RESUMO
Photobiomodulation (PBM)-the irradiation of tissue with low-intensity light-mitigates neuropathology in rodent models of Parkinson's disease (PD) when targeted at the head ('transcranial PBM'). In humans, however, attenuation of light energy by the scalp and skull necessitates a different approach. We have reported that targeting PBM at the body also protects the brain by a mechanism that spreads from the irradiated tissue ('remote PBM'), although the optimal peripheral tissue target for remote PBM is currently unclear. This study compared the neuroprotective efficacy of remote PBM targeting the abdomen or leg with transcranial PBM, in mouse and non-human primate models of PD. In a pilot study, the neurotoxin MPTP was used to induce PD in non-human primates; PBM (670 nm, 50 mW/cm2 , 6 min/day) of the abdomen (n = 1) was associated with fewer clinical signs and more surviving midbrain dopaminergic cells relative to MPTP-injected non-human primates not treated with PBM. Validation studies in MPTP-injected mice (n = 10 per group) revealed a significant rescue of midbrain dopaminergic cells in mice receiving PBM to the abdomen (~80%, p < .0001) or legs (~80%, p < .0001), with comparable rescue of axonal terminals in the striatum. Strikingly, this degree of neuroprotection was at least as, if not more, pronounced than that achieved with transcranial PBM. These findings confirm that remote PBM provides neuroprotection against MPTP-induced destruction of the key circuitry underlying PD, with both the abdomen and legs serving as viable remote targets. This should provide the impetus for a comprehensive investigation of remote PBM-induced neuroprotection in other models of PD and, ultimately, human patients.
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Neuroproteção , Doença de Parkinson , Humanos , Camundongos , Animais , Perna (Membro) , Projetos Piloto , Doença de Parkinson/terapia , AbdomeRESUMO
Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. In addition, we show that iron accumulation is increased in lung sections from patients with IPF and that human lung fibroblasts show greater proliferation and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1+ macrophages that display altered phenotype in disease, and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Fibrose Pulmonar Idiopática/patologia , Ferro/metabolismo , Remodelação das Vias Aéreas/efeitos dos fármacos , Animais , Bleomicina/farmacologia , Proliferação de Células , Células Cultivadas , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/patologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Humanos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos KnockoutRESUMO
Accumulating evidence highlights links between iron regulation and respiratory disease. Here, we assessed the relationship between iron levels and regulatory responses in clinical and experimental asthma.We show that cell-free iron levels are reduced in the bronchoalveolar lavage (BAL) supernatant of severe or mild-moderate asthma patients and correlate with lower forced expiratory volume in 1â s (FEV1). Conversely, iron-loaded cell numbers were increased in BAL in these patients and with lower FEV1/forced vital capacity (FVC) ratio. The airway tissue expression of the iron sequestration molecules divalent metal transporter 1 (DMT1) and transferrin receptor 1 (TFR1) are increased in asthma, with TFR1 expression correlating with reduced lung function and increased Type-2 (T2) inflammatory responses in the airways. Furthermore, pulmonary iron levels are increased in a house dust mite (HDM)-induced model of experimental asthma in association with augmented Tfr1 expression in airway tissue, similar to human disease. We show that macrophages are the predominant source of increased Tfr1 and Tfr1+ macrophages have increased Il13 expression. We also show that increased iron levels induce increased pro-inflammatory cytokine and/or extracellular matrix (ECM) responses in human airway smooth muscle (ASM) cells and fibroblasts ex vivo and induce key features of asthma in vivo, including airway hyper-responsiveness (AHR) and fibrosis, and T2 inflammatory responses.Together these complementary clinical and experimental data highlight the importance of altered pulmonary iron levels and regulation in asthma, and the need for a greater focus on the role and potential therapeutic targeting of iron in the pathogenesis and severity of disease.
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Asma , Animais , Humanos , Interleucina-13 , Ferro , Pulmão , PyroglyphidaeRESUMO
Alzheimer's disease, the most common form of dementia, was first formally described in 1907 yet its etiology has remained elusive. Recent proposals that Aß peptide may be part of the brain immune response have revived longstanding contention about the possibility of causal relationships between brain pathogens and Alzheimer's disease. Research has focused on infectious pathogens that may colonize the brain such as herpes simplex type I. Some researchers have proposed the respiratory bacteria Chlamydia pneumoniae may also be implicated in Alzheimer's disease, however this remains controversial. This review aims to provide a balanced overview of the current evidence and its limitations and future approaches that may resolve controversies. We discuss the evidence from in vitro, animal and human studies proposed to implicate Chlamydia pneumoniae in Alzheimer's disease and other neurological conditions, the potential mechanisms by which the bacterium may contribute to pathogenesis and limitations of previous studies that may explain the inconsistencies in the literature.
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Doença de Alzheimer/etiologia , Doença de Alzheimer/microbiologia , Chlamydophila pneumoniae/patogenicidade , Incerteza , Animais , Encéfalo/microbiologia , Infecções por Chlamydophila/complicações , Infecções por Chlamydophila/microbiologia , Humanos , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: To examine whether near-infrared light (NIr) treatment reduces clinical signs and/or offers neuroprotection in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson disease. METHODS: We implanted an optical fiber device that delivered NIr (670 nm) to the midbrain of macaque monkeys, close to the substantia nigra of both sides. MPTP injections (1.5-2.1mg/kg) were made over a 5- to 7-day period, during which time the NIr device was turned on. This was then followed by a 3-week survival period. Monkeys were evaluated clinically (eg, posture, bradykinesia) and behaviorally (open field test), and their brains were processed for immunohistochemistry and stereology. RESULTS: All monkeys in the MPTP group developed severe clinical and behavioral impairment (mean clinical scores = 21-34; n = 11). By contrast, the MPTP-NIr group developed much less clinical and behavioral impairment (n = 9); some monkeys developed moderate clinical signs (mean scores = 11-15; n = 3), whereas the majority--quite remarkably--developed few clinical signs (mean scores = 1-6; n = 6). The monkeys that developed moderate clinical signs had hematic fluid in their optical fibers at postmortem, presumably limiting NIr exposure and overall clinical improvement. NIr was not toxic to brain tissue and offered neuroprotection to dopaminergic cells and their terminations against MPTP insult, particularly in animals that developed few clinical signs. INTERPRETATION: Our findings indicate NIr to be an effective therapeutic agent in a primate model of the disease and create the template for translation into clinical trials.
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1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Comportamento Animal/efeitos da radiação , Raios Infravermelhos/uso terapêutico , Intoxicação por MPTP/prevenção & controle , Mesencéfalo/efeitos da radiação , Neurotoxinas/farmacologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Terapia com Luz de Baixa Intensidade , Intoxicação por MPTP/fisiopatologia , Macaca fascicularis , Masculino , Mesencéfalo/efeitos dos fármacos , Neurotoxinas/administração & dosagem , Fibras ÓpticasRESUMO
Dietary saffron has shown promise as a neuroprotective intervention in clinical trials of retinal degeneration and dementia and in animal models of multiple CNS disorders, including Parkinson's disease. This therapeutic potential makes it important to define the relationship between dose and protection and the mechanisms involved. To explore these two issues, mice were pre-conditioned by providing an aqueous extract of saffron (0.01% w/v) as their drinking water for 2, 5 or 10 days before administration of the parkinsonian neurotoxin MPTP (50 mg/kg). Five days of saffron pre-conditioning provided the greatest benefit against MPTP-induced neuropathology, significantly mitigating both loss of functional dopaminergic cells in the substantia nigra pars compacta (p < 0.01) and abnormal neuronal activity in the caudate-putamen complex (p < 0.0001). RNA microarray analysis of the brain transcriptome of mice pre-conditioned with saffron for 5 days revealed differential expression of 424 genes. Bioinformatics analysis identified enrichment of molecular pathways (e.g. adherens junction, TNFR1 and Fas signaling) and expression changes in candidate genes (Cyr61, Gpx8, Ndufs4, and Nos1ap) with known neuroprotective actions. The apparent biphasic nature of the dose-response relationship between saffron and measures of neuroprotection, together with the stress-inducible nature of many of the up-regulated genes and pathways, lend credence to the idea that saffron, like various other phytochemicals, is a hormetic stimulus, with functions beyond its strong antioxidant capacity. These findings provide impetus for a more comprehensive evaluation of saffron as a neuroprotective intervention.
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Encéfalo/metabolismo , Crocus , Intoxicação por MPTP/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Transcriptoma/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Transcriptoma/efeitos dos fármacosRESUMO
Aberrant brain iron deposition is observed in both common and rare neurodegenerative disorders, including those categorized as Neurodegeneration with Brain Iron Accumulation (NBIA), which are characterized by focal iron accumulation in the basal ganglia. Two NBIA genes are directly involved in iron metabolism, but whether other NBIA-related genes also regulate iron homeostasis in the human brain, and whether aberrant iron deposition contributes to neurodegenerative processes remains largely unknown. This study aims to expand our understanding of these iron overload diseases and identify relationships between known NBIA genes and their main interacting partners by using a systems biology approach. We used whole-transcriptome gene expression data from human brain samples originating from 101 neuropathologically normal individuals (10 brain regions) to generate weighted gene co-expression networks and cluster the 10 known NBIA genes in an unsupervised manner. We investigated NBIA-enriched networks for relevant cell types and pathways, and whether they are disrupted by iron loading in NBIA diseased tissue and in an in vivo mouse model. We identified two basal ganglia gene co-expression modules significantly enriched for NBIA genes, which resemble neuronal and oligodendrocytic signatures. These NBIA gene networks are enriched for iron-related genes, and implicate synapse and lipid metabolism related pathways. Our data also indicates that these networks are disrupted by excessive brain iron loading. We identified multiple cell types in the origin of NBIA disorders. We also found unforeseen links between NBIA networks and iron-related processes, and demonstrate convergent pathways connecting NBIAs and phenotypically overlapping diseases. Our results are of further relevance for these diseases by providing candidates for new causative genes and possible points for therapeutic intervention.
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Gânglios da Base/metabolismo , Perfilação da Expressão Gênica/métodos , Distúrbios do Metabolismo do Ferro/metabolismo , Distrofias Neuroaxonais/metabolismo , Transcriptoma , Adolescente , Idoso , Idoso de 80 Anos ou mais , Animais , Gânglios da Base/patologia , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Lactente , Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/patologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Transgênicos , Distrofias Neuroaxonais/patologia , Neurônios/metabolismo , Neurônios/patologia , Receptores da Transferrina/genética , Receptores da Transferrina/metabolismo , Substância Branca/metabolismo , Substância Branca/patologia , Adulto JovemRESUMO
We have shown previously that near-infrared light (NIr), when applied at the same time as a parkinsonian insult (e.g. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPTP), reduces behavioural deficits and offers neuroprotection. Here, we explored whether the timing of NIr intervention-either before, at the same time or after the MPTP insult-was important. Mice received MPTP injections (total of 50 mg/kg) and, at various stages in relation to these injections, extracranial application of NIr. Locomotor activity was tested with an open-field test, and brains were processed for immunohistochemistry. Our results showed that regardless of when NIr was applied in relation to MPTP insult, behavioural impairment was reduced by a similar magnitude. The beneficial effect of NIr was fast-acting (within minutes) and long-lasting (for several days). There were more dopaminergic cells in the NIr-treated MPTP groups than in the MPTP group; there was no clear indication that a particular combination of NIr treatment and MPTP injection resulted in a higher cell number. In summary, irrespective of whether it was applied before, at the same time as or after MPTP insult, NIr reduced both behavioural and structural measures of damage by a similar magnitude. There was a broad therapeutic time window of NIr application in relation to the stage of toxic insult, and the NIr was fast-acting and long-lasting.
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Comportamento Animal/efeitos da radiação , Raios Infravermelhos/uso terapêutico , Intoxicação por MPTP/terapia , Atividade Motora/efeitos da radiação , Fototerapia/métodos , Animais , Modelos Animais de Doenças , Terapia com Luz de Baixa Intensidade , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Espectroscopia de Luz Próxima ao Infravermelho , Fatores de TempoRESUMO
We have reported previously that intracranial application of near-infrared light (NIr) reduces clinical signs and offers neuroprotection in a subacute MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) monkey model of Parkinson's disease. In this study, we explored whether NIr reduces the gliosis in this animal model. Sections of midbrain (containing the substantia nigra pars compacta; SNc) and striatum were processed for glial fibrillary acidic protein (to label astrocytes; GFAP) and ionised calcium-binding adaptor molecule 1 (to label microglia; IBA1) immunohistochemistry. Cell counts were undertaken using stereology, and cell body sizes were measured using ImageJ. Our results showed that NIr treatment reduced dramatically (~75 %) MPTP-induced astrogliosis in both the SNc and striatum. Among microglia, however, NIr had a more limited impact in both nuclei; although there was a reduction in overall cell size, there were no changes in the number of microglia in the MPTP-treated monkeys after NIr treatment. In summary, we showed that NIr treatment influenced the glial response, particularly that of the astrocytes, in our monkey MPTP model of Parkinson's disease. Our findings raise the possibility of glial cells as a future therapeutic target using NIr.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Gliose/etiologia , Gliose/terapia , Raios Infravermelhos/uso terapêutico , Intoxicação por MPTP/complicações , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Análise de Variância , Animais , Proteínas de Ligação ao Cálcio , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Proteínas de Ligação a DNA/metabolismo , Modelos Animais de Doenças , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Terapia com Luz de Baixa Intensidade , Intoxicação por MPTP/patologia , Macaca fascicularis , Masculino , Proteínas dos Microfilamentos , Neuroglia/efeitos dos fármacos , Neuroglia/efeitos da radiação , Neurotoxinas/toxicidade , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Substância Negra/patologiaRESUMO
We have used the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model to explore whether (i) the neuroprotective effect of near infrared light (NIr) treatment in the SNc is dose-dependent and (ii) the relationship between tyrosine hydroxylase (TH)+ terminal density and glial cells in the caudate-putamen complex (CPu). Mice received MPTP injections (50 mg/kg) and 2 J/cm2 NIr dose with either 2 d or 7 d survival period. In another series, with a longer 14 d survival period, mice had a stronger MPTP regime (100 mg/kg) and either 2 J/cm2 or 4 J/cm2 NIr dose. Brains were processed for routine immunohistochemistry and cell counts were made using stereology. Our findings were that in the 2 d series, no change in SNc TH+ cell number was evident after any treatment. In the 7 d series however, MPTP insult resulted in â¼45% reduction in TH+ cell number; after NIr (2 J/cm2) treatment, many cells were protected from the toxic insult. In the 14 d series, MPTP induced a similar reduction in TH+ cell number. NIr mitigated the loss of TH+ cells, but only at the higher dose of 4 J/cm2; the lower dose of 2 J/cm2 had no neuroprotective effect in this series. The higher dose of NIr, unlike the lower dose, also mitigated the MPTP- induced increase in CPu astrocytes after 14 d; these changes were independent of TH+ terminal density, of which, did not vary across the different experimental groups. In summary, we showed that neuroprotection by NIr irradiation in MPTP-treated mice was dose-dependent; with increasing MPTP toxicity, higher doses of NIr were required to protect cells and reduce astrogliosis.
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Neurônios Dopaminérgicos/efeitos da radiação , Gliose/radioterapia , Raios Infravermelhos/uso terapêutico , Intoxicação por MPTP/radioterapia , Transtornos Parkinsonianos/radioterapia , Parte Compacta da Substância Negra/efeitos da radiação , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/administração & dosagem , Animais , Astrócitos/patologia , Astrócitos/efeitos da radiação , Núcleo Caudado/patologia , Núcleo Caudado/efeitos da radiação , Contagem de Células , Sobrevivência Celular/efeitos da radiação , Neurônios Dopaminérgicos/efeitos dos fármacos , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Gliose/patologia , Terapia com Luz de Baixa Intensidade , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/análise , Transtornos Parkinsonianos/patologia , Parte Compacta da Substância Negra/patologia , Putamen/patologia , Putamen/efeitos da radiação , Tirosina 3-Mono-Oxigenase/análiseRESUMO
Although it is well established that a vegetable-rich (Mediterranean) diet is associated with health benefits in later life, the mechanisms and biological origins of this benefit are not well established. This review seeks to identify the components a healthful diet that reduce the individual's suffering from non-communicable disease and extend longevity. We note the difference between the claims made for an essential diet (that prevents deficiency syndromes) and those argued for a diet that also prevents or delays non-communicable diseases and ask: what chemicals in our food induce this added resilience, which is effective against cardiovascular and neurodegenerative diseases, diabetes and even cancer? Working in the framework of acquired resilience (tissue resilience induced by a range of stresses), we arguethat the toxins evolved by plants as part of allelopathy (the competition between plant species) are key in making the 'healthful difference'. We further suggest the recognition of a category of micronutrients additional to the established 'micro' categories of vitamins and trace elements and suggest also that the new category be called 'trace toxins'. Implications of these suggestions are discussed.
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This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent in the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer's disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed to hemoglobin, amyloid- (A), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of A (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and A; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, A expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Hemorragia Cerebral/complicações , Encéfalo/patologia , Hemoglobinas/metabolismo , GlutamatosRESUMO
BACKGROUND: We have shown previously that near-infrared light (NIr) treatment or photobiomodulation neuroprotects dopaminergic cells in substantia nigra pars compacta (SNc) from degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Balb/c albino mice, a well-known model for Parkinson's disease. The present study explores whether NIr treatment offers neuroprotection to these cells in C57BL/6 pigmented mice. In addition, we examine whether NIr influences behavioural activity in both strains after MPTP treatment. We tested for various locomotive parameters in an open-field test, namely velocity, high mobility and immobility. RESULTS: Balb/c (albino) and C57BL/6 (pigmented) mice received injections of MPTP (total of 50 mg/kg) or saline and NIr treatments (or not) over 48 hours. After each injection and/or NIr treatment, the locomotor activity of the mice was tested. After six days survival, brains were processed for TH (tyrosine hydroxylase) immunochemistry and the number of TH⺠cells in the substantia nigra pars compacta (SNc) was estimated using stereology. Results showed higher numbers of TH⺠cells in the MPTP-NIr groups of both strains, compared to the MPTP groups, with the protection greater in the Balb/c mice (30% vs 20%). The behavioural tests revealed strain differences also. For Balb/c mice, the MPTP-NIr group showed greater preservation of locomotor activity than the MPTP group. Behavioural preservation was less evident in the C57BL/6 strain however, with little effect of NIr being recorded in the MPTP-treated cases of this strain. Finally, there were differences between the two strains in terms of NIr penetration across the skin and fur. Our measurements indicated that NIr penetration was considerably less in the pigmented C57BL/6, compared to the albino Balb/c mice. CONCLUSIONS: In summary, our results revealed the neuroprotective benefits of NIr treatment after parkinsonian insult at both cellular and behavioural levels and suggest that Balb/c strain, due to greater penetration of NIr through skin and fur, provides a clearer model of protection than the C57BL/6 strain.
Assuntos
Neurônios Dopaminérgicos/efeitos da radiação , Raios Infravermelhos , Intoxicação por MPTP/patologia , Intoxicação por MPTP/terapia , Mesencéfalo/patologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Análise de Variância , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/patologia , Comportamento Exploratório/efeitos da radiação , Terapia com Luz de Baixa Intensidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos da radiação , Neurotoxinas/toxicidade , Especificidade da Espécie , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Of all our organs, the brain is perhaps the best protected from trauma. The skull has evolved to enclose it and, within the skull, the brain floats in a protective bath of cerebrospinal fluid. It is becoming evident, however, that head trauma experienced in young adult life can cause a dementia that appears decades later. The level of trauma that induces such destruction is still being assessed but includes levels well below that which cracks the skull or causes unconsciousness or concussion. Clinically this damage appears as dementia, in people who played body-contact sports in their youth or have survived accidents or the blasts of combat; and appears also, we argue, in old age, without a history of head trauma. The dementias have been given different names, including dementia pugilistica (affecting boxers), chronic traumatic encephalopathy (following certain sports, particularly football), traumatic brain injury (following accidents, combat) and Alzheimer's (following decades of life). They share common features of clinical presentation and neuropathology, and this conceptual analysis seeks to identify features common to these forms of brain injury and to identify where in the brain the damage common to them occurs; and how it occurs, despite the protection provided by the skull and cerebrospinal fluid. The analysis suggests that the brain's weak point in the face of trauma is its capillary bed, which is torn by the shock of trauma. This identification in turn allows discussion of ways of delaying, avoiding and even treating these trauma-induced degenerations.
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As human longevity has increased, we have come to understand the ability of the brain to function into advanced age, but also its vulnerability with age, apparent in the age-related dementias. Against that background of success and vulnerability, this essay reviews how the brain is protected by (by our count) 12 mechanisms, including: the cranium, a bony helmet; the hydraulic support given by the cerebrospinal fluid; the strategically located carotid body and sinus, which provide input to reflexes that protect the brain from blood-gas imbalance and extremes of blood pressure; the blood brain barrier, an essential sealing of cerebral vessels; the secretion of molecules such as haemopexin and (we argue) the peptide Aß to detoxify haemoglobin, at sites of a bleed; autoregulation of the capillary bed, which stabilises metabolites in extracellular fluid; fuel storage in the brain, as glycogen; oxygen storage, in the haemoprotein neuroglobin; the generation of new neurones, in the adult, to replace cells lost; acquired resilience, the stress-induced strengthening of cell membranes and energy production found in all body tissues; and cognitive reserve, the ability of the brain to maintain function despite damage. Of these 12 protections, we identify 5 as unique to the brain, 3 as protections shared with all body tissues, and another 4 as protections shared with other tissues but specialised for the brain. These protections are a measure of the brain's vulnerability, of its need for protection. They have evolved, we argue, to maintain cognitive function, the ability of the brain to function despite damage that accumulates during life. Several can be tools in the hands of the individual, and of the medical health professional, for the lifelong care of our brains.
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Alzheimer's disease (AD) is an age-related disease, with loss of integrity of the blood-brain barrier (BBB) being an early feature. Cellular senescence is one of the reported nine hallmarks of aging. Here, we show for the first time the presence of senescent cells in the vasculature in AD patients and mouse models of AD. Senescent endothelial cells and pericytes are present in APP/PS1 transgenic mice but not in wild-type littermates at the time of amyloid deposition. In vitro, senescent endothelial cells display altered VE-cadherin expression and loss of cell junction formation and increased permeability. Consistent with this, senescent endothelial cells in APP/PS1 mice are present at areas of vascular leak that have decreased claudin-5 and VE-cadherin expression confirming BBB breakdown. Furthermore, single cell sequencing of endothelial cells from APP/PS1 transgenic mice confirms that adhesion molecule pathways are among the most highly altered pathways in these cells. At the pre-plaque stage, the vasculature shows significant signs of breakdown, with a general loss of VE-cadherin, leakage within the microcirculation, and obvious pericyte perturbation. Although senescent vascular cells were not directly observed at sites of vascular leak, senescent cells were close to the leak area. Thus, we would suggest in AD that there is a progressive induction of senescence in constituents of the neurovascular unit contributing to an increasing loss of vascular integrity. Targeting the vasculature early in AD, either with senolytics or with drugs that improve the integrity of the BBB may be valid therapeutic strategies.
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Doença de Alzheimer , Barreira Hematoencefálica , Humanos , Camundongos , Animais , Barreira Hematoencefálica/metabolismo , Doença de Alzheimer/metabolismo , Células Endoteliais , Camundongos Transgênicos , EnvelhecimentoRESUMO
In recent times, photobiomodulation has been shown to be beneficial in animal models of Parkinson's disease, improving locomotive behavior and being neuroprotective. Early observations in people with Parkinson's disease have been positive also, with improvements in the non-motor symptoms of the disease being evident most consistently. Although the precise mechanisms behind these improvements are not clear, two have been proposed: direct stimulation, where light reaches and acts directly on the distressed neurons, and remote stimulation, where light influences cells and/or molecules that provide systemic protection, thereby acting indirectly on distressed neurons. In relation to Parkinson's disease, given that the major zone of pathology lies deep in the brain and that light from an extracranial or external photobiomodulation device would not reach these vulnerable regions, stimulating the distressed neurons directly would require intracranial delivery of light using a device implanted close to the vulnerable regions. For indirect systemic stimulation, photobiomodulation could be applied to either the head and scalp, using a transcranial helmet, or to a more remote body part (e.g., abdomen, leg). In this review, we discuss the evidence for both the direct and indirect neuroprotective effects of photobiomodulation in Parkinson's disease and propose that both types of treatment modality, when working together using both intracranial and extracranial devices, provide the best therapeutic option.
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Encéfalo/efeitos da radiação , Terapia com Luz de Baixa Intensidade , Fármacos Neuroprotetores/efeitos da radiação , Doença de Parkinson/terapia , Neurônios Dopaminérgicos/efeitos da radiação , Humanos , MitocôndriasRESUMO
Maternal iron deficiency occurs in 40-50% of all pregnancies and is associated with an increased risk of respiratory disease and asthma in children. We used murine models to examine the effects of lower iron status during pregnancy on lung function, inflammation and structure, as well as its contribution to increased severity of asthma in the offspring. A low iron diet during pregnancy impairs lung function, increases airway inflammation, and alters lung structure in the absence and presence of experimental asthma. A low iron diet during pregnancy further increases these major disease features in offspring with experimental asthma. Importantly, a low iron diet increases neutrophilic inflammation, which is indicative of more severe disease, in asthma. Together, our data demonstrate that lower dietary iron and systemic deficiency during pregnancy can lead to physiological, immunological and anatomical changes in the lungs and airways of offspring that predispose to greater susceptibility to respiratory disease. These findings suggest that correcting iron deficiency in pregnancy using iron supplements may play an important role in preventing or reducing the severity of respiratory disease in offspring. They also highlight the utility of experimental models for understanding how iron status in pregnancy affects disease outcomes in offspring and provide a means for testing the efficacy of different iron supplements for preventing disease.
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Deficiências de Ferro/complicações , Ferro/administração & dosagem , Doenças Respiratórias/etiologia , Animais , Colágeno/metabolismo , Proteínas Dietéticas do Ovo , Feminino , Inflamação/etiologia , Pulmão/crescimento & desenvolvimento , Pulmão/patologia , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Fenômenos Fisiológicos da Nutrição Pré-NatalRESUMO
Photobiomodulation (PBM) with low-intensity red to near infrared light elicits neuroprotection in various pre-clinical models and in some clinical contexts, yet the intracellular mechanisms triggered by PBM, and their temporal sequence of modulation, remain unclear. We aimed to address this uncertainty by mapping the temporal transcriptomic response to PBM. Human SH-SY5Y neuroblastoma cells were treated with 670 nm PBM and RNA collected a various time points over 24 h. The transcriptome was screened by RNA microarray, and gene co-expression analysis by hierarchical clustering was coupled with bioinformatics analysis to reveal the molecular systems modulated by PBM and their expression patterns over the time course. The findings suggest that PBM induces distinct early phase (up to 8 h post-PBM) and late phase (24 h post-PBM) intracellular responses. The early intracellular response features enrichment of pathways relating to transcriptional regulation and cellular stress responses, while the late intracellular response demonstrates a physiological shift to enrichment of downstream pathways such as cell death and DNA damage. These findings provide support for the hypothesis that PBM acts as a transient stressful stimulus, activating endogenous stress response pathways that in turn enhance cellular resilience. Further, the study introduces a novel method for retaining the richness of the temporal component when analysing transcriptomic time course data sets.
Assuntos
Raios Infravermelhos , Transcriptoma/efeitos da radiação , Apoptose/genética , Apoptose/efeitos da radiação , Linhagem Celular Tumoral , Análise por Conglomerados , Biologia Computacional , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , Humanos , Terapia com Luz de Baixa Intensidade , Análise de Sequência com Séries de Oligonucleotídeos , RNA Neoplásico/metabolismo , Fatores de TempoRESUMO
The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease (PD) as it specifically damages the nigrostriatal dopaminergic pathway. Recent studies in mice have, however, provided evidence that MPTP also compromises the integrity of the brain's vasculature. Photobiomodulation (PBM), the irradiation of tissue with low-intensity red light, mitigates MPTP-induced loss of dopaminergic neurons in the midbrain, but whether PBM also mitigates MPTP-induced damage to the cerebrovasculature has not been investigated. This study aimed to characterize the time course of cerebrovascular disruption following MPTP exposure and to determine whether PBM can mitigate this disruption. Young adult male C57BL/6 mice were injected with 80 mg/kg MPTP or isotonic saline and perfused with fluorescein isothiocyanate FITC-labelled albumin at various time points post-injection. By 7 days post-injection, there was substantial and significant leakage of FITC-labelled albumin into both the substantia nigra pars compacta (SNc; p < 0.0001) and the caudate-putamen complex (CPu; p ≤ 0.0003); this leakage partly subsided by 14 days post-injection. Mice that were injected with MPTP and treated with daily transcranial PBM (670 nm, 50 mW/cm2, 3 min/day), commencing 24 hours after MPTP injection, showed significantly less leakage of FITC-labelled albumin in both the SNc (p < 0.0001) and CPu (p = 0.0003) than sham-treated MPTP mice, with levels of leakage that were not significantly different from saline-injected controls. In summary, this study confirms that MPTP damages the brain's vasculature, delineates the time course of leakage induced by MPTP out to 14 days post-injection, and provides the first direct evidence that PBM can mitigate this leakage. These findings provide new understanding of the use of the MPTP mouse model as an experimental tool and highlight the potential of PBM as a therapeutic tool for reducing vascular dysfunction in neurological conditions.