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3.
Exp Neurol ; 373: 114656, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38114054

RESUMO

Studies have reported that Prosaposin (PSAP) is neuroprotective in cerebrovascular diseases. We hypothesized that PSAP would reduce infarct volume by attenuating neuronal apoptosis and promoting cell survival through G protein-coupled receptor 37(GPR37)/PI3K/Akt/ASK1 pathway in middle cerebral artery occlusion (MCAO) rats. Two hundred and thirty-five male and eighteen female Sprague-Dawley rats were used. Recombinant human PSAP (rPSAP) was administered intranasally 1 h (h) after reperfusion. PSAP small interfering ribonucleic acid (siRNA), GPR37 siRNA, and PI3K specific inhibitor LY294002 were administered intracerebroventricularly 48 h before MCAO. Infarct volume, neurological score, immunofluorescence staining, Western blot, Fluoro-Jade C (FJC) and TUNEL staining were examined. The expression of endogenous PSAP and GPR37 were increased after MCAO. Intranasal administration of rPSAP reduced brain infarction, neuronal apoptosis, and improved both short- and long-term neurological function. Knockdown of endogenous PSAP aggravated neurological deficits. Treatment with exogenous rPSAP increased PI3K expression, Akt and ASK1 phosphorylation, and Bcl-2 expression; phosphorylated-JNK and Bax levels were reduced along with the number of FJC and TUNEL positive neurons. GPR37 siRNA and LY294002 abolished the anti-apoptotic effect of rPSAP at 24 h after MCAO. In conclusion, rPSAP attenuated neuronal apoptosis and improved neurological function through GPR37/PI3K/Akt/ASK1 pathway after MCAO in rats. Therefore, further exploration of PSAP as a potential treatment option in ischemic stroke is warranted.


Assuntos
Fármacos Neuroprotetores , Proteínas Proto-Oncogênicas c-akt , Ratos , Masculino , Feminino , Humanos , Animais , Ratos Sprague-Dawley , Proteínas Proto-Oncogênicas c-akt/metabolismo , Infarto da Artéria Cerebral Média/complicações , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Saposinas/metabolismo , Saposinas/farmacologia , Saposinas/uso terapêutico , Transdução de Sinais , Administração Intranasal , Apoptose , RNA Interferente Pequeno/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico
4.
Sci Rep ; 13(1): 17149, 2023 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-37816947

RESUMO

Vascular pulsation at the optic nerve head (ONH) reflects vessel properties. Reduction in the stimulated retinal vasodilatory capacity has been reported in diabetes, but its relation with vascular pulsation is unknown. Here we report a new retinal imaging system for correlative assessment of ONH vascular pulsation and stimulated retinal vasodilation. Retinal reflectance images were acquired before and during light flicker stimulation to quantify arterial and venous vasodilation (DAR, DVR) in subjects with and without diabetic retinopathy (N = 25). ONH vascular pulsation amplitude and frequency (PA, PF), were quantified by curve fitting of periodic intensity waveforms acquired in retinal vasculature (RV) and ONH tissue (ONHT) regions. The relationships between pulsation metrics, heart rate (HR), intraocular pressure (IOP), and vasodilatory responses were evaluated. Pulsation metrics were not significantly different between regions (p ≥ 0.70). In RV, inter-image variabilities of PA and PF were 10% and 6%, whereas inter-observer variabilities were 7% and 2% respectively. In both regions, PF was correlated with HR (p ≤ 0.001). PA was associated with DAR in both regions (p ≤ 0.03), but only with DVR in RV (p ≤ 0.05). Overall, ONH vascular pulsation was associated with stimulated retinal vasodilation, suggesting diabetes may have concomitant effects on retinal vasculature compliance and neurovascular coupling.


Assuntos
Diabetes Mellitus , Disco Óptico , Humanos , Disco Óptico/irrigação sanguínea , Vasodilatação , Retina/diagnóstico por imagem , Vasos Retinianos , Pressão Intraocular
5.
Microvasc Res ; 148: 104535, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37024073

RESUMO

Impairments of blood flow and autoregulation have been implicated in diabetic retinopathy and glaucoma. Thus, identifying biomarkers of retinal vascular compliance and regulatory capacity is of potential value for understanding the pathophysiology and evaluating onset or progression of disease. Pulse wave velocity (PWV) represents the speed of the pulse-propagated pressure wave within blood vessels and has shown promise as a marker of vascular compliance. The purpose of the current study was to report a method for comprehensive assessment of retinal PWV based on spectral analysis of pulsatile intravascular intensity waveforms and determine alterations due to experimental ocular hypertension. Retinal PWV was linearly related to vessel diameter. Increased retinal PWV was associated with elevated intraocular pressure. Retinal PWV has the potential to serve as a vasoregulation biomarker for investigating vascular factors that contribute to the development of retinal diseases in animal models.


Assuntos
Glaucoma , Hipertensão , Hipertensão Ocular , Humanos , Análise de Onda de Pulso , Velocidade do Fluxo Sanguíneo , Resistência Vascular/fisiologia , Hipertensão Ocular/diagnóstico , Biomarcadores , Pressão Sanguínea/fisiologia
6.
Exp Eye Res ; 230: 109439, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36931487

RESUMO

We here attempt to improve quantification of the ischemic retinal insult, that is, what is imposed on the retinal tissue by ischemia, especially in experimental models of ischemia. The ischemic retinal insult initiates the ischemic retinal injury (or outcome). Accordingly, it is reasonable to assume that the better the quantification of the insult, the better the correlation with, and thereby estimation of, the injury. The insult seldom has been quantified in terms of the relevant physiological factors, especially in connection with the rate of oxygen delivery (DO2). We here propose the accumulated oxygen deficit (AO2D) as an indicator of the ischemic retinal insult. We hypothesized that AO2D is correlated with the rate of oxygen metabolism measured 1 h after reperfusion following an episode of ischemia (MO2_1_Hr). Previously, we showed that MO2_1_Hr is related to the electroretinogram amplitude and the retinal thickness when they are measured seven days after reperfusion. We studied 27 rats, as well as 26 rats from our published data on retinal ischemia in which we had measurements of DO2 and duration of ischemia (T) of various levels and durations. We also measured DO2 in 29 rats treated with sham surgery. Ischemia was induced by either ipsilateral or bilateral common carotid artery occlusion or by ophthalmic artery occlusion, which gave a wide range of DO2. DO2 and MO2_1_Hr were evaluated based on three types of images: 1) red-free images to measure vessel diameters, 2) fluorescence images to estimate blood velocities by the displacement of intravascular fluorescent microspheres over time, and 3) phosphorescence images to quantify vascular oxygen tension from the phosphorescence lifetime of an intravascular oxygen sensitive phosphor. Loss of oxygen delivery (DO2L) was calculated as the difference between DO2 under normal/sham condition and DO2 during ischemia. AO2D, a volume of oxygen, was calculated as the product DO2L and T. Including all data, the linear relationship between AO2D and MO2_1_Hr was significant (R2 = 0.261, P = 0.0003). Limiting data to that in which T or DO2L was maximal also yielded significant relationships, and revealed that DO2L at a long duration of ischemia contributed disproportionately more than T to MO2_1_Hr. We discuss the potential of AO2D for quantifying the ischemic retinal insult, predicting the ischemic retinal injury and evaluating the likelihood of infarction.


Assuntos
Oxigênio , Doenças Retinianas , Ratos , Animais , Oxigênio/metabolismo , Retina/metabolismo , Doenças Retinianas/metabolismo , Vasos Retinianos/metabolismo , Isquemia/metabolismo
7.
Exp Eye Res ; 225: 109278, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36252653

RESUMO

Ischemia-reperfusion (I/R) is an established model for retinal neurodegeneration. However, there is limited knowledge of retinal physiological metrics and their relationships to retinal function and morphology in the I/R model. The purpose of the study was to test the hypotheses that retinal hemodynamic and oxygen metrics are impaired and associated with visual dysfunction, retinal thinning, and retinal ganglion cell (RGC) loss due to I/R injury. Intraocular pressure (IOP) was increased in one eye of 10 rats for 90 min followed by reperfusion. Fellow eyes served as controls. After one week of reperfusion, multimodal imaging was performed to quantify total retinal blood flow (TRBF) and retinal vascular oxygen contents. Retinal oxygen delivery (DO2) and metabolism (MO2) were calculated. Pattern-evoked electroretinography (PERG) and optical coherence tomography were performed to measure RGC function and retinal thicknesses, respectively. RGCs were counted from retina whole mounts. After one week of reperfusion, TRBF was lower in study eyes than in control eyes (p < 0.0003). Similarly, DO2 and MO2 were reduced in study eyes compared to control eyes (p < 0.003). PERG amplitude, TRT, IRT, ORT, and RGCs were also lower in study eyes (p ≤ 0.01). DO2 and MO2 were correlated with PERG amplitude, TRT, IRT, and ORT (r ≥ 0.6, p ≤ 0.005). The findings improve knowledge of physiological metrics affected by I/R injury and have the potential for identifying biomarkers of injury and outcomes for evaluating experimental treatments.


Assuntos
Glaucoma , Hipertensão Ocular , Traumatismo por Reperfusão , Ratos , Animais , Oxigênio/metabolismo , Benchmarking , Retina/metabolismo , Hipertensão Ocular/metabolismo , Traumatismo por Reperfusão/metabolismo , Reperfusão , Isquemia/metabolismo , Hemodinâmica , Eletrorretinografia , Modelos Animais de Doenças
8.
Oxid Med Cell Longev ; 2022: 6422202, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36035227

RESUMO

Background: Recent cerebrovascular recanalization therapy clinical trials have validated delayed recanalization in patients outside of the conventional window. However, a paucity of information on the pathophysiology of delayed recanalization and favorable outcomes remains. Since macrophages are extensively studied in tissue repair, we anticipate that they may play a critical role in delayed recanalization after ischemic stroke. Methods: In adult male Sprague-Dawley rats, two ischemic stroke groups were used: permanent middle cerebral artery occlusion (pMCAO) and delayed recanalization at 3 days following middle cerebral artery occlusion (rMCAO). To evaluate outcome, brain morphology, neurological function, macrophage infiltration, angiogenesis, and neurodegeneration were reported. Confirming the role of macrophages, after their depletion, we assessed angiogenesis and neurodegeneration after delayed recanalization. Results: No significant difference was observed in the rate of hemorrhage or animal mortality among pMCAO and rMCAO groups. Delayed recanalization increased angiogenesis, reduced infarct volumes and neurodegeneration, and improved neurological outcomes compared to nonrecanalized groups. In rMCAO groups, macrophage infiltration contributed to increased angiogenesis, which was characterized by increased vascular endothelial growth factor A and platelet-derived growth factor B. Confirming these links, macrophage depletion reduced angiogenesis, inflammation, neuronal survival in the peri-infarct region, and favorable outcome following delayed recanalization. Conclusion: If properly selected, delayed recanalization at day 3 postinfarct can significantly improve the neurological outcome after ischemic stroke. The sanguineous exposure of the infarct/peri-infarct to macrophages was essential for favorable outcomes after delayed recanalization at 3 days following ischemic stroke.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média , Macrófagos , Masculino , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular
9.
Cells ; 11(15)2022 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-35954257

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that affects the brain and retina and lacks reliable biomarkers for early diagnosis. As amyloid beta (Aß) manifestations emerge prior to clinical symptoms and plaques of amyloid may cause vascular damage, identification of retinal vascular biomarkers may improve knowledge of AD pathophysiology and potentially serve as therapeutic targets. The purpose of the current study was to test the hypothesis that retinal hemodynamic and oxygen metrics are altered in 5XFAD mice. METHODS: Thirty-two male mice were evaluated at 3 months of age: sixteen 5XFAD transgenic and sixteen wild-type mice. Spectral-domain optical coherence tomography, vascular oxygen tension, and blood flow imaging were performed in one eye of each mouse. After imaging, the imaged and fellow retinal tissues were submitted for histological sectioning and amyloid protein analysis, respectively. Protein analysis was also performed on the brain tissues. RESULTS: Retinal physiological changes in venous diameter and blood velocity, arterial and venous oxygen contents, coupled with anatomical alterations in the thickness of retinal cell layers were detected in 5XFAD mice. Moreover, an increase in Aß42 levels in both the retina and brain tissues was observed in 5XFAD mice. Significant changes in retinal oxygen delivery, metabolism, or extraction fraction were not detected. Based on compiled data from both groups, arterial oxygen content was inversely related to venous blood velocity and nerve fiber/ganglion cell layer thickness. CONCLUSIONS: Concurrent alterations in retinal hemodynamic and oxygen metrics, thickness, and tissue Aß42 protein levels in 5XFAD mice at 3 months of age corresponded to previously reported findings in human AD. Overall, these results suggest that this mouse model can be utilized for studying pathophysiology of AD and evaluating potential therapies.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Oxigênio/metabolismo , Retina/metabolismo
10.
Invest Ophthalmol Vis Sci ; 63(6): 30, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35767246

RESUMO

Purpose: The purpose of the current study was to test the hypothesis that responses of total retinal blood flow (TRBF), inner retinal oxygen delivery (DO2), metabolism (MO2), and extraction fraction (OEF) to hyperoxia are higher after minutes of bilateral common carotid artery occlusion (BCCAO) as compared to days of BCCAO. Methods: Twenty-eight rats were subjected to BCCAO for 30 minutes (n = 12), 1 day (n = 8), or 3 days (n = 8). Eight of the 12 rats were also evaluated at baseline, prior to BCCAO. During room air breathing (RA) and 100% O2 inspiration (hyperoxia), blood flow and phosphorescence lifetime imaging were performed to measure TRBF and vascular O2 contents, respectively. DO2, MO2, and OEF were calculated from these measurements. Results: After 30 minutes or 3 days of BCCAO, TRBF did not differ between RA and hyperoxia conditions (P ≥ 0.14) but decreased under hyperoxia after 1 day (P = 0.01). Compared to RA, DO2 and MO2 were increased under hyperoxia after 30 minutes of BCCAO (P ≤ 0.02). Additionally, MO2 was decreased under hyperoxia after 1 day of BCCAO (P = 0.04). OEF was decreased under hyperoxia compared to RA (P < 0.001). Under hyperoxia, TRBF and DO2 were reduced after all BCCAO durations compared to baseline (P ≤ 0.04), whereas MO2 did not differ from baseline after 30 minutes of BCCAO (P = 1.00). Conclusions: The findings indicate that hyperoxia introduced minutes after ischemia can reduce DO2 impairments and potentially return MO2 to approximately normal values. This information contributes to the knowledge of the effect of supplemental oxygen intervention on TRBF, DO2, MO2, and OEF outcomes after variable durations of ischemia.


Assuntos
Hiperóxia , Animais , Artéria Carótida Primitiva/metabolismo , Oxigênio/metabolismo , Consumo de Oxigênio/fisiologia , Ratos , Fluxo Sanguíneo Regional/fisiologia , Vasos Retinianos
11.
Exp Eye Res ; 213: 108838, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34774489

RESUMO

After total retinal ischemia induced experimentally by ophthalmic vessel occlusion followed by reperfusion, studies have reported alterations in retinal oxygen metabolism (MO2), delivery (DO2), and extraction fraction (OEF), as well as visual dysfunction and cell loss. In the current study, under variable durations of ischemia/reperfusion, changes in these oxygen metrics, visual function, retinal thickness, and degeneration markers (gliosis and apoptosis) were assessed and related. Additionally, the prognostic value of MO2 for predicting visual function and retinal thickness outcomes was reported. Sixty-one rats were divided into 5 groups of ischemia duration (0 [sham], 60, 90, 120, or 180 min) and 2 reperfusion durations (1 h, 7 days). Phosphorescence lifetime and blood flow imaging, electroretinography, and optical coherence tomography were performed. MO2 reduction was related to visual dysfunction, retinal thinning, increased gliosis and apoptosis after 7-days reperfusion. Impairment in MO2 after 1-h reperfusion predicted visual function and retinal thickness outcomes after 7-days reperfusion. Since MO2 can be measured in humans, findings from analogous studies may find value in the clinical setting.


Assuntos
Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Degeneração Retiniana/metabolismo , Vasos Retinianos/metabolismo , Acuidade Visual/fisiologia , Animais , Apoptose , Velocidade do Fluxo Sanguíneo/fisiologia , Eletrorretinografia , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/patologia , Marcação In Situ das Extremidades Cortadas , Masculino , Consumo de Oxigênio/fisiologia , Ratos , Ratos Long-Evans , Fluxo Sanguíneo Regional , Traumatismo por Reperfusão/fisiopatologia , Retina/fisiopatologia , Degeneração Retiniana/fisiopatologia , Tomografia de Coerência Óptica
12.
Front Neurol ; 12: 669276, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220678

RESUMO

Carotid artery dissection (CAD) is the leading cause of ischemic stroke in young patients; however, the etiology and pathophysiology of CAD remain largely unknown. In our study, two types of dissections (length × width: 1.5 cm × 1/3 circumference of intima, Group I, n = 6; or 1.5 cm × 2/3 circumference of intima, Group II, n = 6) were created between the media and intima. Ultrasound (within 2 h after dissection) showed a dissociated intima in the lumen and obstructed blood flow in the surgical area. Digital subtraction angiography (DSA, 72 h after dissection), magnetic resonance imaging (MRI, 72 h after dissection), and hematoxylin-eosin (H&E, 7 days after dissection) staining confirmed stenosis (33.67 ± 5.66%) in Group I and total occlusion in Group II. In 10 out of 12 swine, the CAD model was established using a detacher and balloon dilation, and morphological outcomes (stenosis or occlusion) after CAD were determined by the size of intimal incision.

13.
Sci Rep ; 11(1): 4824, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33649406

RESUMO

To characterize rod- and cone-pathway function in the 5xFAD mouse model of Alzheimer's disease (AD) using the full-field electroretinogram (ERG). Dark-adapted (DA; rod-pathway) and light-adapted (LA; cone-pathway) ERGs were recorded from three-month-old 5xFAD and wild type (WT) mice. ERGs were elicited by achromatic flashes (0.01-25 cd-s-m-2). Amplitude and implicit time (IT) of the a-wave, b-wave, and oscillatory potentials (OPs) were calculated according to convention. In addition, the amplitude and IT of the photopic negative response (PhNR) were measured from the LA recordings. Amplitude and IT differences between the 5xFAD and WT groups were evaluated using quantile regression models. Under DA conditions, there were significant differences between the 5xFAD and WT groups in post-receptor function, whereas photoreceptor function did not differ significantly. Specifically, the DA a-wave amplitude did not differ between groups (p = 0.87), whereas the b-wave amplitude was reduced in the 5xFAD mice (p = 0.003). There were significant OP (p < 0.001) and a-wave (p = 0.04) delays, but the a-wave delay may be attributable to a post-receptor abnormality. Under LA conditions, the only 5xFAD abnormalities were in the PhNR, which was reduced (p = 0.009) and delayed (p = 0.04). The full-field ERG can be abnormal in the 5xFAD model of AD, with the greatest effects on post-receptor rod pathway function. These results indicate that retinal electrophysiology may be a useful tool for evaluating neural dysfunction in AD.


Assuntos
Doença de Alzheimer/metabolismo , Células Fotorreceptoras Retinianas Cones/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Transdução de Sinais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Células Fotorreceptoras Retinianas Cones/patologia , Células Fotorreceptoras Retinianas Bastonetes/patologia
14.
Exp Eye Res ; 205: 108480, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33539865

RESUMO

The retinal degeneration 1 (rd1) mouse is a well-established model of inherited retinal degeneration, displaying photoreceptor degeneration and retinal vasculature damage. The purpose of the current study was to determine alterations in the rate of oxygen delivery from retinal circulation (DO2), the rate of oxygen extraction from the retinal circulation for metabolism (MO2), and oxygen extraction fraction (OEF) in rd1 mice. The study was performed in a total of 18 wild type (WT) and 10 rd1 mice at both 3-weeks and 12-weeks of age. Retinal arterial and venous oxygen contents (O2A and O2V) were measured using phosphorescence lifetime imaging. Total retinal blood flow (TRBF) was determined by fluorescence and red-free imaging. DO2 and MO2 were determined as TRBF × O2A and TRBF × (O2A-O2V), respectively. OEF was calculated as MO2/DO2. The thickness of individual retinal layers was measured from histology sections and inner retina (IR) and total retina (TR) thickness were calculated. TRBF, DO2 and MO2 were lower in rd1 mice compared to WT mice (P ≤ 0.001), whereas OEF was not significantly different between rd1 and WT mice (P = 0.4). TRBF and DO2 were lower at 3-weeks of age compared to 12-weeks of age (P ≤ 0.01), while MO2 was not significantly different between age groups (P = 0.4) and OEF was higher at 3-weeks of age compared to 12-weeks of age (P = 0.003). Additionally, the outer and inner retinal cell layer thicknesses were decreased in rd1 mice at 12-weeks of age compared to both age-matched WT mice and rd1 mice at 3-weeks of age (P ≤ 0.02). MO2 was directly correlated with both IR and TR thickness (R ≥ 0.50; P ≤ 0.03, N = 20). The findings indicate that the rate oxygen is supplied by the retinal circulation is decreased and the reduction in oxygen extracted for metabolism is related to retinal cell layer thinning in rd1 mice.


Assuntos
Modelos Animais de Doenças , Oxigênio/sangue , Retina/patologia , Degeneração Retiniana/fisiopatologia , Vasos Retinianos/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Mutantes , Tamanho do Órgão , Consumo de Oxigênio/fisiologia , Fluxo Sanguíneo Regional/fisiologia
15.
J Neuroinflammation ; 18(1): 40, 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531049

RESUMO

BACKGROUND: Nucleotide-binding oligomerization domain-like receptor pyrin domain-containing protein 3 (NLRP3) plays an important role in mediating inflammatory responses during ischemic stroke. Bile acid receptor Takeda-G-protein-receptor-5 (TGR5) has been identified as an important component in regulating brain inflammatory responses. In this study, we investigated the mechanism of TGR5 in alleviating neuroinflammation after middle cerebral artery occlusion (MCAO). METHODS: Sprague-Dawley rats were subjected to MCAO and TGR5 agonist INT777 was administered intranasally 1 h after MCAO. Small interfering RNAs (siRNA) targeting TGR5 and Pellino3 were administered through intracerebroventricular injection 48 h before MCAO. Infarct volumes and neurologic scores were evaluated, and ELISA, flow cytometry, immunofluorescence staining, immunoblotting, and co-immunoprecipitation were used for the evaluations. RESULTS: Endogenous TGR5 and Pellino3 levels increased after MCAO. TGR5 activation by INT777 significantly decreased pro-inflammatory cytokine, cleaved caspase-8, and NLRP3 levels, thereby reducing brain infarctions; both short- and long-term neurobehavioral assessments showed improvements. Ischemic damage induced the interaction of TGR5 with Pellino3. Knockdown of either TGR5 or Pellino3 increased the accumulation of cleaved caspase-8 and NLRP3, aggravated cerebral impairments, and abolished the anti-inflammatory effects of INT777 after MCAO. CONCLUSIONS: TGR5 activation attenuated brain injury by inhibiting neuroinflammation after MCAO, which could be mediated by Pellino3 inhibition of caspase-8/NLRP3.


Assuntos
Caspase 8/metabolismo , Infarto da Artéria Cerebral Média/metabolismo , Mediadores da Inflamação/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Administração Intranasal , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ácidos Cólicos/administração & dosagem , Infarto da Artéria Cerebral Média/prevenção & controle , Mediadores da Inflamação/antagonistas & inibidores , Injeções Intraventriculares , Masculino , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/agonistas , Ubiquitina-Proteína Ligases/antagonistas & inibidores
16.
J Cereb Blood Flow Metab ; 41(5): 945-957, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33325765

RESUMO

While the time window for reperfusion after ischemic stroke continues to increase, many patients are not candidates for reperfusion under current guidelines that allow for reperfusion within 24 h after last known well time; however, many case studies report favorable outcomes beyond 24 h after symptom onset for both spontaneous and medically induced recanalization. Furthermore, modern imaging allows for identification of penumbra at extended time points, and reperfusion risk factors and complications are becoming better understood. Taken together, continued urgency exists to better understand the pathophysiologic mechanisms and ideal setting of delayed recanalization beyond 24 h after onset of ischemia.


Assuntos
Encéfalo/irrigação sanguínea , AVC Isquêmico/fisiopatologia , Reperfusão/métodos , Tempo para o Tratamento/normas , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Volume Sanguíneo Cerebral/fisiologia , Circulação Cerebrovascular/fisiologia , Criança , Terapia Combinada/métodos , Imagem de Difusão por Ressonância Magnética/métodos , Imagem de Difusão por Ressonância Magnética/estatística & dados numéricos , Feminino , Fibrinolíticos/uso terapêutico , Humanos , AVC Isquêmico/diagnóstico , AVC Isquêmico/cirurgia , Angiografia por Ressonância Magnética/métodos , Angiografia por Ressonância Magnética/estatística & dados numéricos , Masculino , Trombólise Mecânica/métodos , Pessoa de Meia-Idade , Reperfusão/efeitos adversos , Fatores de Risco , Terapia Trombolítica/métodos , Fatores de Tempo , Tempo para o Tratamento/tendências , Ativador de Plasminogênio Tecidual/uso terapêutico , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
17.
J Cereb Blood Flow Metab ; 41(2): 267-281, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32151222

RESUMO

Sodium butyrate, a short-chain fatty acid, is predominantly produced by gut microbiota fermentation of dietary fiber and serves as an important neuromodulator in the central nervous system. Recent experimental evidence has suggested that sodium butyrate may be an endogenous ligand for two orphan G protein-coupled receptors, GPR41 and GP43, which regulate apoptosis and inflammation in ischemia-related pathologies, including stroke. In the present study, we evaluated the potential efficacy and mechanism of action of short-chain fatty acids in a rat model of middle cerebral artery occlusion (MCAO). Fatty acids were intranasally administered 1 h post MCAO. Short-chain fatty acids, especially sodium butyrate, reduced infarct volume and improved neurological function at 24 and 72 h after MCAO. At 24 h, the effects of MCAO, increased apoptosis, were ameliorated after treatment with sodium butyrate, which increased the expressions of GPR41, PI3K and phosphorylated Akt. To confirm these mechanistic links and characterize the GPR active subunit, PC12 cells were subjected to oxygen-glucose deprivation and reoxygenation, and pharmacological and siRNA interventions were used to reverse efficacy. Taken together, intranasal administration of sodium butyrate activated PI3K/Akt via GPR41/Gßγ and attenuated neuronal apoptosis after MCAO.


Assuntos
Ácido Butírico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Apoptose , Infarto da Artéria Cerebral Média/patologia , Masculino , Ratos , Ratos Sprague-Dawley
18.
J Biomed Sci ; 27(1): 71, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32487075

RESUMO

An amendment to this paper has been published and can be accessed via the original article.

19.
J Biomed Sci ; 27(1): 61, 2020 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-32381096

RESUMO

BACKGROUND: The disruption of the blood-brain barrier (BBB) plays a critical event in the pathogenesis of ischemia stroke. TGR5 is recognized as a potential target for the treatment for neurologic disorders. METHODS: This study investigated the roles of TGR5 activation in attenuating BBB damage and underlying mechanisms after middle cerebral artery occlusion (MCAO). Sprague-Dawley rats were subjected to model of MCAO and TGR5 agonist, INT777, was administered intranasally. Small interfering RNA (siRNA) for TGR5 and BRCA1 were administered through intracerebroventricular injection 48 h before MCAO. Infarct volumes, brain water content, BBB permeability, neurological scores, Western blot, immunofluorescence staining and co- immunoprecipitation were evaluated. RESULTS: Endogenous TGR5 and BRCA1 were upregulated in the injured hemisphere after MCAO and TGR5 expressed in endothelial cells. Treatment with INT777 alleviated brain water content and BBB permeability, reduced infarction volume and improved neurological scores at 24 h and 72 h after ischemia. INT777 administration increased BRCA1 and Sirt1 expression, as well as upregulated expressions of tight junction proteins. Ischemic damage induced interaction of TGR5 with BRCA1. TGR5 siRNA and BRCA1 siRNA significantly inhibited expressions of BRCA1 and Sirt1, aggravated BBB permeability and exacerbated stroke outcomes after MCAO. The protective effects of INT777 at 24 h after MCAO were also abolished by TGR5 siRNA or BRCA1 siRNA. CONCLUSIONS: Our findings demonstrate that activating TGR5 could reduce BBB breakdown and improve neurological functions through BRCA1/Sirt1 signaling pathway after MCAO. TGR5 may serve as a potential new candidate to relieve brain injury after MCAO.


Assuntos
Barreira Hematoencefálica/fisiologia , Infarto da Artéria Cerebral Média/patologia , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/genética , Animais , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo
20.
Transl Stroke Res ; 11(6): 1273-1286, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32207038

RESUMO

Studies in experimental ischemia models by permanent bilateral common carotid artery occlusion (BCCAO) have reported reduced retinal electrophysiological function, coupled with inner retinal degeneration and gliosis. In the current study, we tested the hypothesis that long-term (up to 14 days) BCCAO impairs oxygen delivery (DO2), which affects oxygen metabolism (MO2) and extraction fraction (OEF), electrophysiological function, morphology, and biochemical pathways. Twenty-one rats underwent BCCAO (N = 12) or sham surgery (N = 9) and were evaluated in separate groups after 3, 7, or 14 days. Electroretinography (ERG), optical coherence tomography, blood flow and vascular oxygen tension imaging, and morphological and biochemical evaluations were performed in both eyes. Reduced ERG b-wave amplitudes and delayed implicit times were reported at 3, 7, and 14 days following BCCAO. Total retinal blood flow, MO2, and DO2 were reduced in all BCCAO groups. OEF was increased in both 3- and 7-day groups, while no significant difference was observed in OEF at 14 days compared to the sham group. At 14 days following BCCAO, total and inner retinal layer thickness was reduced, while the outer nuclear layer thickness and gliosis were increased. There was an increase in nuclei containing fragmented DNA at 3 days following BCCAO. The compensatory elevation in OEF following BCCAO did not meet the tissue demand, resulting in the subsequent reduction of MO2. The associations between retinal MO2, DO2, and retinal function were shown to be significant in the sequelae of persistent ischemia. In sum, measurements of DO2, MO2, and OEF may become useful for characterizing salvageable tissue in vision-threatening pathologies.


Assuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Isquemia/metabolismo , Oxigênio/metabolismo , Retina/metabolismo , Vasos Retinianos/metabolismo , Animais , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/metabolismo , Eletrorretinografia/métodos , Isquemia/diagnóstico por imagem , Masculino , Ratos , Ratos Long-Evans , Retina/diagnóstico por imagem , Vasos Retinianos/diagnóstico por imagem
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