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1.
Sci Adv ; 7(42): eabg6702, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34652936

RESUMO

In the coming decade, astronauts will travel back to the moon in preparation for future Mars missions. Exposure to galactic cosmic radiation (GCR) is a major obstacle for deep space travel. Using multivariate principal components analysis, we found sex-dimorphic responses in mice exposed to accelerated charged particles to simulate GCR (GCRsim); males displayed impaired spatial learning, whereas females did not. Mechanistically, these GCRsim-induced learning impairments corresponded with chronic microglia activation and synaptic alterations in the hippocampus. Temporary microglia depletion shortly after GCRsim exposure mitigated GCRsim-induced deficits measured months after the radiation exposure. Furthermore, blood monocyte levels measured early after GCRsim exposure were predictive of the late learning deficits and microglia activation measured in the male mice. Our findings (i) advance our understanding of charged particle­induced cognitive challenges, (ii) provide evidence for early peripheral biomarkers for identifying late cognitive deficits, and (iii) offer potential therapeutic strategies for mitigating GCR-induced cognitive loss.

2.
J Neuroinflammation ; 18(1): 232, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34654458

RESUMO

BACKGROUND: Brain-resident microglia have a distinct origin compared to macrophages in other organs. Under physiological conditions, microglia are maintained by self-renewal from the local pool, independent of hematopoietic progenitors. Pharmacological depletion of microglia during whole-brain radiotherapy prevents synaptic loss and long-term recognition memory deficits. However, the origin or repopulated cells and the mechanisms behind these protective effects are unknown. METHODS: CD45low/int/CD11b+ cells from naïve brains, irradiated brains, PLX5622-treated brains and PLX5622 + whole-brain radiotherapy-treated brains were FACS sorted and sequenced for transcriptomic comparisons. Bone marrow chimeras were used to trace the origin and long-term morphology of repopulated cells after PLX5622 and whole-brain radiotherapy. FACS analyses of intrinsic and exotic synaptic compartments were used to measure phagocytic activities of microglia and repopulated cells. In addition, concussive brain injuries were given to PLX5622 and brain-irradiated mice to study the potential protective functions of repopulated cells after PLX5622 + whole-brain radiotherapy. RESULTS: After a combination of whole-brain radiotherapy and microglia depletion, repopulated cells are brain-engrafted macrophages that originate from circulating monocytes. Comparisons of transcriptomes reveal that brain-engrafted macrophages have an intermediate phenotype that resembles both monocytes and embryonic microglia. In addition, brain-engrafted macrophages display reduced phagocytic activity for synaptic compartments compared to microglia from normal brains in response to a secondary concussive brain injury. Importantly, replacement of microglia by brain-engrafted macrophages spare mice from whole-brain radiotherapy-induced long-term cognitive deficits, and prevent concussive injury-induced memory loss. CONCLUSIONS: Brain-engrafted macrophages prevent radiation- and concussion-induced brain injuries and cognitive deficits.


Assuntos
Lesões Encefálicas/prevenção & controle , Encéfalo/fisiologia , Encéfalo/efeitos da radiação , Fracionamento da Dose de Radiação , Macrófagos/fisiologia , Macrófagos/transplante , Animais , Lesões Encefálicas/radioterapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
3.
Brain Behav Immun ; 98: 122-135, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34403733

RESUMO

Traumatic brain injury (TBI) is one of the leading causes of long-term neurological disability in the world. Currently, there are no therapeutics for treating the deleterious consequences of brain trauma; this is in part due to a lack of complete understanding of cellular processes that underlie TBI-related pathologies. Following TBI, microglia, the brain resident immune cells, turn into a "reactive" state characterized by the production of inflammatory mediators that contribute to the development of cognitive deficits. Utilizing multimodal, state-of-the-art techniques that widely span from ultrastructural analysis to optogenetic interrogation of circuit function, we investigated the reactive microglia phenotype one week after injury when learning and memory deficits are also measured. Microglia displayed increased: (i) phagocytic activity in vivo, (ii) synaptic engulfment, (iii) increased neuronal contact, including with dendrites and somata (termed 'satellite microglia'). Functionally, satellite microglia might impact somatic inhibition as demonstrated by the associated reduction in inhibitory synaptic drive. Cumulatively, here we demonstrate novel microglia-mediated mechanisms that may contribute to synaptic loss and cognitive impairment after traumatic brain injury.


Assuntos
Lesões Encefálicas Traumáticas , Disfunção Cognitiva , Animais , Encéfalo , Lesões Encefálicas Traumáticas/complicações , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Microglia
4.
J Neurotrauma ; 37(11): 1370-1380, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31884883

RESUMO

Mild repetitive traumatic brain injury (rTBI) induces chronic behavioral and cognitive alterations and increases the risk for dementia. Currently, there are no therapeutic strategies to prevent or mitigate chronic deficits associated with rTBI. Previously we developed an animal model of rTBI that recapitulates the cognitive and behavioral deficits observed in humans. We now report that rTBI results in an increase in risk-taking behavior in male but not female mice. This behavioral phenotype is associated with chronic activation of the integrated stress response and cell-specific synaptic alterations in the type A subtype of layer V pyramidal neurons in the medial prefrontal cortex. Strikingly, by briefly treating animals weeks after injury with ISRIB, a selective inhibitor of the integrated stress response (ISR), we (1) relieve ISR activation, (2) reverse the increased risk-taking behavioral phenotype and maintain this reversal, and (3) restore cell-specific synaptic function in the affected mice. Our results indicate that targeting the ISR even at late time points after injury can permanently reverse behavioral changes. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat rTBI-induced behavioral dysfunction.


Assuntos
Acetamidas/administração & dosagem , Concussão Encefálica/tratamento farmacológico , Concussão Encefálica/psicologia , Cicloexilaminas/administração & dosagem , Assunção de Riscos , Caracteres Sexuais , Animais , Concussão Encefálica/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/administração & dosagem
5.
Pediatr Res ; 14(3): 183-6, 1980 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-6992081

RESUMO

The present investigation was undertaken to find the differences, if any, in the pattern of nephrotoxic acute renal failure (HgCl2, 4.7 mg/kg body weight SC), in the developing rat and its relationship to the renin angiotensin system. No differences in renal cortical renin content were found between 2, 4, and 8 week olds, but plasma renin concentration was highest at 2 weeks and declined with age. Plasma renin was significantly increased in all groups 6 hr after HgCl2 injection, and the percentage of increase was highest in the 4 week olds. Despite these differences in initial plasma renin and in changes in plasma renin after HgCl2, the pattern of acute renal failure (as assessed by changes in blood urea nitrogen) was similar in the three groups for the first three days. Subsequently, the 4 and 8 week olds exhibited recovery (blood urea nitrogen began to decline), whereas blood urea nitrogen continued to increase to the fifth day in the 2 week olds. The mortality was highest in this group. No simple correlation was observed between basal renal renin, plasma renin, the increase in plasma renin following HgCl2 injection, and the pattern or severity of acute renal failure.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Angiotensina II/sangue , Renina/sangue , Injúria Renal Aguda/sangue , Fatores Etários , Animais , Modelos Animais de Doenças , Feminino , Masculino , Mercúrio , Ratos
6.
J Lab Clin Med ; 91(4): 660-5, 1978 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-641389

RESUMO

These experiments were designed to test the hypothesis that renal renin is an important determinant of the severity of acute renal failure in rats. Two-kidney "Goldblatt rats" were prepared by constricting the left renal arteries with silver clips and leaving the contralateral arteries untouched. After 2 to 5 weeks, the clips were removed, and HgCl2 was injected in 13 rats (1 ml/kg body weight of 4.7 mg of HgCl2 per milliliter of 140 mM NaCl). These rats exhibited the characteristic features of acute renal failure 24 hr later. As compared with a group of seven similarly treated rats injected with 140 mM NaCl without HgCl2, GFR, V, and UNaV were reduced, and %FE H2O and %FE Na were increased. As assessed by these parameters, severity of functional impairment was equal in both kidneys. However, cortical renin was 28 times higher in the left kidney than in the right. These results are inconsistent with the hypothesis.


Assuntos
Injúria Renal Aguda/metabolismo , Córtex Renal/metabolismo , Renina/metabolismo , Injúria Renal Aguda/induzido quimicamente , Angiotensina II/metabolismo , Animais , Diurese , Taxa de Filtração Glomerular , Mercúrio , Ratos , Sódio/urina , Cloreto de Sódio/metabolismo , Ácido p-Aminoipúrico/metabolismo
7.
Nephron ; 22(4-6): 529-37, 1978.
Artigo em Inglês | MEDLINE | ID: mdl-740114

RESUMO

The interrelationships of renal cortical renin content RCRC, sodium chloride excreting and the severity of renal failure were studied in the glycerol-induced acute myohemoglobinuric renal failure model in the rat. Protocols were designed to increase sodium chloride excretion without necessarily resulting in RCRC depletion. Our data fail to demonstrate a relationship between RCRC and severity of renal failure, but they demonstrate an excellent inverse correlation between the sodium chloride excretion of the animals in the 24 h prior to glycerol administration and the severity of resulitng renal failure. The protection of long-term saline-drinking animals should properly be ascribed to the associated natriuresis which develops much before RCRC depletion during the time course of saline drinking. The exact mechanism by which natriuresis exerts its protective effect needs further elucidation, but our data argue against a major role for RCRC in the pathogenesis of acute experimental renal failure.


Assuntos
Injúria Renal Aguda/prevenção & controle , Hemoglobinúria/prevenção & controle , Córtex Renal/metabolismo , Mioglobinúria/prevenção & controle , Natriurese , Renina/metabolismo , Injúria Renal Aguda/induzido quimicamente , Animais , Nitrogênio da Ureia Sanguínea , Cloretos/urina , Modelos Animais de Doenças , Feminino , Glicerol , Hemoglobinúria/induzido quimicamente , Mioglobinúria/induzido quimicamente , Potássio/urina , Ratos , Cloreto de Sódio/urina
8.
Am J Physiol ; 233(3): F247-52, 1977 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-910921

RESUMO

One to four weeks after the left renal artery was clipped and the contralateral kidney was left untouched in Sprague-Dawley rats (two-kidney Goldblatt preparation), the clips were removed under ether anesthesia and 10 ml/kg body wt of either 150 mM NaCl (control) or 50% glycerol in water (experimental) were injected intramuscularly. The next day the rats were anesthetized (sodium pentobarbital) and the renal function of both kidneys was measured, after which the renal cortical renin content was measured by incubation of tissue homogenate with angiotensinase-free rat renin substrate. Radioimmunoassay was used to determine the rate of angiotensin I production. Compared with controls, both kidneys of glycerol-injected rats had reduced GFR (left 28, right 18% of controls), increased percentage of fractional water excretion (left 5, right 6 times controls), and increased percentage of fractional Na excretion (left 3, right 4 times controls). Despite large differences in renal renin (left 28, 676, right 1,329 ng angiotensin I/h per mg protein), the extent of renal failure produced by glycerol was equal in the left and right kidneys. These results are inconsistent with the hypothesis that renal renin content is directly related to the severity of glycerol-induced renal failure in rats.


Assuntos
Injúria Renal Aguda/induzido quimicamente , Glicerol , Rim/metabolismo , Renina/metabolismo , Injúria Renal Aguda/metabolismo , Animais , Modelos Animais de Doenças , Taxa de Filtração Glomerular , Rim/fisiopatologia , Ratos
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