blue assay was used to explore the blood-brain barrier (BBB) permeability. We found that BSSG activates NO production on days 15 and 30 and LPX on day 120. Throughout the study, high levels of TNF-α were present in BSSG-treated animals, whereas IL-1ß was induced until day 60 and IL-6 until day 30. Immunoreactivity of activated microglia (899.0 ± 80.20%) and reactive astrocytes (651.50 ± 11.28%) progressively increased until day 30 and then decreased to remain 251.2 ± 48.8% (microglia) and 91.02 ± 39.8 (astrocytes) higher over controls on day 120. C3(+) cells were also GFAP and S100ß immunoreactive, showing they were neurotoxic A1 reactive astrocytes. BBB remained permeable until day 15 when immune cell infiltration was maximum. TH immunoreactivity progressively declined, reaching 83.6 ± 1.8% reduction on day 120. Our data show that BSSG acute administration causes chronic neuroinflammation mediated by activated microglia, neurotoxic A1 reactive astrocytes, and infiltrated immune cells. The severe neuroinflammation might trigger Parkinson's disease in BSSG intoxication.
Assuntos
Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Inflamação/etiologia , Neurotoxinas/imunologia , Sitosteroides/administração & dosagem , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Animais , Astrócitos/metabolismo , Biomarcadores , Doença Crônica , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Microglia/imunologia , Microglia/metabolismo , Neurotoxinas/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Ratos , Substância Negra/patologiaRESUMO
The spreading and accumulation of α-synuclein and dopaminergic neurodegeneration, two hallmarks of Parkinson's disease (PD), have been faithfully reproduced in rodent brains by chronic, oral administration of ß-sitosterol ß-D-glucoside (BSSG). We investigated whether a single injection of BSSG (6 µg BSSG/µL DMSO) in the left substantia nigra of Wistar rats causes the same effects. Mock DMSO injections and untreated rats formed control groups. We performed immunostainings against the pathological α-synuclein, the dopaminergic marker tyrosine hydroxylase (TH), the neuroskeleton marker ß-III tubulin, the neurotensin receptor type 1 (NTSR1) as non-dopaminergic phenotype marker and Fluro-Jade C (F-J C) label for neurodegeneration. Using ß-galactosidase (ß-Gal) assay and active caspase-3 immunostaining, we assessed cell death mechanisms. Golgi-Cox staining was used to measure the density and types of dendritic spines of striatal medium spiny neurons. Motor and non-motor alterations were also evaluated. The study period comprised 15 to 120 days after the lesion. In the injured substantia nigra, BSSG caused a progressive α-synuclein aggregation and dopaminergic neurodegeneration caused by senescence and apoptosis. The α-synuclein immunoreactivity was also present within microglia cells. Decreased density of dopaminergic fibers and dendritic spines also occurred in the striatum. Remarkably, all the histopathological changes also appeared on the contralateral nigrostriatal system, and α-synuclein aggregates were present in other brain regions. Motor and non-motor behavioral alterations were progressive. Our data show that the stereotaxic BSSG administration reproduces PD α-synucleinopathy phenotype in the rat. This approach will aid in identifying the spread mechanism of α-synuclein pathology and validate anti-synucleinopathy therapies.