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1.
Front Mol Neurosci ; 11: 338, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30271324

RESUMO

Although epidemiological evidence suggests significant sex and gender-based differences in stroke risk and recovery, females have been widely under-represented in preclinical stroke research. The neurovascular sequelae of brain ischemia in females, in particular, are largely uncertain. We set out to address this gap by a multimodal in vivo study of neurovascular recovery from endothelin-1 model of cortical focal-stroke in sham vs. ovariectomized female rats. Three weeks post ischemic insult, sham operated females recapitulated the phenotype previously reported in male rats in this model, of normalized resting perfusion but sustained peri-lesional cerebrovascular hyperreactivity. In contrast, ovariectomized (Ovx) females showed reduced peri-lesional resting blood flow, and elevated cerebrovascular responsivity to hypercapnia in the peri-lesional and contra-lateral cortices. Electrophysiological recordings showed an attenuation of theta to low-gamma phase-amplitude coupling in the peri-lesional tissue of Ovx animals, despite relative preservation of neuronal power. Further, this chronic stage neuronal network dysfunction was inversely correlated with serum estradiol concentration. Our pioneering data demonstrate dramatic differences in spontaneous recovery in the neurovascular unit between Ovx and Sham females in the chronic stage of stroke, underscoring the importance of considering hormonal-dependent aspects of the ischemic sequelae in the development of novel therapeutic approaches and patient recruitment in clinical trials.

2.
Theranostics ; 8(17): 4824-4836, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30279740

RESUMO

Traumatic brain injury (TBI) research has focused on moderate to severe injuries as their outcomes are significantly worse than those of a mild TBI (mTBI). However, recent epidemiological evidence has indicated that a series of even mild TBIs greatly increases the risk of neurodegenerative and psychiatric disorders. Neuropathological studies of repeated TBI have identified changes in neuronal ionic concentrations, axonal injury, and cytoskeletal damage as important determinants of later life neurological and mood compromise; yet, there is a paucity of data on the contribution of neurogliovascular dysfunction to the progression of repeated TBI and alterations of brain function in the intervening period. Methods: Here, we established a mouse model of repeated TBI induced via three electromagnetically actuated impacts delivered to the intact skull at three-day intervals and determined the long-term deficits in neurogliovascular functioning in Thy1-ChR2 mice. Two weeks post the third impact, cerebral blood flow and cerebrovascular reactivity were measured with arterial spin labelling magnetic resonance imaging. Neuronal function was investigated through bilateral intracranial electrophysiological responses to optogenetic photostimulation. Vascular density of the site of impacts was measured with in vivo two photon fluorescence microscopy. Pathological analysis of neuronal survival and astrogliosis was performed via NeuN and GFAP immunofluorescence. Results: Cerebral blood flow and cerebrovascular reactivity were decreased by 50±16% and 70±20%, respectively, in the TBI cohort relative to sham-treated animals. Concomitantly, electrophysiological recordings revealed a 97±1% attenuation in peri-contusional neuronal reactivity relative to sham. Peri-contusional vascular volume was increased by 33±2% relative to sham-treated mice. Pathological analysis of the peri-contusional cortex demonstrated astrogliosis, but no changes in neuronal survival. Conclusion: This work provides the first in-situ characterization of the long-term deficits of the neurogliovascular unit following repeated TBI. The findings will help guide the development of diagnostic markers as well as therapeutics targeting neurogliovascular dysfunction.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Transtornos Cerebrovasculares/patologia , Modelos Animais de Doenças , Neuroglia/patologia , Neurônios/patologia , Animais , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Transtornos Cerebrovasculares/diagnóstico por imagem , Imagem por Ressonância Magnética , Camundongos , Microscopia de Fluorescência , Optogenética , Recidiva
3.
Neuroscience ; 371: 166-177, 2018 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-29229555

RESUMO

To better understand the effects of a diet high in fat, sugar, and sodium on cerebrovascular function, Sprague Dawley rats were chronically exposed to a Cafeteria diet. Resting cerebral perfusion and cerebrovascular reactivity was quantified using continuous arterial spin labeling (CASL) magnetic resonance imaging (MRI). In addition, structural changes to the cerebrovasculature and susceptibility to ischemic lesion were examined. Compared to control animals fed standard chow (SD), Cafeteria diet (CAF) rats exhibited increased resting brain perfusion in the hippocampus and reduced cerebrovascular reactivity in response to 10% inspired CO2 challenges in both the hippocampus and the neocortex. CAF rats switched to chow for one month (SWT) exhibited improved resting perfusion in the hippocampus as well as improved cerebrovascular reactivity in the neocortex. However, the diet switch did not correct cerebrovascular reactivity in the hippocampus. These changes were not accompanied by alterations in the structural integrity of the cerebral microvasculature, examined using rat endothelial cell antigen-1 (RECA-1) and immunoglobulin G (IgG) immunostaining. Also, the extent of tissue damage induced by endothelin-1 injection into sensorimotor cortex was not affected by the Cafeteria diet. These results demonstrate that short-term consumption of an ultra-processed diet reduces cerebrovascular reactivity. This effect persists after dietary normalization despite recovery of peripheral symptomatology.


Assuntos
Circulação Cerebrovascular/fisiologia , Dieta Ocidental/efeitos adversos , Hemodinâmica/fisiologia , Animais , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Modelos Animais de Doenças , Endotelina-1 , Hipocampo/irrigação sanguínea , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Síndrome Metabólica/diagnóstico por imagem , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Distribuição Aleatória , Ratos Sprague-Dawley , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
4.
J Magn Reson Imaging ; 46(2): 505-517, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28703413

RESUMO

PURPOSE: Stroke is the leading cause of adult disability worldwide. The absence of more effective interventions in the chronic stage-that most patients stand to benefit from-reflects uncertainty surrounding mechanisms that govern recovery. The present work investigated the effects of a novel treatment (selective cyclooxygenase-1, COX-1, inhibition) in a model of focal ischemia. MATERIALS AND METHODS: FR122047 (COX-1 inhibitor) was given beginning 7 days following stroke (cortical microinjection of endothelin-1) in 23 adult male rats. Longitudinal continuous-arterial-spin-labeling was performed prior to treatment (7 days), and repeated following treatment (21 days) on a 7T magnetic resonance imaging (MRI) system to estimate resting perfusion and reactivity to hypercapnia. These in vivo measurements were buttressed by immunohistochemistry. RESULTS: Stroke caused an increase in perilesional resting perfusion (peri-/contralesional perfusion ratio of 170 ± 10%) and perfusion responses to hypercapnia (180 ± 10%) at 7 days. At 21 days, placebo-administered rats showed normalized perilesional perfusion (100 ± 20%) but persistent hyperreactivity (190 ± 20%). Treated animals exhibited sustained perilesional hyperperfusion (180 ± 10%). Further, reactivity lateralization did not persist following treatment (peri- vs. contralesional reactivity: P = 0.002 at 7 vs. P = 0.2 at 21 days). Hemodynamic changes were accompanied by neuronal loss, increased endothelial density, and widespread microglial and astrocytic activation. Moreover, relative to controls, treated rats showed increased perilesional neuronal survival (22 ± 1% vs. 14.9 ± 0.8%, P = 0.02) and decreased microglia/macrophage recruitment (17 ± 1% vs. 20 ± 1%, P = 0.05). Finally, perilesional perfusion was correlated with neuronal survival (slope = 0.14 ± 0.05; R2 = 0.7, P = 0.03). CONCLUSION: These findings shed light on the role of COX-1 in chronic ischemic injury and suggest that delayed selective COX-1 inhibition exerts multiple beneficial effects on the neurogliovascular unit. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. MAGN. RESON. IMAGING 2017;46:505-517.


Assuntos
Inibidores de Ciclo-Oxigenase/farmacologia , Isquemia/diagnóstico por imagem , Imagem por Ressonância Magnética , Proteínas de Membrana/antagonistas & inibidores , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/fisiopatologia , Animais , Ciclo-Oxigenase 1 , Modelos Animais de Doenças , Endotelina-1/química , Macrófagos/patologia , Masculino , Microglia/patologia , Neuroglia/patologia , Neurônios/patologia , Perfusão , Piperazinas/química , Ratos , Ratos Sprague-Dawley , Marcadores de Spin , Tiazóis/química
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