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1.
J Neuroinflammation ; 9: 106, 2012 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-22642825

RESUMO

BACKGROUND: Neuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer's disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD. METHODS: The potential benefits of a novel TNF-α-lowering agent, 3,6'-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aß(1-42) challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6'-dithiothaliodmide. RESULTS: 3,6'-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with A(ß1-42) peptide, prior systemic 3,6'-dithiothalidomide suppressed Aß-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6'-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aß peptide and Aß-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment. CONCLUSIONS: Our data suggest a strong beneficial effect of 3,6'-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Modelos Animais de Doenças , Talidomida/análogos & derivados , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/fisiologia , Doença de Alzheimer/fisiopatologia , Animais , Biomarcadores/metabolismo , Inflamação/tratamento farmacológico , Inflamação/patologia , Inflamação/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ratos , Ratos Endogâmicos F344 , Talidomida/farmacologia , Talidomida/uso terapêutico
2.
PLoS One ; 7(1): e31094, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22299052

RESUMO

Exposure to uncontrolled irradiation in a radiologic terrorism scenario, a natural disaster or a nuclear battlefield, will likely be concomitantly superimposed on other types of injury, such as trauma. In the central nervous system, radiation combined injury (RCI) involving irradiation and traumatic brain injury may have a multifaceted character. This may entail cellular and molecular changes that are associated with cognitive performance, including changes in neurogenesis and the expression of the plasticity-related immediate early gene Arc. Because traumatic stimuli initiate a characteristic early increase in polyamine metabolism, we hypothesized that treatment with the polyamine inhibitor alpha-difluoromethylornithine (DFMO) would reduce the adverse effects of single or combined injury on hippocampus structure and function. Hippocampal dependent cognitive impairments were quantified with the Morris water maze and showed that DFMO effectively reversed cognitive impairments after all injuries, particularly traumatic brain injury. Similar results were seen with respect to the expression of Arc protein, but not neurogenesis. Given that polyamines have been found to modulate inflammatory responses in the brain we also assessed the numbers of total and newly born activated microglia, and found reduced numbers of newly born cells. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, the present study provides new and compelling data regarding the potential use of DFMO as a potential countermeasure against the adverse effects of single or combined injury.


Assuntos
Lesões Encefálicas/fisiopatologia , Eflornitina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Animais , Lesões Encefálicas/tratamento farmacológico , Cognição/efeitos dos fármacos , Cognição/fisiologia , Cognição/efeitos da radiação , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/prevenção & controle , Eflornitina/uso terapêutico , Inibidores Enzimáticos/farmacologia , Hipocampo/efeitos da radiação , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Memória/fisiologia , Memória/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Poliaminas/antagonistas & inibidores , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/efeitos da radiação , Natação/fisiologia , Irradiação Corporal Total
3.
Hippocampus ; 22(3): 544-54, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21192069

RESUMO

Exposure to ionizing irradiation may affect brain functions directly, but may also change tissue sensitivity to a secondary insult such as trauma, stroke, or degenerative disease. To determine if a low dose of particulate irradiation sensitizes the brain to a subsequent injury, C56BL6 mice were exposed to brain only irradiation with 0.5 Gy of (56) Fe ions. Two months later, unilateral traumatic brain injury was induced using a controlled cortical impact system. Three weeks after trauma, animals received multiple BrdU injections and 30 days later were tested for cognitive performance in the Morris water maze. All animals were able to locate the visible and hidden platform during training; however, treatment effects were seen when spatial memory retention was assessed in the probe trial (no platform). Although sham and irradiated animals showed spatial memory retention, mice that received trauma alone did not. When trauma was preceded by irradiation, performance in the water maze was not different from sham-treated animals, suggesting that low-dose irradiation had a protective effect in the context of a subsequent traumatic injury. Measures of hippocampal neurogenesis showed that combined injury did not induce any changes greater that those seen after trauma or radiation alone. After trauma, there was a significant decrease in the percentage of neurons expressing the behaviorally induced immediate early gene Arc in both hemispheres, without associated neuronal loss. After combined injury there were no differences relative to sham-treated mice. Our results suggest that combined injury resulted in decreased alterations of our endpoints compared to trauma alone. Although the underlying mechanisms are not yet known, these results resemble a preconditioning, adaptive, or inducible-like protective response, where a sublethal or potentially injurious stimulus (i.e., irradiation) induces tolerance to a subsequent and potentially more damaging insult (trauma).


Assuntos
Lesões Encefálicas/metabolismo , Encéfalo/efeitos da radiação , Cognição/efeitos da radiação , Proteínas do Citoesqueleto/metabolismo , Aprendizagem em Labirinto/efeitos da radiação , Proteínas do Tecido Nervoso/metabolismo , Neurônios/efeitos da radiação , Animais , Encéfalo/metabolismo , Lesões Encefálicas/psicologia , Cognição/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Neurogênese/fisiologia , Neurogênese/efeitos da radiação , Neurônios/fisiologia
4.
Radiat Res ; 176(4): 521-6, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21823976

RESUMO

Ionizing radiation reduces the numbers of neurons expressing activity-regulated cytoskeleton-associated protein (Arc) in the hippocampal dentate gyrus (DG). It is currently unclear if that change relates to cognitive function. We assessed the effects of 1 Gy of head-only 56Fe-particle irradiation on hippocampus-dependent and hippocampus-independent fear conditioning and determined how those changes related to Arc expression within the DG. Irradiated mice that did not receive tone-shock pairings on day 1 showed less freezing in the same context on a second day and a lower fraction of Arc-expressing neurons in the free (lower) blade of the DG than sham-irradiated mice. Those data suggested reduced hippocampus-dependent spatial habituation learning. Changes in Arc expression in the free blade correlated positively with freezing in mice that did not receive tone-shock pairings. However, irradiated mice that did receive tone-shock pairings showed enhanced contextual freezing but a reduced percentage of Arc-expressing neurons in the enclosed (upper) blade. Changes in Arc expression correlated negatively with freezing in mice that received tone-shock pairings. In animals receiving cued fear conditioning, radiation did not affect cognitive performance or the fractions of Arc-expressing neurons. While the relationship between Arc expression and cognitive performance is complex, our data suggest that radiation effects on hippocampus-dependent cognition might depend on the prominence (salience) of environmental stimuli and blade-specific Arc expression.


Assuntos
Cognição/efeitos da radiação , Meio Ambiente , Hipocampo/fisiologia , Hipocampo/efeitos da radiação , Ferro , Crânio/efeitos da radiação , Animais , Comportamento Animal/fisiologia , Comportamento Animal/efeitos da radiação , Cognição/fisiologia , Condicionamento Psicológico/fisiologia , Condicionamento Psicológico/efeitos da radiação , Proteínas do Citoesqueleto/metabolismo , Giro Denteado/citologia , Giro Denteado/metabolismo , Giro Denteado/fisiologia , Giro Denteado/efeitos da radiação , Medo/fisiologia , Medo/psicologia , Medo/efeitos da radiação , Regulação da Expressão Gênica/efeitos da radiação , Hipocampo/citologia , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/efeitos da radiação
5.
Free Radic Biol Med ; 47(10): 1459-67, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19703553

RESUMO

Ionizing irradiation significantly affects hippocampal neurogenesis and is associated with cognitive impairments; these effects may be influenced by an altered microenvironment. Oxidative stress is a factor that has been shown to affect neurogenesis, and one of the protective pathways that deal with such stress involves the antioxidant enzyme superoxide dismutase (SOD). This study addressed what impact a deficiency in cytoplasmic (SOD1) or mitochondrial (SOD2) SOD has on radiation effects on hippocampal neurogenesis. Wild-type (WT) and SOD1 and SOD2 knockout (KO) mice received a single X-ray dose of 5 Gy, and quantification of the survival and phenotypic fate of newly generated cells in the dentate subgranular zone was performed 2 months later. Radiation exposure reduced neurogenesis in WT mice but had no apparent effect in KO mice, although baseline levels of neurogenesis were reduced in both SOD KO strains before irradiation. Additionally, there were marked and significant differences between WT and both KO strains in how irradiation affected newly generated astrocytes and activated microglia. The mechanism(s) responsible for these effects is not yet known, but a pilot in vitro study suggests a "protective" effect of elevated levels of superoxide. Overall, these data suggest that under conditions of SOD deficiency, there is a common pathway dictating how neurogenesis is affected by ionizing irradiation.


Assuntos
Neurogênese/efeitos da radiação , Neurônios/citologia , Neurônios/efeitos da radiação , Superóxido Dismutase/deficiência , Animais , Relação Dose-Resposta à Radiação , Heterozigoto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/enzimologia , Neurônios/metabolismo , Estresse Oxidativo , Radiação Ionizante , Superóxido Dismutase/metabolismo
6.
Cancer Res ; 68(23): 9763-70, 2008 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19047155

RESUMO

Therapeutic irradiation of the brain is commonly used to treat brain tumors but can induce cognitive impairments that can severely affect quality of life. The underlying mechanisms responsible for radiation-induced cognitive deficits are unknown but likely involve alterations in neuronal activity. To gain some mechanistic insight into how irradiation may affect hippocampal neurons known to be associated with cognitive function, we quantitatively assessed the molecular distribution of the behaviorally induced immediate-early gene Arc (activity-regulated cytoskeleton-associated protein) at the level of mRNA and the protein. Young adult C57BL/6J mice received whole-brain irradiation with 0 or 10 Gy, and 1 week or 2 months later, exploration of a novel environment was used to induce Arc expression. The fractions of neurons expressing Arc mRNA and Arc protein were detected using fluorescence in situ hybridization and immunocytochemistry, respectively. Our results showed that there was a significant reduction in the percentage of neurons expressing Arc protein 1 week after irradiation, whereas 2 months after irradiation, there was a reduction in the percentage of neurons expressing both Arc mRNA and Arc protein. Importantly, radiation-induced changes in Arc expression were not a result of neuronal cell loss. The changes observed at 2 months were associated with a significant increase in the number of activated microglia, supporting the idea that inflammation may contribute to neuronal dysfunction. These findings are the first to show that local brain irradiation initiates changes in hippocampal neurons that disrupt the activity patterns (Arc expression) associated with neuroplasticity and memory.


Assuntos
Irradiação Craniana/efeitos adversos , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/efeitos da radiação , Giro Denteado/efeitos da radiação , Genes Precoces/efeitos da radiação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/efeitos da radiação , Neurônios/efeitos da radiação , Animais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/metabolismo , Proteínas do Citoesqueleto/biossíntese , Giro Denteado/metabolismo , Giro Denteado/fisiologia , Hibridização in Situ Fluorescente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/biossíntese , Neurônios/metabolismo , Neurônios/fisiologia , Projetos Piloto , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Lesões Experimentais por Radiação/etiologia , Lesões Experimentais por Radiação/genética , Lesões Experimentais por Radiação/metabolismo , Ativação Transcricional/efeitos da radiação
7.
Radiat Res ; 169(6): 626-32, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18494546

RESUMO

Exposure to heavy-ion radiation is considered a potential health risk in long-term space travel. In the central nervous system (CNS), loss of critical cellular components may lead to performance decrements that could ultimately compromise mission goals and long-term quality of life. Hippocampal-dependent cognitive impairments occur after exposure to ionizing radiation, and while the pathogenesis of this effect is not yet clear, it may involve the production of newly born neurons (neurogenesis) in the hippocampal dentate gyrus. We irradiated mice with 0.5-4 Gy of (56)Fe ions and 2 months later quantified neurogenesis and numbers of activated microglia as a measure of neuroinflammation in the dentate gyrus. Results showed that there were few changes after 0.5 Gy, but that there was a dose-related decrease in hippocampal neurogenesis and a dose-related increase in numbers of newly born activated microglia from 0.5-4.0 Gy. While those findings were similar to what was reported after X irradiation, there were also some differences, particularly in the response of newly born glia. Overall, this study showed that hippocampal neurogenesis was sensitive to relatively low doses of (56)Fe particles, and that those effects were associated with neuroinflammation. Whether these changes will result in functional impairments or if/how they can be managed are topics for further investigation.


Assuntos
Encéfalo/patologia , Hipocampo/metabolismo , Ferro/química , Animais , Encéfalo/metabolismo , Encéfalo/efeitos da radiação , Sistema Nervoso Central/efeitos da radiação , Relação Dose-Resposta à Radiação , Hipocampo/efeitos da radiação , Inflamação , Íons , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Microglia/efeitos da radiação , Neurônios/metabolismo , Fenótipo , Raios X
8.
Free Radic Biol Med ; 42(8): 1133-45; discussion 1131-2, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17382195

RESUMO

Ionizing irradiation results in significant alterations in hippocampal neurogenesis that are associated with cognitive impairments. Such effects are influenced, in part, by alterations in the microenvironment within which the neurogenic cells exist. One important factor that may affect neurogenesis is oxidative stress, and this study was done to determine if and how the extracellular isoform of superoxide dismutase (SOD3, EC-SOD) mediated radiation-induced alterations in neurogenic cells. Wild-type (WT) and EC-SOD knockout (KO) mice were irradiated with 5 Gy and acute (8-48 h) cellular changes and long-term changes in neurogenesis were quantified. Acute radiation responses were not different between genotypes, suggesting that the absence of EC-SOD did not influence mechanisms responsible for acute cell death after irradiation. On the other hand, the extent of neurogenesis was decreased by 39% in nonirradiated KO mice relative to WT controls. In contrast, while neurogenesis was decreased by nearly 85% in WT mice after irradiation, virtually no reduction in neurogenesis was observed in KO mice. These findings show that after irradiation, an environment lacking EC-SOD is much more permissive in the context of hippocampal neurogenesis. This finding may have a major impact in developing strategies to reduce cognitive impairment after cranial irradiation.


Assuntos
Transtornos Cognitivos/etiologia , Hipocampo/efeitos da radiação , Neurônios/efeitos da radiação , Radiação Ionizante , Superóxido Dismutase/deficiência , Superóxido Dismutase/genética , Animais , Córtex Cerebral/enzimologia , Córtex Cerebral/efeitos da radiação , Hipocampo/enzimologia , Masculino , Camundongos , Camundongos Knockout , Microglia/enzimologia , Neurônios/fisiologia , Estresse Oxidativo , Superóxido Dismutase/metabolismo , Superóxido Dismutase-1
9.
Exp Neurol ; 202(1): 189-99, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16876159

RESUMO

Clinical and experimental data show that traumatic brain injury (TBI)-induced cognitive changes are often manifest as deficits in hippocampal-dependent functions of spatial information processing. The underlying mechanisms for these effects have remained elusive, although recent studies have suggested that the changes in neuronal precursor cells in the dentate subgranular zone (SGZ) of the hippocampus might be involved. Here, we assessed the effects of unilateral controlled cortical impact on neurogenic cell populations in the SGZ in 2-month-old male C57BL6 mice by quantifying numbers of dying cells (TUNEL), proliferating cells (Ki-67) and immature neurons (Doublecortin, Dcx) up to 14 days after TBI. Dying cells were seen 6 h after injury, peaked at 24 h and returned to control levels at 14 days. Proliferating cells were decreased on the ipsilateral and contralateral sides at all the time points studied except 48 h after injury when a transient increase was seen. Simultaneously, immature neurons were reduced up to 84% relative to controls on the ipsilateral side. In the first week post-TBI, reduced numbers of Dcx-positive cells were also seen in the contralateral side; a return to control levels occurred at 14 days. To determine if these changes translated into longer-term effects, BrdU was administered 1 week post-injury and 3 weeks later the phenotypes of the newly born cells were assessed. TBI induced decreases in the numbers of BrdU-positive cells and new neurons (BrdU/NeuN) on the ipsilateral side without apparent changes on the contralateral side, whereas astrocytes (BrdU/GFAP) were increased on the ipsilateral side and activated microglia (BrdU/CD68) were increased on both ipsi- and contralateral sides. No differences were noted in oligodendrocytes (BrdU/NG2). Taken together, these data demonstrate that TBI alters both neurogenesis and gliogenesis. Such alterations may play a contributory role in TBI-induced cognitive impairment.


Assuntos
Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Hipocampo/patologia , Neurônios/fisiologia , Organogênese/fisiologia , Animais , Bromodesoxiuridina/metabolismo , Morte Celular/fisiologia , Proliferação de Células , Modelos Animais de Doenças , Proteína Duplacortina , Lateralidade Funcional , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica/métodos , Marcação In Situ das Extremidades Cortadas/métodos , Antígeno Ki-67/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores CCR2 , Receptores de Quimiocinas/metabolismo , Células-Tronco/patologia , Fatores de Tempo
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