RESUMO
Postnatal development of the visual cortex is modulated by experience, especially during the critical period. In rats, a stable neuronal population is only acquired after this relatively prolonged period. Vascular endothelial growth factor (VEGF) is the most important angiogenic factor and also has strong neuroprotective, neurotrophic and neurogenic properties. Similar effects have been described for rearing in enriched environments. Our aim is to investigate the vascular and neuronal effects of combining VEGF infusion and environmental enrichment on the visual cortex during the initial days of the critical period. Results showed that a small percentage of Cleaved Caspase-3 positive cells colocalized with neuronal markers. The lesion produced by the cannula implantation resulted in decreased vascular, neuronal and Caspase-3 positive cell densities. Rearing under enriched environment was unable to reverse these effects in any group, whereas VEGF infusion alone partially corrected those effects. A higher effectiveness was reached by combining both the procedures, the most effective combination being when enriched-environment rearing was introduced only after minipump implantation. In addition to the angiogenic effect of VEGF, applied strategies also had synergic neuroprotective effects, and the combination of the two strategies had more remarkable effects than those achieved by each strategy applied individually.
Assuntos
Encéfalo/fisiologia , Meio Ambiente , Fármacos Neuroprotetores , Fator A de Crescimento do Endotélio Vascular/farmacologia , Córtex Visual/crescimento & desenvolvimento , Animais , Encéfalo/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Capilares/metabolismo , Caspase 3/metabolismo , Contagem de Células , Implantes de Medicamento , Técnica Indireta de Fluorescência para Anticorpo , Imuno-Histoquímica , Proteínas do Tecido Nervoso/metabolismo , Ratos , Ratos Long-Evans , Fixação de Tecidos , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Córtex Visual/fisiologiaRESUMO
After birth, exposure to visual inputs modulates cortical development, inducing numerous changes in all of the components of the visual cortex. Most of the cortical changes thus induced occur during what is called the critical period. Astrocytes play an important role in the development, maintenance and plasticity of the cortex as well as in the structure and function of the vascular network. Visual deprivation induces a decrease in the astroglial population, whereas enhanced experience increases it. Exposure to an enriched environment has been shown to prevent the effects of dark-rearing in the visual cortex. Our purpose was to study the effects of an enriched environment on the density of astrocytes per reference surface at the visual cortex of dark-reared rats, in order to determine if enhanced experience is able to compensate the quantitative effects of visual deprivation and the role of physical exercise on the enrichment paradigm. Pregnant Sprague-Dawley rats were raised in one of the following rearing conditions: control rats with standard housing (12-h light/dark cycle); in total darkness for the dark-rearing experiments; and dark-rearing in conditions of enriched environment without and with physical exercise. The astrocytic density was estimated by immunohistochemistry for S-100beta protein. Quantifications were performed in layer IV. The somatosensorial cortex barrel field was also studied as control. The volume of layer IV was stereologically calculated for each region, age and experimental condition. From the beginning of the critical period, astrocyte density was higher in control rats than in the enriched environment group without physical exercise, with densities of astrocytes around 20% higher at all of the different ages. In contrast, when the animals had access to voluntary exercise, densities were significantly higher than even the control rats. Our main result shows that strategies to apply environmental enrichment should always consider the incorporation of physical exercise, even for sensorial areas such as the visual area, where complex enriched experience by itself is not enough to compensate the effects of visual deprivation.
Assuntos
Astrócitos/citologia , Fatores de Crescimento Neural/análise , Esforço Físico/fisiologia , Proteínas S100/análise , Privação Sensorial/fisiologia , Córtex Visual/crescimento & desenvolvimento , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Astrócitos/química , Contagem de Células , Escuridão , Meio Ambiente , Plasticidade Neuronal/fisiologia , Ratos , Ratos Sprague-Dawley , Subunidade beta da Proteína Ligante de Cálcio S100 , Córtex Somatossensorial/citologia , Córtex Somatossensorial/crescimento & desenvolvimento , Córtex Visual/citologia , Córtex Visual/fisiologiaRESUMO
The development of the cortical vascular network depends on functional maturation. External inputs are an essential requirement in the modeling of the visual cortex, mainly during the critical period, when the functional and structural properties of visual cortical neurons are particularly susceptible to alterations. Vascular endothelial growth factor (VEGF) is the major angiogenic factor, a key signal in the induction of vessel growth. Our study focused on the role of visual stimuli on the development of the vascular pattern correlated with VEGF levels. Vascular density and the expression of VEGF were examined in the primary visual cortex of rats reared under different visual environments (dark rearing, dark-rearing in conditions of enriched environment, enriched environment, and laboratory standard conditions) during postnatal development (before, during, and after the critical period). Our results show a restricted VEGF cellular expression to astroglial cells. Quantitative differences appeared during the critical period: higher vascular density and VEGF protein levels were found in the enriched environment group; both dark-reared groups showed lower vascular density and VEGF levels, which means that enriched environment without the physical exercise component does not exert effects in dark-reared rats.
Assuntos
Memória/fisiologia , Neovascularização Fisiológica/fisiologia , Plasticidade Neuronal/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Córtex Visual/irrigação sanguínea , Córtex Visual/fisiologia , Animais , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Silicon (SiO2) nanoparticles or silica dust is quite common form of exposure to soldiers engaged in gulf war that may influence their health and brain function. It is quite likely that traumatic injuries to the CNS may be influenced by exposure to these nanoparticles. However, the details of silicon nanoparticles on human health functions are still unknown. In this investigation we examined the effects of chronic silicon dioxide nanoparticles (SiO2, 40-50 nm) exposure on spinal cord injury (SCI) induced alterations on the functional outcome and the cord pathology in a rat model. Since nanoparticles induce oxidative stress, the influence of an antioxidant compound H-290/51 was also examined in these nanoparticles treated injured rats as well. Rats treated with SiO2 for 7 days did not show any significant alteration in behaviour on rota rod performances or on capacity angle tests. However, subjection of these nanoparticles exposed rats to SCI resulted in a profound deterioration in motor functions compared to normal rats with SCI. The magnitude of blood-spinal cord barrier (BSCB) disruption to Evans blue and radioiodine tracers and edema formation was much more aggravated following SCI in nanoparticles treated animals compared to untreated traumatized rats. Pretreatment with H-290/51 (50 mg/kg, p.o.) 30 min before SCI in nanoparticle treated rats did not alter spinal cord pathology or functional outcome, however, this dose of the compound was very effective in reducing pathophysiology of SCI in normal animals. These observations are the first to suggest that exposure of nanoparticles enhances the sensitivity of CNS to injuries and alter the effect of neuroprotective drugs.
Assuntos
Nanopartículas , Dióxido de Silício/química , Traumatismos da Medula Espinal/fisiopatologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod , Medula Espinal/irrigação sanguínea , Medula Espinal/patologia , Traumatismos da Medula Espinal/patologiaRESUMO
Parkinson's disease (PD) is characterized by the degeneration of dopaminergic neurons in the substantia nigra, the depletion of striatal dopamine and the presence of Lewy aggregates containing alpha-synuclein. Clinically, there are motor impairments involving cardinal movement symptoms, bradykinesia, resting tremor, muscle rigidity, and postural abnormalities, along with non-motor symptoms such as sleep, behavior and mood disorders. The current treatment for PD focuses on restoring dopaminergic neurotransmission by l-3,4-dihydroxyphenylalanine (levodopa), which loses therapeutic efficacy and induces disabling abnormal involuntary movements known as levodopa-induced dyskinesia (LID) after several years. Evidence indicates that the pathophysiology of both PD and LID disorders is also associated with the dysfunctional activity of the serotonergic (5-HT) neurons that may be responsible for motor and non-motor disturbances. The main population of 5-HT neurons is located in the dorsal raphe nuclei (DRN), which provides extensive innervation to almost the entire neuroaxis and controls multiple functions in the brain. The degeneration of DRN 5-HT neurons occurs in early PD. These neurons can also take exogenous levodopa to transform it into dopamine, which may disturb neuron activity. This review will provide an overview of the underlying mechanisms responsible for 5-HT dysfunction and its clinical relevance in PD and dyskinesia.
Assuntos
Encéfalo/fisiologia , Encéfalo/fisiopatologia , Discinesia Induzida por Medicamentos/fisiopatologia , Doença de Parkinson/fisiopatologia , Neurônios Serotoninérgicos/fisiologia , Animais , Humanos , Levodopa/efeitos adversos , Modelos NeurológicosRESUMO
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 fármacosRESUMO
Previous studies from our laboratory show that intraperitoneal injections of 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridin (MPTP, 20 mg/kg) daily within 2-h intervals for 5 days in mice induce Parkinson's disease (PD)-like symptoms on the 8th day. A significant decrease in dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) along with a marked decrease in the number of tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta (SNpc) and striatum (STr) confirms the validity of this model for studying PD. Since cerebrolysin (CBL) is a well-balanced composition of several neurotrophic factors and active peptide fragments, in the present investigation we examined the timed release of CBL using titanate nanospheres (TiNS) in treating PD in our mouse model. Our observations show that TiNS-CBL (in a dose of 3 ml/kg, i.v.) given after 2 days of MPTP administration for 5 days resulted in a marked increase in TH-positive cells in the SNpc and STr as compared to normal CBL. Also, TiNS-CBL resulted in significantly higher levels of DA, DOPAC, and HVA in SNpc and STr on the 8th day as compared to normal CBL therapy. TiNS-CBL also thwarted increased α-synuclein levels in the brain and in the cerebrospinal fluid (CSF) as well as neuronal nitric oxide synthase (nNOS) in the in PD brain as compared to untreated group. Behavioral function was also significantly improved in MPTP-treated animals that received TiNS-CBL. These observations are the first to demonstrate that timed release of TiNS-CBL has far more superior neuroprotective effects in PD than normal CBL.
Assuntos
Aminoácidos/administração & dosagem , Encéfalo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Nanosferas/administração & dosagem , Transtornos Parkinsonianos/tratamento farmacológico , Titânio/administração & dosagem , Aminoácidos/farmacocinética , Animais , Encéfalo/patologia , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Nanosferas/metabolismo , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/patologiaRESUMO
BACKGROUND: In previous studies, we have observed that specific N-methyl-d-aspartic acid (NMDA) antagonists and non-NMDA antagonists injected within the nucleus accumbens septi (NAS) induced an anxiolytic-like effect in the plus maze test in rats. In the present study, the effect of intracanalicular blockade of NMDA receptors using dizocilpine in the plus maze was studied in male rats bilaterally cannulated NAS. METHODS: Rats were divided into five groups that received either 1 µL injections of saline or dizocilpine (MK-801, [5R,10S]-[+]-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine) in different doses (0.5, 1, 2, or 4 µg) 15 min before testing. RESULTS: Time spent in the open arm increased under dizocilpine treatment with the two higher doses (2 and 4 µg, p<0.05), extreme arrivals were increased by the three higher doses (1 µg, p<0.05; 2 and 4 µg, p<0.01), and open arm entries by the three higher doses (1, 2, and 4 µg, p<0.05). A dose-effect relationship was observed in all cases. CONCLUSIONS: We conclude that dizocilpine-glutamatergic blockade in the accumbens lead to an anxiolytic-like effect and a behavioral disinhibition related to an increase in some motoric parameters, showing specific behavioral patterns.
Assuntos
Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Maleato de Dizocilpina/administração & dosagem , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Masculino , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Two mechanisms of brain cell death coexist, necrosis and apoptosis. We investigated the correlation between the apoptotic index and the expression of apoptosis modulators and stress response in an ultraviolet-induced cortical microinfarct. Adult rat neocortex was exposed to an ultraviolet beam and brains removed at different intervals after injury were paraffin-embedded and processed for TUNEL assay and immunohistochemistry against apoptotic modulators Bax and Bcl-2, and stress protein HSP70. During the 12-72h postirradiation period, apoptotic nuclei decreased from 11% to 4% in the infarcted area whereas only 1.2% of such nuclei was seen in the perilesional area. While Bcl-2 was always negative in the lesion focus, Bax was positive at all survival times, mainly in glial cells. HSP70 was expressed over a broad area of the ipsilateral hemisphere from 3h after brain injury, firstly in neurons and progressively in glial cells and finally in endothelium. At longer survival times, positive cells could be also seen in the contralateral hemisphere. Apoptosis seems to play only a quantitatively modest role in the progression of brain damage in penumbra areas despite the wide expression of pro-apoptotic factors. On the other hand HSP70 appears to be one of the main protective responses to injury stress.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Infarto Encefálico/fisiopatologia , Córtex Cerebral/fisiopatologia , Estresse Fisiológico/fisiopatologia , Animais , Apoptose/fisiologia , Apoptose/efeitos da radiação , Infarto Encefálico/metabolismo , Contagem de Células , Sobrevivência Celular/fisiologia , Sobrevivência Celular/efeitos da radiação , Córtex Cerebral/metabolismo , Córtex Cerebral/efeitos da radiação , Modelos Animais de Doenças , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Degeneração Neural/etiologia , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Neuroglia/metabolismo , Neuroglia/efeitos da radiação , Neurônios/metabolismo , Neurônios/efeitos da radiação , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Fisiológico/etiologia , Estresse Fisiológico/metabolismo , Fatores de Tempo , Raios Ultravioleta/efeitos adversos , Proteína X Associada a bcl-2/metabolismoRESUMO
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 terapêuticoRESUMO
More than 5.5 million Americans of all ages are suffering from Alzheimer's disease (AD) till today for which no suitable therapy has been developed so far. Thus, there is an urgent need to explore novel therapeutic measures to contain brain pathology in AD. The hallmark of AD includes amyloid-beta peptide (AßP) deposition and phosphorylation of tau in AD brain. Recent evidences also suggest a marked decrease in neurotrophic factors in AD. Thus, exogenous supplement of neurotrophic factors could be one of the possible ways for AD therapy. Human postmortem brain in AD shows alterations in histamine receptors as well, indicating an involvement of the amine in AD-induced brain pathology. In this review, we focused on role of histamine 3 and 4 receptor-modulating drugs in the pathophysiology of AD. Moreover, antibodies to histamine and tau appear to be also beneficial in reducing brain pathology, blood-brain barrier breakdown, and edema formation in AD. Interestingly, TiO2-nanowired delivery of cerebrolysin-a balanced composition of several neurotrophic factors attenuated AßP deposition and reduced tau phosphorylation in AD brain leading to neuroprotection. Coadministration of cerebrolysin with histamine antibodies or tau antibodies has further enhanced neuroprotection in AD. These novel observations strongly suggest a role of nanomedicine in AD that requires further investigation.
Assuntos
Doença de Alzheimer/terapia , Aminoácidos/administração & dosagem , Anticorpos/administração & dosagem , Histamínicos/administração & dosagem , Titânio , Proteínas tau/imunologia , Animais , Modelos Animais de Doenças , Sistemas de Liberação de Medicamentos , HumanosRESUMO
The possibility that histamine influences the spinal cord pathophysiology following trauma through specific receptor-mediated upregulation of neuronal nitric oxide synthase (nNOS) was examined in a rat model. A focal spinal cord injury (SCI) was inflicted by a longitudinal incision into the right dorsal horn of the T10-11 segments. The animals were allowed to survive 5h. The SCI significantly induced breakdown of the blood-spinal cord barrier to protein tracers, reduced the spinal cord blood flow at 5h, and increased the edema formation and massive upregulation of nNOS expression. Pretreatment with histamine H1 receptor antagonist mepyramine (1mg, 5mg, and 10mg/kg, i.p., 30min before injury) failed to attenuate nNOS expression and spinal cord pathology following SCI. On the other hand, blockade of histamine H2 receptors with cimetidine or ranitidine (1mg, 5mg, or 10mg/kg) significantly reduced these early pathophysiological events and attenuated nNOS expression in a dose-dependent manner. Interestingly, TiO2-naowire delivery of cimetidine or ranitidine (5mg doses) exerted superior neuroprotective effects on SCI-induced nNOS expression and cord pathology. It appears that effects of ranitidine were far superior than cimetidine at identical doses in SCI. On the other hand, pretreatment with histamine H3 receptor agonist α-methylhistamine (1mg, 2mg, or 5mg/kg, i.p.) that inhibits histamine synthesis and release in the central nervous system thwarted the spinal cord pathophysiology and nNOS expression when used in lower doses. Interestingly, histamine H3 receptor antagonist thioperamide (1mg, 2mg, or 5mg/kg, i.p.) exacerbated nNOS expression and cord pathology after SCI. These novel observations suggest that blockade of histamine H2 receptors or stimulation of histamine H3 receptors attenuates nNOS expression and induces neuroprotection in SCI. Taken together, our results are the first to demonstrate that histamine-induced pathophysiology of SCI is mediated via nNOS expression involving specific histamine receptors.
Assuntos
Nanofios/administração & dosagem , Óxido Nítrico Sintase Tipo I/metabolismo , Receptores Histamínicos/metabolismo , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/prevenção & controle , Regulação para Cima/fisiologia , Animais , Cimetidina/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Humanos , Masculino , Pirilamina/administração & dosagem , Ratos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacosRESUMO
Influence of iron oxide magnetic nanoparticles (IOMNPs, 10nm in diameter, 0.25 or 0.50mg/mL in 100µL, i.v.) on the blood-brain barrier (BBB) permeability, edema formation, and neuronal or glial changes within 4-24h after administration was examined in normal rats and after a focal spinal cord injury (SCI). Furthermore, effect of cerebrolysin, a balanced composition of several neurotrophic factors, and active peptide fragments was also evaluated on IOMNP-induced changes in central nervous system (CNS) pathology. The SCI was inflicted in rats by making a longitudinal incision into the right dorsal horn of the T10-11 segments and allowed to survive 4 or 24h after trauma. Cerebrolysin (2.5mL/kg, i.v.) was given either 30min before IOMNP injection in the 4-h SCI group or 4h after injury in the 24-h survival groups. Control group received cerebrolysin in identical situation following IOMNP administration. In all groups, leakage of serum albumin in the CNS as a marker of BBB breakdown and activation of astrocytes using glial fibrillary acidic protein was evaluated by immunohistochemistry. The neuronal injury was examined by Nissl staining. The IOMNPs alone in either low or high doses did not induce CNS pathology either following 4 or 24h after administration. However, administration of IOMNPs in SCI group slightly enhanced the pathological changes in the CNS after 24h but not 4h after trauma. Cerebrolysin treatment markedly attenuated IOMNP-induced aggravation of SCI-induced cord pathology and induced significant neuroprotection. These observations are the first to show that IOMNPs are safe for the CNS and cerebrolysin treatment prevented CNS pathology following a combination of trauma and IOMNP injection. This indicated that cerebrolysin might be used as adjunct therapy during IOMNP administration in disease conditions, not reported earlier.
Assuntos
Aminoácidos/uso terapêutico , Compostos Férricos/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Traumatismos da Medula Espinal/terapia , Administração Intravenosa , Animais , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Nanopartículas/administração & dosagem , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/induzido quimicamente , Traumatismos da Medula Espinal/patologia , Resultado do TratamentoRESUMO
Cerebral syndromes related to high-altitude exposure are becoming more frequent as the number of trips to high altitudes has increased in the last decade. The commonest symptom is headache, followed by acute mountain sickness (AMS) and high-altitude cerebral edema (HACE), which can be fatal. The pathophysiology of these syndromes is not fully understood. The classical "tight-fit hypothesis" posits that there are some anatomical variations that would obstruct the sinovenous outflow and worsen vasogenic edema and intracranial hypertension reactive to hypoxia. This could explain microhemorrhages seen in autopsies. However, recent magnetic resonance imaging studies have demonstrated some components of cytotoxic edema in HACE absent in AMS, suggesting a dysfunction in water balance at the cellular level. Currently, the "red-ox theory" supports trigemino-vascular system activation by free radicals formed after hypoxia and the consequent oxidative stress cascades. Apart from trigemino-vascular system activation, free radicals can also provoke membrane destabilisation mediated by lipid peroxidation, inflammation, and local hypoxia inducible factor-1α and vascular endothelial growth factor activation, resulting in gross blood-brain barrier (BBB) dysfunction. Besides alterations in endothelial cells such as increased pinocytotic vesicles and disassembly of interendothelial tight junction proteins, capillary permeability may also increase with subsequent swelling of astrocyte end-feet. In conclusion, although the pathophysiology of AMS and HACE is not completely understood, recent evidence proposes a multifactorial entity, with brain swelling and compromise of the BBB considered to play an important role. A fuller comprehension of these processes is crucial to reduce and prevent BBB alterations during high-altitude exposure.
Assuntos
Altitude , Barreira Hematoencefálica/metabolismo , Animais , Barreira Hematoencefálica/lesões , Barreira Hematoencefálica/patologia , HumanosRESUMO
The blood-brain barrier (BBB) is a physiological regulator of transport of essential items from blood to brain for the maintenance of homeostasis of the central nervous system (CNS) within narrow limits. The BBB is also responsible for export of harmful or metabolic products from brain to blood to keep the CNS fluid microenvironment healthy. However, noxious insults to the brain caused by trauma, ischemia or environmental/chemical toxins alter the BBB function to small as well as large molecules e.g., proteins. When proteins enter the CNS fluid microenvironment, development of brain edema occurs due to altered osmotic balance between blood and brain. On the other hand, almost all neurodegenerative diseases and traumatic insults to the CNS and subsequent BBB dysfunction lead to edema formation and cell injury. To treat these brain disorders suitable drug therapy reaching their brain targets is needed. However, due to edema formation or only a focal disruption of the BBB e.g., around brain tumors, many drugs are unable to reach their CNS targets in sufficient quantity. This results in poor therapeutic outcome. Thus, new technology such as nanodelivery is needed for drugs to reach their CNS targets and be effective. In this review, use of nanowires as a possible novel tool to enhance drug delivery into the CNS in various disease models is discussed based on our investigations. These data show that nanowired delivery of drugs may have superior neuroprotective ability to treat several CNS diseases effectively indicating their role in future therapeutic strategies.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Fármacos do Sistema Nervoso Central/administração & dosagem , Doenças do Sistema Nervoso Central/tratamento farmacológico , Sistema Nervoso Central/lesões , Sistemas de Liberação de Medicamentos , Nanofios , Animais , Barreira Hematoencefálica/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Doenças do Sistema Nervoso Central/metabolismo , HumanosRESUMO
The blood-brain barrier (BBB) plays a pivotal role in the maintenance of central nervous system function in health and disease. Thus, in almost all neurodegenerative, traumatic or metabolic insults BBB breakdown occurs, allowing entry of serum proteins into the brain fluid microenvironment with subsequent edema formation and cellular injury. Accordingly, pharmacological restoration of BBB function will lead to neurorepair. However, brain injury which occurs following blast, bullet wounds, or knife injury appears to initiate different sets of pathophysiological responses. Moreover, other local factors at the time of injury such as cold or elevated ambient temperatures could also impact the final outcome. Obviously, drug therapy applied to different kinds of brain trauma occurring at either cold or hot environments may respond differently. This is largely due to the fact that internal defense mechanisms of the brain, gene expression, release of neurochemicals and binding of drugs to specific receptors are affected by external ambient temperature changes. These factors may also affect BBB function and development of edema formation after brain injury. In this review, the effects of seasonal exposure to heat and cold on traumatic brain injury using different models i.e., concussive brain injury and cerebral cortical lesion, on BBB dysfunction in relation to drug therapy are discussed. Our observations clearly suggest that closed head injury and open brain injury are two different entities and the external hot or cold environments affect both of them remarkably. Thus, effective pharmacological therapeutic strategies should be designed with these views in mind, as military personnel often experience blunt or penetrating head injuries in either cold or hot environments.
Assuntos
Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/fisiopatologia , Lesões Encefálicas/tratamento farmacológico , Lesões Encefálicas/fisiopatologia , Temperatura Baixa , Temperatura Alta , Fármacos Neuroprotetores/farmacologia , Animais , Barreira Hematoencefálica/patologia , Lesões Encefálicas/patologia , Meio Ambiente , Humanos , Fármacos Neuroprotetores/uso terapêuticoRESUMO
The development of the cortical vascular tree depends on functional development. External inputs are an essential requirement in the modeling of the visual cortex, mainly during the critical period, when congruous blood supply is needed. The blood brain barrier (BBB) function regulates the passage of substances between the blood and the brain parenchyma, which is one of the main differential features of central nervous system (CNS) microvessels. The endothelial barrier antigen (EBA) has been reported as a specific marker for the BBB physiological function in rats. We studied the postnatal development of EBA expression in the visual cortex of rats reared under opposite paradigms of visual experience, e.g., standard laboratory conditions, dark rearing, and enriched environment at 14, 21, 28, 35, 42, 49, 56, and 63 days postnatal (dpn). Parallel sections were immunohistochemically processed for endothelial barrier antigen (EBA) and glucose transporter-1 (GluT-1). Total vasculature was quantified by Lycopersicon esculentum (LEA) lectin histochemistry. No differences in EBA expression were found between groups, although quantitative differences were recorded paralleling differences in vascular density. Paradoxically, there was no expression in certain cortical vessels which were GluT-1 immunopositive and positivity was consistent in non-barrier areas such as the pineal gland. These findings were completely independent of age or experimental conditions. Therefore, the role of the EBA antigen in the BBB remains unclear: it has been undeniably linked to vascular permeability, but its presence in non-barrier vessels suggests another vascular function. Although visual experience modifies vascular density in the visual cortex, it has not been shown to have an influence on the maturation of the BBB function.
Assuntos
Antígenos de Superfície/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Proteínas de Transporte de Monossacarídeos/metabolismo , Córtex Visual/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Escuridão , Meio Ambiente , Feminino , Transportador de Glucose Tipo 1 , Imuno-Histoquímica/métodos , Solanum lycopersicum/metabolismo , Masculino , Microscopia Confocal/métodos , Gravidez , Ratos , Ratos Sprague-Dawley , Córtex Visual/anatomia & histologia , Córtex Visual/crescimento & desenvolvimentoRESUMO
Increased levels of ubiquitin and heat shock protein (HSP) 72 kD are often seen in spinal cord injury (SCI). However, their roles in cell injury or survival are not well known. Thus, we have investigated the possible relationship between ubiquitin and HSP expressions in relation to cell injury in healthy animals, or following nanoparticle (NP) intoxication in SCI animals. A focal SCI was inflicted on the T10-11 segments over the right dorsal horn; animals were allowed to survive from 5 to 8 h after trauma. Separate groups of rats were exposed to SiO2, Ag, or Cu NPs for 7 days and subjected to SCI on the eighth day. A marked increase in ubiquitin or HSP immunoreactive cells occurred in the T9 to T12 segments 5 h after the injury, which further extended to the T4 and L5 after 8 h of survival. At this time, a marked increase in blood-spinal cord barrier (BSCB) permeability to Evans blue and radioiodine, accompanied by an intense edema formation, was observed. Changes were further exacerbated in NP-treated traumatized rats. The most marked expressions of ubiquitin and HSP in SCI were seen in rats treated with SiO2, followed by Ag, and Cu NPs. Treatment with H-290/51 (50 mg/kg p.o., 30 to 60 min after injury) or carfilzomib (1 mg/kg, i.v., 30 to 60 min after trauma) significantly reduced the ubiquitin or HSP expressions, as well as the BSCB breakdown, the edema formation, and the cell injury in the cord both 5 and 8 h after the injury, in normal animals. However, a double dose of H-290/51 (100 mg/kg) or carfilzomib (2 mg/kg) is needed to reduce cord pathology or ubiquitin and HSP expressions in traumatized animals treated with NPs. H-290/51 showed superior beneficial effects in reducing cord pathology in SCI than carfilzomib. These observations are the first to demonstrate that (i) NP-treated traumatized animals induce a widespread BSCB leakage, edema formation, and cord pathology as well as an overexpression of ubiquitin and HSP, (ii) high doses of antioxidant compounds or proteasome inhibitors are required for neuroprotection in the NP-exposed traumatized group, and (iii) ubiquitin and HSP expressions play a key role in neuronal injury in SCI, not reported earlier.
Assuntos
Antioxidantes/uso terapêutico , Cobre/toxicidade , Proteínas de Choque Térmico HSP72/biossíntese , Indóis/uso terapêutico , Nanopartículas/toxicidade , Proteínas do Tecido Nervoso/biossíntese , Fármacos Neuroprotetores/uso terapêutico , Oligopeptídeos/uso terapêutico , Inibidores de Proteassoma/uso terapêutico , Prata/toxicidade , Traumatismos da Medula Espinal/tratamento farmacológico , Ubiquitina/biossíntese , Animais , Antioxidantes/farmacologia , Cobre/administração & dosagem , Avaliação Pré-Clínica de Medicamentos , Edema/etiologia , Edema/prevenção & controle , Proteínas de Choque Térmico HSP72/genética , Indóis/farmacologia , Masculino , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/farmacologia , Oligopeptídeos/farmacologia , Inibidores de Proteassoma/farmacologia , Ratos , Ratos Wistar , Dióxido de Silício/administração & dosagem , Dióxido de Silício/toxicidade , Prata/administração & dosagem , Medula Espinal/metabolismo , Medula Espinal/patologia , Traumatismos da Medula Espinal/complicações , Traumatismos da Medula Espinal/etiologia , Traumatismos da Medula Espinal/metabolismo , Vértebras Torácicas , Ubiquitina/genética , Regulação para CimaRESUMO
We have shown previously that heat stroke produced by whole body hyperthermia (WBH) for 4 h at 38°C in diabetic rats exacerbates blood-brain barrier breakdown, brain edema formation and neuronal cell injury as compared to healthy animals after identical heat exposure. In this combination of diabetes and WBH, normal therapeutic measures do not induce sufficient neuroprotection. Thus, we investigated whether nanowired mesenchymal cells (MSCs) when delivered systemically may have better therapeutic effects on brain damage in diabetic rats after WBH. Diabetes induced by streptozotocin administration (75 mg/kg, i.p, daily for 3 days) in rats resulted in clinical symptoms of the disease within 4 to 6 weeks (blood glucose level 20 to 30 mmoles/l as compared to saline control groups (4 to 6 mmoles/l). When subjected to WBH, these diabetic rats showed a 4-to 6-fold exacerbation of blood-brain barrier breakdown to Evans blue and radioiodine, along with brain edema formation and neuronal cell injury. Intravenous administration of rat MSCs (1x10(6)) to diabetic rats one week before WBH slightly reduced brain pathology, whereas TiO2 nanowired MSCs administered in an identical manner resulted in almost complete neuroprotection. On the other hand, MSCs alone significantly reduced brain pathology in saline-treated rats after WBH. These observations indicate that nanowired delivery of stem cells has superior therapeutic potential in heat stroke with diabetes, pointing to novel clinical perspectives in the future.
Assuntos
Encéfalo/patologia , Diabetes Mellitus Experimental/patologia , Golpe de Calor/patologia , Golpe de Calor/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Animais , Axônios/fisiologia , Axônios/ultraestrutura , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/fisiopatologia , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Permeabilidade Capilar/fisiologia , Diabetes Mellitus Experimental/fisiopatologia , Marcha/fisiologia , Golpe de Calor/fisiopatologia , Masculino , Transplante de Células-Tronco Mesenquimais/instrumentação , Células-Tronco Mesenquimais/patologia , Células-Tronco Mesenquimais/fisiologia , Nanopartículas Metálicas , Bainha de Mielina/fisiologia , Bainha de Mielina/ultraestrutura , Ratos Sprague-Dawley , Titânio , Caminhada/fisiologiaRESUMO
Military personnel are often subjected to sleep deprivation (SD) during combat operations. Since SD is a severe stress and alters neurochemical metabolism in the brain, a possibility exists that acute or long-term SD will influence blood-brain barrier (BBB) function and brain pathology. This hypothesis was examined in young adult rats (age 12 to 14 weeks) using an inverted flowerpot model. Rats were placed over an inverted flowerpot platform (6.5 cm diameter) in a water pool where the water levels are just 3 cm below the surface. In this model, animals can go to sleep for brief periods but cannot achieve deep sleep as they would fall into water and thus experience sleep interruption. These animals showed leakage of Evans blue in the cerebellum, hippocampus, caudate nucleus, parietal, temporal, occipital, cingulate cerebral cortices, and brain stem. The ventricular walls of the lateral and fourth ventricles were also stained blue, indicating disruption of the BBB and the blood-cerebrospinal fluid barrier (BCSFB). Breakdown of the BBB or the BCSFB fluid barrier was progressive in nature from 12 to 48 h but no apparent differences in BBB leakage were seen between 48 and 72 h of SD. Interestingly, rats treated with metal nanoparticles, e.g., Cu or Ag, showed profound exacerbation of BBB disruption by 1.5- to 4-fold, depending on the duration of SD. Measurement of plasma and brain serotonin showed a close correlation between BBB disruption and the amine level. Repeated treatment with the serotonin 5-HT3 receptor antagonist ondansetron (1 mg/kg, s.c.) 4 and 8 h after SD markedly reduced BBB disruption and brain pathology after 12 to 24 h SD but not following 48 or 72 h after SD. However, TiO2-nanowired ondansetron (1 mg/kg, s.c) in an identical manner induced neuroprotection in rats following 48 or 72 h SD. However, plasma and serotonin levels were not affected by ondansetron treatment. Taken together, our observations are the first to show that (i) SD could induce BBB disruption and brain pathology, (ii) nanoparticles exacerbate SD-induced brain damage, and (iii) serotonin 5-HT3 receptor antagonist ondansetron is neuroprotective in SD that is further potentiated byTiO2-nanowired delivery, not reported earlier.