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1.
Int Rev Neurobiol ; 171: 163-203, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37783555

RESUMO

Curcumin is a natural polyphenol, which has a variety of pharmacological activities, including, antineoplastic, antioxidative and neuroprotective effects. Recent studies provided evidence for the bioactive role of curcumin in the prevention and treatment of various central nervous system (CNS)-related diseases including Parkinson's, Alzheimer's, Schizophrenia disease and glioma neoplasia. Schizophrenia is a disabling psychiatric disorder related with an aberrant functional coupling between hippocampus and prefrontal cortex that might be crucial for cognitive dysfunction. Animal studies have lent support to the hypothesis that curcumin could improve cognitive functioning and enhance cell proliferation of dentate gyrus. In relation to brain tumors, specifically gliomas, the antineoplastic action of curcumin is based on the inhibition of cell growth promoting apoptosis or autophagy and preventing angiogenesis. However, one of the main impediments for the application of curcumin to patients is its low bioavailability. In intracranial lesions, curcumin has problems to cross the blood-brain barrier (BBB). Currently nano-based drug delivery systems are opening a new horizon to tackle this problem. The bioavailability and effective release of curcumin can be made possible in the form of nanocurcumin. This nanoformulation preserves the properties of curcumin and makes it reach tissues with pathology. This review try to study the beneficial effects of the curcumin nanodelivery in central nervous pathologies such us schizophrenia and glioma disease.


Assuntos
Antineoplásicos , Curcumina , Glioblastoma , Esquizofrenia , Animais , Humanos , Curcumina/farmacologia , Curcumina/uso terapêutico , Glioblastoma/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Antineoplásicos/farmacologia , Barreira Hematoencefálica
2.
Int Rev Neurobiol ; 172: 103-143, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37833010

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta and the subsequent motor disability. The most frequently used treatments in clinics, such as L-DOPA, restore dopaminergic neurotransmission in the brain. However, these treatments are only symptomatic, have temporary efficacy, and produce side effects. Part of the side effects are related to the route of administration as the consumption of oral tablets leads to unspecific pulsatile activation of dopaminergic receptors. For this reason, it is necessary to not only find alternative treatments, but also to develop new administration systems with better security profiles. Nanoparticle delivery systems are new administration forms designed to reach the pharmacological target in a highly specific way, leading to better drug bioavailability, efficacy and safety. Some of these delivery systems have shown promising results in animal models of PD not only when dopaminergic drugs are administered, but even more when neurotrophic factors are released. These latter compounds promote maturation and survival of dopaminergic neurons and can be exogenously administered in the form of pharmacological therapy or endogenously generated by non-pharmacological methods. In this sense, experimental exposure to enriched environments, a non-invasive strategy based on the combination of social and inanimate stimuli, enhances the production of neurotrophic factors and produces a neuroprotective effect in parkinsonian animals. In this review, we will discuss new nanodelivery systems in PD with a special focus on therapies that increase the release of neurotrophic factors.


Assuntos
Pessoas com Deficiência , Transtornos Motores , Doença de Parkinson , Animais , Humanos , Doença de Parkinson/tratamento farmacológico , Levodopa/uso terapêutico , Fatores de Crescimento Neural/uso terapêutico
3.
Exp Biol Med (Maywood) ; 248(7): 553-560, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37309729

RESUMO

The structure and functions of the central nervous system are influenced by environmental stimuli, which also play an important role in brain diseases. Enriched environment (EE) consists of producing modifications in the environment of standard laboratory animals to induce an improvement in their biological conditions. This paradigm promotes transcriptional and translational effects that result in ameliorated motor, sensory, and cognitive stimulation. EE has been shown to enhance experience-dependent cellular plasticity and cognitive performance in animals housed under these conditions compared with animals housed under standard conditions. In addition, several studies claim that EE induces nerve repair by restoring functional activities through morphological, cellular, and molecular adaptations in the brain that have clinical relevance in neurological and psychiatric disorders. In fact, the effects of EE have been studied in different animal models of psychiatric and neurological diseases, such as Alzheimer's disease, Parkinson's disease, schizophrenia, ischemic brain injury, or traumatic brain injury, delaying the onset and progression of a wide variety of symptoms of these disorders. In this review, we analyze the action of EE focused on diseases of the central nervous system and the translation to humans to develop a bridge to its application.


Assuntos
Encéfalo , Meio Ambiente , Animais , Humanos , Modelos Animais de Doenças
4.
Sci Data ; 8(1): 240, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526510

RESUMO

The development of new effective and safer therapies for osteoporosis, in addition to improved diagnostic and prevention strategies, represents a serious need in the scientific community. Micro-CT image-based analyses in association with biomechanical testing have become pivotal tools in identifying osteoporosis in animal models by assessment of bone microarchitecture and resistance, as well as bone strength. Here, we describe a dataset of micro-CT scans and reconstructions of 15 whole femurs and biomechanical tests on contralateral femurs from C57BL/6JOlaHsd ovariectomized (OVX), resembling human post-menopausal osteoporosis, and sham operated (sham) female mice. Data provided for each mouse include: the acquisition images (.tiff), the reconstructed images (.bmp) and an.xls file containing the maximum attenuations for each reconstructed image. Biomechanical data include an.xls file with the recorded load-displacement, a movie with the filmed test and an.xls file collecting all biomechanical results.


Assuntos
Fêmur/diagnóstico por imagem , Osteoporose , Microtomografia por Raio-X , Animais , Fenômenos Biomecânicos , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Osteoporose/diagnóstico por imagem , Osteoporose/fisiopatologia , Ovariectomia
5.
Br J Pharmacol ; 178(12): 2516-2532, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33686657

RESUMO

BACKGROUND AND PURPOSE: l-DOPA prolonged treatment leads to disabling motor complications as dyskinesia that could be decreased by drugs acting on 5-HT1A receptors. Since the internal segment of the globus pallidus, homologous to the entopeduncular nucleus in rodents, seems to be involved in the etiopathology of l-DOPA-induced dyskinesia, we investigated whether the entopeduncular nucleus is modulated by the 5-HT1A receptor partial and full agonists, buspirone, and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in control and 6-hydroxydopamine (6-OHDA)-lesioned rats with or without long-term l-DOPA treatment. EXPERIMENTAL APPROACH: Extracellular single-unit electrocorticogram and local field potential recordings under anaesthesia, immunostaining assays and optogenetic manipulation coupled to electrophysiological recordings were performed. KEY RESULTS: Systemic buspirone reduced the entopeduncular nucleus firing rate in the sham animals and burst activity in the 6-OHDA-lesioned rats (with or without l-DOPA treatment), while local administration reduced entopeduncular nucleus activity in all the groups, regardless of DA integrity. Systemic 8-OH-DPAT also induced inhibitory effects only in the sham animals. Effects triggered by buspirone and 8-OH-DPAT were reversed by the 5-HT1A receptor antagonist, WAY-100635. Neither buspirone nor 8-OH-DPAT modified the low-frequency oscillatory activity in the entopeduncular nucleus or its synchronization with the motor cortex. Buspirone did not alter the response induced by subthalamic nucleus opto-stimulation in the entopeduncular nucleus. CONCLUSION AND IMPLICATIONS: Systemic 5-HT1A receptor activation elicits different effects on the electrophysiological properties of the entopeduncular nucleus depending on the integrity of the nigrostriatal pathway and it does not alter the relationship between subthalamic nucleus and entopeduncular nucleus neuron activity.


Assuntos
Núcleo Entopeduncular , Receptor 5-HT1A de Serotonina , 8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Animais , Buspirona/farmacologia , Levodopa/farmacologia , Oxidopamina/toxicidade , Ratos , Ratos Sprague-Dawley
6.
Br J Pharmacol ; 177(17): 3957-3974, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32464686

RESUMO

BACKGROUND AND PURPOSE: l-DOPA-induced dyskinesia (LID) is considered a major complication in the treatment of Parkinson's disease (PD). Buspirone (5-HT1A partial agonist) have shown promising results in the treatment of PD and LID, however no 5-HT-based treatment has been approved in PD. The present study was aimed to investigate how the substantia nigra pars reticulata (SNr) is affected by buspirone and whether it is a good target to study 5-HT antidyskinetic treatments. EXPERIMENTAL APPROACH: Buspirone was studied using in vivo single-unit, electrocorticogram, local field potential recordings along with microdialysis and immunohistochemistry in naïve/sham, 6-hydroxydopamine (6-OHDA)-lesioned or 6-OHDA-lesioned and l-DOPA-treated (6-OHDA/l-DOPA) rats. KEY RESULTS: Local buspirone inhibited SNr neuron activity in all groups. However, systemic buspirone reduced burst activity in 6-OHDA-lesioned rats (with or without l-DOPA treatment), whereas 8-OH-DPAT, a full 5-HT1A agonist induced larger inhibitory effects in sham animals. Neither buspirone nor 8-OH-DPAT markedly modified the low-frequency oscillatory activity in the SNr or synchronization within the SNr with the cortex. In addition, local perfusion of buspirone increased GABA and glutamate release in the SNr of naïve and 6-OHDA-lesioned rats but no effect in 6-OHDA/l-DOPA rats. In the 6-OHDA/l-DOPA group, increased 5-HT transporter and decreased 5-HT1A receptor expression was found. CONCLUSIONS AND IMPLICATIONS: The effects of buspirone in SNr are influenced by dopamine loss and l-DOPA treatment. The present results suggest that the regulation of burst activity of the SNr induced by DA loss may be a good target to test new drugs for the treatment of PD and LID.


Assuntos
Levodopa , Parte Reticular da Substância Negra , Animais , Antiparkinsonianos/farmacologia , Buspirona/farmacologia , Dopamina , Oxidopamina , Ratos , Substância Negra
7.
Mol Neurobiol ; 57(1): 125-134, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31506899

RESUMO

Dysregulation of the inhibitory drive has been proposed to be a central mechanism to explain symptoms and pathophysiological hallmarks in schizophrenia. A number of recent neuroanatomical studies suggest that certain types of inhibitory cells are deficient in schizophrenia, including somatostatin-immunoreactive interneurons (SST+). The present study sought to use stereological methods to investigate whether the number of SST+ interneurons decreased after repeated injections of NMDA receptor antagonist MK-801 (0.5 mg/kg) and to determine the effect of limited exposure to an enriched environment (EE) in adult life on this sub-population of inhibitory cells. Considering that somatostatin expression is highly dependent on neurotrophic support, we explored the changes in the relative expression of proteins related to brain-derived neurotrophic factor-tyrosine kinase B (BDNF-TrkB) signaling between the experimental groups. We observed that early-life MK-801 treatment significantly decreased the number of SST+ interneurons in the medial prefrontal cortex (mPFC) and the hippocampus (HPC) of adult Long Evans rats. Contrarily, short-term exposure to EE increased the number of SST+ interneurons in MK-801-injected animals, except in the CA1 region of the hippocampus, whereas this increase was not observed in vehicle-injected rats. We also found upregulated BDNF-TrkB signaling after EE that triggered an increase in the pERK/ERK ratio in mPFC and HPC, and the pAkt/Akt ratio in HPC. Thus, the present results support the notion that SST+ interneurons are markedly affected after early-life NMDAR blockade and that EE promotes SST+ interneuron expression, which is partly mediated through the BDNF-TrkB signaling pathway. These results may have important implications for schizophrenia, as SST+ interneuron loss is also observed in the MK-801 pre-clinical model, and its expression can be rescued by non-pharmacological approaches.


Assuntos
Maleato de Dizocilpina/farmacologia , Hipocampo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Somatostatina/farmacologia , Animais , Hipocampo/metabolismo , Interneurônios/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos Long-Evans , Esquizofrenia/induzido quimicamente , Esquizofrenia/metabolismo , Transdução de Sinais/efeitos dos fármacos
8.
Int Rev Neurobiol ; 146: 229-257, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31349929

RESUMO

The basal ganglia (BG), an organized network of nuclei that integrates cortical information, play a crucial role in controlling motor function. In fact, movement disorders such as Parkinson's disease (PD) and Huntington's disease (HD) are caused by the degeneration of specific structures within the BG. There is substantial evidence supporting the idea that cannabinoids may constitute novel promising compounds for the treatment of movement disorders as neuroprotective and anti-inflammatory agents. This potential therapeutic role of cannabinoids is based, among other qualities, on their capacity to reduce oxidative injury and excitotoxicity, control calcium influx and limit the toxicity of reactive microglia. The mechanisms involved in these effects are related to CB1 and CB2 receptor activation, although some of the effects are CB receptor independent. Thus, taking into account the aforementioned properties, compounds that act on the endocannabinoid system could be useful as a basis for developing disease-modifying therapies for PD and HD.


Assuntos
Canabinoides/uso terapêutico , Endocanabinoides/fisiologia , Doença de Huntington/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Animais , Gânglios da Base/patologia , Gânglios da Base/fisiologia , Canabinoides/farmacologia , Endocanabinoides/uso terapêutico , Humanos , Doença de Huntington/patologia , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/patologia
9.
Eur Neuropsychopharmacol ; 29(5): 590-600, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30926324

RESUMO

Schizophrenia is a mental disorder characterized by psychosis, negative symptoms and cognitive impairment. Cognitive deficits are enduring and represent the most disabling symptom but are currently poorly treated. N-methyl D-aspartate receptor (NMDAR) hypofunction hypothesis has been notably successful in explaining the pathophysiological findings and symptomatology of schizophrenia. Thereby, NMDAR blockade in rodents represents a useful tool to identify new therapeutic approaches. In this regard, enriched environment (EE) could play an essential role. Using a multilevel approach of behavior, electrophysiology and protein analysis, we showed that a short-term exposure to EE in adulthood ameliorated spatial learning and object-place associative memory impairment observed in postnatally MK-801-treated Long Evans rats. Moreover, EE in adult life restored long-term potentiation (LTP) in hippocampal-medial prefrontal pathway abolished by MK-801 treatment. EE in adulthood also induced a set of modifications in the expression of proteins related to glutamatergic neurotransmission. Taken together, these findings shed new light on the neurobiological effects of EE to reverse the actions of MK-801 and offer a preclinical testing of a therapeutic strategy that may be remarkably effective for managing cognitive symptoms of schizophrenia.


Assuntos
Maleato de Dizocilpina/toxicidade , Hipocampo/metabolismo , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/biossíntese , Esquizofrenia/metabolismo , Fatores Etários , Animais , Cognição/efeitos dos fármacos , Cognição/fisiologia , Meio Ambiente , Antagonistas de Aminoácidos Excitatórios/toxicidade , Expressão Gênica , Hipocampo/efeitos dos fármacos , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/induzido quimicamente , Esquizofrenia/terapia
10.
Mol Neurobiol ; 55(1): 42, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28963705

RESUMO

The original version of this article unfortunately contained a mistake. The name of author was changed from "Pascual Gargiulo" to "Pascual Ángel Gargiulo.

11.
Mol Neurobiol ; 55(1): 43-59, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28842826

RESUMO

Exposure to an enriched environment (EE) has neuroprotective benefits and improves recovery from brain injury due to, among other, increased neurotrophic factor expression. Through these neurotrophins, important cortical and hippocampal changes occur. Vandetanib acts as a tyrosine kinase inhibitor of cell receptors, among others, the vascular endothelial growth factor receptor (VEGFR). Our aim was to investigate the effectiveness of EE counteracting cognitive and cellular effects after tyrosine kinase receptor blockade. Animals were reared under standard laboratory condition or EE; both groups received vandetanib or vehicle. Visuospatial learning was tested with Morris water maze. Neuronal, interneuronal, and vascular densities were measured by inmunohistochemistry and histochemistry techniques. Quantifications were performed in the hippocampus and in the visual cortex. Brain-derived neurotrophic factor (BDNF), tyrosine kinase B receptor (TrkB), Akt, and Erk were measured by Western blot technique. Vandetanib produces a significant decrease in vascular and neuronal densities and reduction in the expression of molecules involved in survival and proliferation processes such as phospho-Akt/Akt and phospho-Erk/Erk. These results correlated to a cognitive impairment in visuospatial test. On the other hand, animals reared in an EE are able to reverse the negative effects, activating PI3K-AKT and MAP kinase pathways mediated by BDNF-TrkB binding. Present results provide novel and consistent evidences about the usefulness of living in EE as a strategy to improve deleterious effects of blocking neurotrophic pathways by vandetanib and the notable role of the BDNF-TrkB pathway to balance the neurovascular unit and cognitive effects.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Meio Ambiente , Inibidores de Proteínas Quinases/toxicidade , Receptor trkB/antagonistas & inibidores , Receptor trkB/metabolismo , Transdução de Sinais/fisiologia , Animais , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Ratos , Ratos Long-Evans , Transdução de Sinais/efeitos dos fármacos
12.
Mol Neurobiol ; 55(1): 26-41, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28822057

RESUMO

Perinatal injections of N-methyl-D-aspartate (NMDA) receptor antagonist in rodents emulate some cognitive impairments and neurochemical alterations, such as decreased GABAergic (gamma aminobutyric acid) interneuron immunoreactivity, also found in schizophrenia. These features are pervasive, and developing neuroprotective or neurorestorative strategies is of special interest. In this work, we aimed to investigate if a short exposure to enriched environment (EE) in early adulthood (P55-P73) was an effective strategy to improve cognitive dysfunction and to restore interneuron expression in medial prefrontal cortex (mPFC) and hippocampus (HPC). For that purpose, we administered MK-801 intraperitoneally to Long Evans rats from postnatal days 10 to 20. Twenty-four hours after the last injection, MK-801 produced a transient decrease in spontaneous motor activity and exploration, but those abnormalities were absent at P24 and P55. The open field test on P73 manifested that EE reduced anxiety-like behavior. In addition, MK-801-treated rats showed cognitive impairment in novel object recognition test that was reversed by EE. We quantified different interneuron populations based on their calcium-binding protein expression (parvalbumin, calretinin, and calbindin), glutamic acid decarboxylase 67, and neuronal nuclei-positive cells by means of unbiased stereology and found that EE enhanced interneuron immunoreactivity up to normal values in MK-801-treated rats. Our results demonstrate that a timely intervention with EE is a powerful tool to reverse long-lasting changes in cognition and neurochemical markers of interneurons in an animal model of schizophrenia.


Assuntos
Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Maleato de Dizocilpina/toxicidade , Meio Ambiente , Neurônios GABAérgicos/metabolismo , Interneurônios/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Antagonistas de Aminoácidos Excitatórios/toxicidade , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/patologia , Interneurônios/efeitos dos fármacos , Interneurônios/patologia , Masculino , Ratos , Ratos Long-Evans , Fatores de Tempo
13.
Front Cell Neurosci ; 12: 532, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30687018

RESUMO

Exposure to hypobaric hypoxia at high altitude (above 2500 m asl) causes cognitive impairment, mostly attributed to changes in brain perfusion and consequently neuronal death. Enriched environment and voluntary exercise has been shown to improve cognitive function, to enhance brain microvasculature and neurogenesis, and to be neuroprotective. Here we show that high-altitude exposure (3540 m asl) of Long Evans rats during early adulthood (P48-P59) increases brain microvasculature and neurogenesis but impairs spatial and visual memory along with an increase in neuronal apoptosis. We tested whether enriched environment including a running wheel for voluntary exercise (EE) can prevent cognitive impairment at high-altitude and whether apoptosis is prevented. We found that EE retained spatial and visual memory at high altitude, and prevented neuronal apoptosis. Further, we tested whether vascular endothelial growth factor (VEGF) signaling is required for the EE-mediated recovery of spatial and visual memory and the reduction in apoptosis. Pharmacological inhibition of VEGF signaling by oral application of a tyrosine kinase inhibitor (Vandetanib) prevented the recovery of spatial and visual memory in animals housed in EE, along with an increase in apoptosis and a reduction in neurogenesis. Surprisingly, inhibition of VEGF signaling also caused impairment in spatial memory in EE-housed animals reared at low altitude, affecting mainly dentate gyrus microvasculature but not neurogenesis. We conclude that EE-mediated VEGF signaling is neuroprotective and essential for the maintenance of cognition and neurogenesis during high-altitude exposure, and for the maintenance of spatial memory at low altitude. Finally, our data also underlines the potential risk of cognitive impairment and disturbed high altitude adaption from the use of VEGF-signaling inhibitors for therapeutic purposes.

14.
Int Rev Neurobiol ; 137: 99-122, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29132545

RESUMO

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder, but current therapies are only symptomatic. Experimental models are necessary to go deeper in the comprehension of pathophysiological mechanism and to assess new therapeutic strategies. The unilateral 6-hydroxydopamine (6-OHDA) lesion either in medial forebrain bundle (MFB) or into the striatum in rats affords to study various stages of PD depending on the evolution time lapsed. A promising alternative to address the neurodegenerative process is the use of neurotrophic factors; but its clinical use has been limited due to its short half-life and rapid degradation after in vivo administration, along with difficulties for crossing the blood-brain barrier (BBB). Tyrosine hydroxylase (TH) immunostaining revealed a significant decrease of the TH-immunopositive striatal volume in 6-OHDA group from rostral to caudal one. The loss of TH-ir neurons and axodendritic network (ADN) was higher in caudal sections showing a selective vulnerability of the topological distributed dopaminergic system. In addition to a remarkable depletion of dopamine in the nigrostriatal system, the administration of 6-OHDA into MFB induces some other neuropathological changes such as an increase of glial fibrillary acidic protein (GFAP) positive cells in substantia nigra (SN) as well as in striatum. Intrastriatal implantation of micro- or nanosystems delivering neurotrophic factor in parkinsonized rats for bypassing BBB leads to a significative functional and morphological recovery. Neurorestorative morphological changes (preservation of the TH-ir cells and ADN) along the rostrocaudal axis of caudoputamen complex and SN have been probed supporting a selective recovering after the treatment as well. Others innovative therapeutic strategies, such as the intranasal delivery, have been recently assessed in order to search the NTF effects. In addition some others methodological key points are reviewed.


Assuntos
Nanopartículas/administração & dosagem , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Doença de Parkinson/tratamento farmacológico , Animais , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , Humanos , Fármacos Neuroprotetores/uso terapêutico
15.
Int J Nanomedicine ; 9: 2677-87, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24920904

RESUMO

Current research efforts are focused on the application of growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), as neuroregenerative approaches that will prevent the neurodegenerative process in Parkinson's disease. Continuing a previous work published by our research group, and with the aim to overcome different limitations related to growth factor administration, VEGF and GDNF were encapsulated in poly(lactic-co-glycolic acid) nanospheres (NS). This strategy facilitates the combined administration of the VEGF and GDNF into the brain of 6-hydroxydopamine (6-OHDA) partially lesioned rats, resulting in a continuous and simultaneous drug release. The NS particle size was about 200 nm and the simultaneous addition of VEGF NS and GDNF NS resulted in significant protection of the PC-12 cell line against 6-OHDA in vitro. Once the poly(lactic-co-glycolic acid) NS were implanted into the striatum of 6-OHDA partially lesioned rats, the amphetamine rotation behavior test was carried out over 10 weeks, in order to check for in vivo efficacy. The results showed that VEGF NS and GDNF NS significantly decreased the number of amphetamine-induced rotations at the end of the study. In addition, tyrosine hydroxylase immunohistochemical analysis in the striatum and the external substantia nigra confirmed a significant enhancement of neurons in the VEGF NS and GDNF NS treatment group. The synergistic effect of VEGF NS and GDNF NS allows for a reduction of the dose by half, and may be a valuable neurogenerative/neuroreparative approach for treating Parkinson's disease.


Assuntos
Fator Neurotrófico Derivado de Linhagem de Célula Glial/administração & dosagem , Nanocápsulas/química , Nanosferas/química , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/prevenção & controle , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Animais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/química , Difusão , Combinação de Medicamentos , Sinergismo Farmacológico , Fator Neurotrófico Derivado de Linhagem de Célula Glial/química , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Masculino , Camundongos , Nanocápsulas/administração & dosagem , Nanosferas/ultraestrutura , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/química , Doença de Parkinson/diagnóstico , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/química , Fator A de Crescimento do Endotélio Vascular/genética
16.
Front Cell Neurosci ; 7: 170, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24109431

RESUMO

Elimination of sensory inputs (deprivation) modifies the properties of the sensory cortex and serves as a model for studying plasticity during postnatal development. Many studies on the effects of deprivation have been performed in the visual cortex using dark-rearing as a visual deprivation model. It induces changes in all cellular and molecular components, including astrocytes, which play an important role in the development, maintenance, and plasticity of the cortex, mediated by cytokines which have been termed angioglioneurins. When one sense is deprived, a compensatory mechanism called cross-modal plasticity increases performance in the remaining senses. Environmental enrichment is so far the best-known method to compensate sensorial deprivation. The aim of this work is to study the effects of exercise alone, and of an enriched environment combined with exercise, on astroglial population in order to observe the effects of exercise by itself, or the potential synergistic effect during the rat visual system development. Pregnant Sprague-Dawley rats were raised in one of the following rearing conditions: in total darkness and enriched environment conditions with physical exercise, and in total darkness with voluntary physical exercise. Astrocytic density was estimated by immunohistochemistry for S-100ß protein and quantifications were performed in layer IV. The somatosensorial cortex barrel field was also studied as control. Our main result shows that an enriched environment combined with voluntary physical exercise manages to reverse the negative effects induced by darkness over the astroglial population of both the visual and the somatosensory cortices. On the other hand, exercise alone only produces effects upon the astroglial population of the somatosensory cortex, and less so when combined with an enriched environment.

17.
J Signal Transduct ; 2012: 597915, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22852079

RESUMO

The angiogenesis process is a key event for glioma survival, malignancy and growth. The start of angiogenesis is mediated by a cascade of intratumoural events: alteration of the microvasculature network; a hypoxic microenvironment; adaptation of neoplastic cells and synthesis of pro-angiogenic factors. Due to a chaotic blood flow, a consequence of an aberrant microvasculature, tissue hypoxia phenomena are induced. Hypoxia inducible factor 1 is a major regulator in glioma invasiveness and angiogenesis. Clones of neoplastic cells with stem cell characteristics are selected by HIF-1. These cells, called "glioma stem cells" induce the synthesis of vascular endothelial growth factor. This factor is a pivotal mediator of angiogenesis. To elucidate the role of these angiogenic mediators during glioma growth, we have used a rat endogenous glioma model. Gliomas induced by prenatal ENU administration allowed us to study angiogenic events from early to advanced tumour stages. Events such as microvascular aberrations, hypoxia, GSC selection and VEGF synthesis may be studied in depth. Our data showed that for the treatment of gliomas, developing anti-angiogenic therapies could be aimed at GSCs, HIF-1 or VEGF. The ENU-glioma model can be considered to be a useful option to check novel designs of these treatment strategies.

18.
Neural Plast ; 2012: 305693, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22848849

RESUMO

During postnatal development, sensory experience modulates cortical development, inducing numerous changes in all of the components of the cortex. Most of the cortical changes thus induced occur during the critical period, when the functional and structural properties of cortical neurons are particularly susceptible to alterations. Although the time course for experience-mediated sensory development is specific for each system, postnatal development acts as a whole, and if one cortical area is deprived of its normal sensory inputs during early stages, it will be reorganized by the nondeprived senses in a process of cross-modal plasticity that not only increases performance in the remaining senses when one is deprived, but also rewires the brain allowing the deprived cortex to process inputs from other senses and cortices, maintaining the modular configuration. This paper summarizes our current understanding of sensory systems development, focused specially in the visual system. It delineates sensory enhancement and sensory deprivation effects at both physiological and anatomical levels and describes the use of enriched environment as a tool to rewire loss of brain areas to enhance other active senses. Finally, strategies to apply restorative features in human-deprived senses are studied, discussing the beneficial and detrimental effects of cross-modal plasticity in prostheses and sensory substitution devices implantation.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Vias Neurais/fisiologia , Sensação/fisiologia , Privação Sensorial/fisiologia , Animais , Encéfalo/anatomia & histologia , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/fisiologia , Meio Ambiente , Humanos , Plasticidade Neuronal/fisiologia , Ratos , Vias Visuais/anatomia & histologia , Vias Visuais/crescimento & desenvolvimento
19.
Int Rev Neurobiol ; 102: 317-46, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22748835

RESUMO

Angioneurines are a family of molecules that include vascular growth factors such as VEGF, neurotrophins such as BDNF, IGF-I, and Erythropoietin, among others. They affect both neural and vascular processes. Due to the fact that all of them act over glia, we propose the term angioglioneurins to name them. They play a key role in the neurogliovascular unit that represents the functional core maintaining BBB. Although delivery to CNS is still an unsolved problem nowadays, exogenous angioglioneurin administration represents a promising therapeutic strategy for many neurological pathologies due to their neurotrophic and neurogenic role. In brains, VEGF is produced by neurons and astrocytes in different stages and situation, binding to tyrosine kinase receptors and also to neuropilin family. This fact reinforces its key role in the cross talk between neural and vascular development and activity. Angioglioneurins described in this report might become an important therapeutic resource in CNS restoration, especially in pathologies as stroke or traumatic brain injury.


Assuntos
Encefalopatias/tratamento farmacológico , Encéfalo/crescimento & desenvolvimento , Fatores de Crescimento Neural/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Animais , Astrócitos/metabolismo , Barreira Hematoencefálica/fisiologia , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encefalopatias/fisiopatologia , Modelos Animais de Doenças , Humanos , Fatores de Crescimento Neural/farmacologia , Fatores de Crescimento Neural/uso terapêutico , Neuroglia/fisiologia , Neurônios/fisiologia , Fármacos Neuroprotetores/farmacologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Fator A de Crescimento do Endotélio Vascular/uso terapêutico
20.
Brain Res ; 1473: 141-54, 2012 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-22824331

RESUMO

VEGF is the major angiogenic and vascular permeability factor in health and disease. Vascular development depends on function, and in sensory areas is experience-dependent. Our aim was to investigate, qualitatively and quantitatively, the effects of intracortical infusion and neutralisation of VEGF during the first days of the critical visual period, when peak levels of endogenous VEGF secretion are reached. VEGF was intracortically delivered into middle cortical layers of P18 Long-Evans rats. Another cohort received anti-VEGF. Vehicle (PBS)-infused and non-operated animals were used as controls. Various immunopathological analyses were performed: Endothelial Barrier Antigen (EBA) for the BBB integrity and GFAP for astroglial response. Vascular density was measured by Butyryl Cholinesterase Histochemistry, neuronal density by NeuN immunohistochemistry and apoptosis by TUNEL staining. VEGF levels were measured by Western Blot. Decreased vascular permeability was evoked in VEGF-infused rats whilst EBA expression remained constant, suggesting a preserved BBB function. When VEGF was blocked, tissue showed a higher degree of extravasation and a decreased number of EBA-positive vessels surrounding the injury. Lesion induced by cannula implantation annulled the normal increase in vascular density and the decrease in neuronal density during this time. VEGF rescued in part the vascular increase, and also prevented physiological and pathological neuronal death. VEGF blockade induced a higher amount of neural loss and lower astrocytic reaction. Our results support the role of VEGF as extending beyond vascularization, preventing physiological and pathological neuronal death, not only in the injured hemisphere but also in the intact one suggesting a process of transhemispheric diaschisis.


Assuntos
Período Crítico Psicológico , Neovascularização Fisiológica/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Córtex Visual , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Western Blotting , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Injeções Intraventriculares , Microscopia Confocal , Neovascularização Fisiológica/fisiologia , Ratos , Ratos Long-Evans , Córtex Visual/efeitos dos fármacos , Córtex Visual/crescimento & desenvolvimento , Córtex Visual/metabolismo , Córtex Visual/patologia
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