Inhibition of Notch1 signal promotes brain recovery by modulating glial activity after stroke.

BACKGROUND: Notch1 signaling inhibiton with N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester] (DAPT) treatment could promote brain recovery and the intervention effect is different between striatum (STR) and cortex (CTX), which might be accounted for different changes of glial activities, but the in-depth mechanism is still unknown. The purpose of this study was to identify whether DAPT could modulate microglial subtype shifts and astroglial-endfeet aquaporin-4 (AQP4) mediated waste solute drainage. METHODS: Sprague-Dawley rats (n=10) were subjected to 90min of middle cerebral artery occlusion (MCAO) and were treated with DAPT (n=5) or act as control with no treatment (n=5). Two groups of rats underwent MRI scans at 24h and 4 week, and sacrificed at 4 week after stroke for immunofluorescence (IF). RESULTS: Compared with control rats, MRI data showed structural recovery in ipsilateral STR but not CTX. And IF showed decreased pro-inflammatory M1 microglia and increased anti-inflammatory M2 microglia in striatal lesion core and peri-lesions of STR, CTX. Meanwhile, IF showed decreased AQP4 polarity in ischemic brain tissue, however, AQP4 polarity in striatal peri-lesions of DAPT treated rats was higher than that in control rats but shows no difference in cortical peri-lesions between control and treated rats. CONCLUSIONS: The present study indicated that DAPT could promote protective microglia subtype shift and striatal astrocyte mediated waste solute drainage, that the later might be the major contributor of waste solute metabolism and one of the accounts for discrepant recovery of STR and CTX.

Pustular Psoriasis Appearing Induced by Dupilumab Therapy in a Patient With Atopic Dermatitis.

Dupilumab inhibits T-helper 2 (Th2)-driven inflammation cascade by blocking interleukin-4 (IL-4) and IL-13 signaling, which has been recognized to play a crucial role in the pathogenesis of atopic dermatitis (AD) and shown encouraging efficacy on moderate to severe AD.1 We report an interesting Chinese AD case, which developed into pustular psoriasis after treatment with dupilumab.

Different susceptibility of spores and hyphae of Trichophyton rubrum to methylene blue mediated photodynamic treatment in vitro.

BACKGROUND: In recent years, methylene blue mediated-photodynamic therapy (MB-PDT) has proved to be an effective inhibitor to a variety of microorganisms, including Trichophyton rubrum, the most common dermatophyte worldwide. However, previous studies mainly focused on the spore form of T rubrum, but rarely on its hyphal form, although the latter is the main pathogenic form of T rubrum in vivo. OBJECTIVE: To investigate the inhibitory effect of MB-PDT on T rubrum in different growth phases in vitro. METHODS: The suspensions of spores and hyphae obtained from T rubrum (ATCC28188) were prepared, respectively, incubated with MB solution (0.15-40 µg/mL) and irradiated with 635 nm red light. Varied light energy and MB concentration were used. The specimen in the absence of light exposure or/and MB served as controls. MIC determination, colony counts and MTT assay were employed to evaluate the antifungal effect of MB-PDT. RESULTS: The MICs of MB-PDT for hyphae and spores of T. rubrum were 6.300 ± 1.072 µg/mL and 1.984 ± 1.072 µg/mL, respectively, at a fixed light dose of 60 J/cm2 . CFU counts gave the minimum critical combinations of MB concentration and light dose to achieve 100% inhibitory rate. For hyphae, they were 5 µg/mL + 100 J/cm2 or 10 µg/mL + 60 J/cm2 . For spores, they were 1.25 µg/mL + 40 J/cm2 or 5 µg/mL + 20 J/cm2 . The outcomes of MTT assay were consistent with those of CFU counts, but less accurate. CONCLUSION: MB-PDT is a potent inhibitor to both spores and hyphae of T. rubrum in vitro, and the spores are more sensitive to it. Its antifungal efficacy is positively correlated with the concentration of MB and light dose.

Impaired glymphatic system in secondary degeneration areas after ischemic stroke in rats.

BACKGROUND: Pathomechanism of secondary degeneration in remote regions after ischemic stroke has not been totally clarified. Contrast-enhanced MRI with injecting Gd-DTPA in cisterna magna (CM) is regarded as an efficient method to measure glymphatic system function in brain. Our research aimed at evaluating glymphatic system changes in secondary degeneration areas by contrast-enhanced MRI. METHODS: Ischemic stroke was induced by left middle cerebral artery occlusion (MCAO) model. A total of 12 Sprague-Dawley rats were randomly divided into three groups: control group with sham operations (n=4), the group of acute phase (1 day after MCAO) (n=4), and the group of subacute phase (7 days after MCAO) (n=4). Contrast-enhanced MRI was performed in 1days or 7days after operations respectively. All rats received an intrathecal injection of Gd-DTPA (2µl/min, totally 20µl) and high-resolution 3D T1-weighted MRI for 6 h. The time course of the signal-to-noise ratio (SNR) in substantia Nigra (SN) and ventral thalamic nucleus (VTN) was evaluated between two hemispheres in all rats. RESULTS: In control group without ischemia, time-to-peak of SNR in SN was earlier than that in VTN. There were no differences of SNR between two hemispheres after intrathecal Gd-DTPA administration. In the group of acute phase, MRI revealed similar time course and time-to-peak of SNR between ipsilateral and contralateral VTN, while a tendency of higher SNR in ipsilateral SN than contralateral SN at 4h, 5h, 6h after Gd-DTPA injection. And time-to-peak of SNR was similar in bilateral SN. In the group of subacute phase, time-to-peak of SNR was similar in bilateral VTN, while longer in ipsilateral SN compared with contralateral side. In addition, SNR in T1WI in ipsilateral was significantly higher than SNR in contralateral SN and VTN at 5h (VTN, P= 0.003; SN, P=0.004) and 6h (VTN, P=0.015; SN, P=0.006) after Gd-DTPA injection. CONCLUSION: Glymphatic system was impaired in ipsilateral SN and VTN after ischemic stroke, which may contribute to neural degeneration.

Imaging the Transformation of Ipsilateral Internal Capsule Following Focal Cerebral Ischemia in Rat by Diffusion Kurtosis Imaging.

BACKGROUND: The purpose of our study is to explore the relationship between recovery of neural function and transformation of the internal capsule (IC) after transient middle cerebral artery occlusion (MCAO) by using diffusion kurtosis imaging (DKI). METHODS: Six male adult Sprague-Dawley rats implemented with transient MCAO were used in this study. Sensorimotor function was assessed according to repetitive behavioral testing on day 1, 3, 7, 14, and 28 after cerebral ischemia. Metrics of DKI were acquired, and the time course of the region-to-normal ratio was evaluated in IC. RESULTS: After cerebral ischemia, relative fractional anisotropy in IC decreased on day 3 (P < .01). Relative mean diffusivity (rMD) increased on day 28 (P < .05). Relative mean diffusional kurtosis (rMK) increased on day 3 (P < .01) and decreased on day 7 (P < .05). Relative axial diffusional kurtosis (rKa) increased on day 3 (P < .01) and declined on day 7 (P < .05). Relative radial diffusional kurtosis (rKr) was reduced on day 7 (P < .05). Changes in rMK were larger than changes in rMD on day 3 (P < .05). The factor of rKa and rKr revealed marked difference on day 7 (P < .05) and day 14 (P < .05). Neurological function score showed that rats exhibited functional recovery from day 7 (P < .01) post stroke. CONCLUSIONS: This longitudinal multiparametric magnetic resonance imaging study suggested that K metrics offers information complimentary to conventional diffusion metrics and revealed the procedure during the structural modification in the ipsilateral IC following focal cerebral ischemia. After transient MCAO, the neural transformation occurred in a time-dependent procedure.

Combining systemic and stereotactic MEMRI to detect the correlation between gliosis and neuronal connective pathway at the chronic stage after stroke.

BACKGROUND: The early dysfunction and subsequent recovery after stroke, characterized by the destruction and remodeling of connective pathways between cortex and subcortical regions, is associated with neuroinflammation. As major components of the inflammatory process, reactive astrocytes have double-edged effects on pathological progression. The temporal patterns of astrocyte and neuronal pathway activity can be revealed by systemic and stereotactic manganese-enhanced magnetic resonance imaging (MEMRI), respectively. In the present study, we aimed to detect an association between astrocyte activity and recovery of neuronal connective pathways by combining systemic with stereotactic MEMRI. METHODS: Fifty adult rats, divided into two groups, underwent a 60-min occlusion of the middle cerebral artery. The groups were given either a systemic administration or stereotactic injection of MnCl2 at 1, 3, 7, and 14 days after stroke and underwent MRI 4 and 2 days later, respectively. Immunofluorescence (IF) of group 1 was conducted to corroborate the results. Repetitive behavioral testing was also performed with all rats at 1, 3, 7, and 14 days to obtain a functional score. RESULTS: Ring- or crescent-shaped enhancements formed in the striatal peri-infarct regions (STR) at 11 and 18 days. This was concurrent with the activity of glial fibrillary acidic protein (GFAP)-positive astrocytes, which mainly localized at the peri-infarct region and significantly increased in number at 11 and 18 days after stroke. Microglia/macrophages, detected by IF, mainly localized in the lesion core, rather than in the region of enhancement. The ipsilateral substantia nigra (SN) revealed Mn-related signal enhancement reduction and subsequent signs of the recovery process at 3 to 5 days and 9 to 16 days, respectively. Behavioral testing showed that sensorimotor functions were initially disturbed, but subsequently recovered at 7 and 14 days. CONCLUSIONS: We found a positive temporal correlation between astrogliosis and the recovery of neuronal connective pathways at the chronic stage by using the in vivo method of MEMRI. Our results highlighted the potential contribution of astrocytes to the neuronal recovery of these connective pathways.

Inhibition of Notch 1 signaling in the subacute stage after stroke promotes striatal astrocyte-derived neurogenesis.

Inhibition of Notch1 signaling has been shown to promote astrocyte-derived neurogenesis after stroke. To investigate the regulatory role of Notch1 signaling in this process, in this study, we used a rat model of stroke based on middle cerebral artery occlusion and assessed the behavior of reactive astrocytes post-stroke. We used the γ-secretase inhibitor N-[N-(3,5-diuorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT) to block Notch1 signaling at 1, 4, and 7 days after injury. Our results showed that only administration of DAPT at 4 days after stroke promoted astrocyte-derived neurogenesis, as manifested by recovery of white matter fiber bundle integrity on magnetic resonance imaging, which is consistent with recovery of neurologic function. These findings suggest that inhibition of Notch1 signaling at the subacute stage post-stroke mediates neural repair by promoting astrocyte-derived neurogenesis.

Acutely Inhibiting AQP4 With TGN-020 Improves Functional Outcome by Attenuating Edema and Peri-Infarct Astrogliosis After Cerebral Ischemia.

Background: Ischemic stroke is one of the leading causes of human death and disability. Brain edema and peri-infarct astrocyte reactivity are crucial pathological changes, both involving aquaporin-4 (AQP4). Studies revealed that acute inhibition of AQP4 after stroke diminishes brain edema, however, its effect on peri-infarct astrocyte reactivity and the subacute outcome is unclear. And if diffusion-weighted imaging (DWI) could reflect the AQP4 expression patterns is uncertain. Methods: Rats were subjected to middle cerebral artery occlusion (MCAO) and allocated randomly to TGN 020-treated and control groups. One day after stroke, brain swelling and lesion volumes of the rats were checked using T2-weighted imaging (T2-WI). Fourteen days after stroke, the rats successively underwent neurological examination, T2-WI and DWI with standard b-values and ultra-high b-values, apparent diffusion coefficient (ADC) was calculated correspondingly. Finally, the rats' brains were acquired and used for glial fibrillary acidic protein (GFAP) and AQP4 immunoreactive analysis. Results: At 1 day after stroke, the TGN-020-treated animals exhibited reduced brain swelling and lesion volumes compared with those in the control group. At 14 days after stroke, the TGN-020-treated animals showed fewer neurological function deficits and smaller lesion volumes. In the peri-infarct region, the control group showed evident astrogliosis and AQP4 depolarization, which were reduced significantly in the TGN-020 group. In addition, the ultra-high b-values of ADC (ADCuh) in the peri-infarct region of the TGN-020 group was higher than that of the control group. Furthermore, correlation analysis revealed that peri-infarct AQP4 polarization correlated negatively with astrogliosis extent, and ADCuh correlated positively with AQP4 polarization. Conclusion: We found that acutely inhibiting AQP4 using TGN-020 promoted neurological recovery by diminishing brain edema at the early stage and attenuating peri-infarct astrogliosis and AQP4 depolarization at the subacute stage after stroke. Moreover, ADCuh could reflect the AQP4 polarization.

Glymphatic system in the thalamus, secondary degeneration area was severely impaired at 2nd week after transient occlusion of the middle cerebral artery in rats.

Background and objectives: The glymphatic system is a recently discovered cerebrospinal fluid transport system and little is known about its dynamic changes after stroke. This study aimed to dynamically observe the structural and functional changes of the impaired glymphatic system in the thalamus after ischemic stroke by pathology and MRI. Materials and methods: Ischemic stroke was induced by the middle cerebral artery occlusion (MCAO) model. A total of 20 Sprague-Dawley rats were randomly assigned into four groups: sham, MCAO 1 week, MCAO 2 week, and MCAO 2 month. All rats successively underwent neurological examination, dynamic contrast-enhanced MRI (DCE-MRI), and immunofluorescence staining. Immunofluorescence staining of glial fibrillary acidic protein (GFAP), aquaporin-4 (AQP4), ionized calcium-binding adaptor molecule 1 (Iba1), and beta-amyloid precursor protein (APP) were done in thalamus ventroposterior nucleus. Results: The astrocyte and microglial activation and the APP deposition in the MCAO 2 week group were the highest (P < 0.05 for all). The AQP4 polarization rates of the MCAO 2 week and 2 month groups were the lowest (P < 0.05 for all). Although there was no correlation between histological changes and MRI metrics in all four groups (P > 0.05 for all), the tendency of the APP deposition was nearly consistent with the one of the contrast agent retention in DCE-MRI. Conclusion: The glymphatic system in the thalamus was severely impaired at 2nd week after MCAO, and may be revealed by DCE-MRI. This study may provide a relevant theoretical basis for making a thorough inquiry of the mechanism of brain injury after stroke and clinical treatment of ischemic stroke and help readers appreciate the importance of DCE-MRI.

Characterizing the clustered microcalcifications on mammograms to predict the pathological classification and grading: a mathematical modeling approach.

In this study, we explore a mathematical model to characterize the clustered microcalcifications on mammograms for predicting the pathological classification and grading. Our database consists of both retrospective cases (78 cases) and prospective cases (31 cases) with pathologically diagnosed clusters of microcalcifications on mammograms. The microcalcifications were divided into four grades: grade 0, benign breast disease including mastopathies (n = 12) and fibroadenomas (n = 20); grade 1, well-differentiated infiltrating ductal carcinoma (n = 12); grade 2, moderately differentiated infiltrating ductal carcinoma (n = 38); grade 3, poorly differentiated infiltrating ductal carcinoma (n = 27). A feature parameter, defined as the pattern form factor of microcalcification cluster θ by us, combines five computer-extracted image parameters of microcalcification clusters of those mammograms. In every case, only one imaging was selected for modeling analysis. A total of 109 imagings were adopted in current study. We find the existence of a positive relationship between the feature parameter θ and pathological grading G of microcalcifications in retrospective cases, which was expressed as G = 6.438 + 1.186 × Ln <θ>. The model above has been verified further by the prospective study with a comparative evaluation accuracy of approximately 77.42%. The binary predication simply for both benignancy and malignancy was also included using same but reshuffled data, and the receiver operating characteristic (ROC) analysis was performed with ROC value 0.74351∼0.79891. As one candidate for feature parameter in computer-aided diagnosis, the pattern form factor θ of clustered microcalcifications may be useful to predict the pathological grading and classification of microcalcification clusters on mammography in breast cancer.

Carotid Atherosclerotic Calcification Characteristics Relate to Post-stroke Cognitive Impairment.

Background: Together with cerebral small vessel disease (CSVD), large vessel atherosclerosis is considered to be an equally important risk factor in the progression of vascular cognitive impairment. This article aims to investigate whether carotid atherosclerotic calcification is associated with the increased risk of post-stroke cognitive impairment (PSCI). Methods: A total of 128 patients (mean age: 62.1 ± 12.2 years, 37 women) suffering from ischemic stroke underwent brain/neck computer tomography angiography examination. The presence and characteristic of carotid calcification (size, number and location) were analyzed on computer tomography angiography. White matter hyperintensity (WMH) was assessed using Fazekas scales. PSCI was diagnosed based on a battery of neuropsychological assessments implemented 6-12 months after stroke. Results: Among 128 patients, 26 developed post-stroke dementia and 96 had carotid calcification. Logistic regression found carotid calcification (odds ratio [OR] = 7.15, 95% confidence interval [CI]: 1.07-47.69) and carotid artery stenosis (OR = 6.42, 95% CI: 1.03-40.15) both significantly increased the risk for post-stroke dementia. Moreover, multiple, thick/mixed, and surface calcifications exhibited an increasing trend in PSCI (P trend = 0.004, 0.016, 0.045, respectively). The prediction model for post-stroke dementia including carotid calcification (area under curve = 0.67), WMH (area under curve = 0.67) and other covariates yielded an area under curve (AUC) of 0.90 (95% CI: 0.82-0.99). Conclusion: Our findings demonstrated that the quantity and location of carotid calcifications were independent indicators for PSCI. The significant role of large vessel atherosclerosis in PSCI should be concerned in future study.

Prognostic Value of a New Integrated Parameter-Both Collateral Circulation and Permeability Surface-in Hemorrhagic Transformation of Middle Cerebral Artery Occlusion Acute Ischemic Stroke: Retrospective Cohort Study.

BACKGROUND: Multimodal CT, including CT angiography (CTA) and CT perfusion (CTP), was increasingly used in stroke triage. This study was to determine the relationship between a new integrated parameter-both collateral circulation and relative permeability surface (PS)-and the hemorrhagic transformation (HT) in acute ischemic stroke (AIS) with middle cerebral artery occlusion (MCAO). METHODS: We retrospectively reviewed consecutive AIS patients with MCAO who underwent baseline CTA/CTP within 4 h of symptom onset and follow-up susceptibility-weighted imaging (SWI) within 3 weeks. Collateral circulation was assessed on the baseline CTA. Baseline CTP data were postprocessed to generate PS parameter. The patients with poor collateral circulation and at the same time with high relative PS were classified as the group of both poor collateral circulation and high relative PS. HT was defined according to European Cooperative Acute Stroke Study II criteria on follow-up SWI imaging. Multivariate logistic regression analysis was performed using HT as an outcome variable. RESULTS: The group of patients with both poor collateral circulation and high relative PS was thirteen and thirty-three (52%) developed HT of the final cohort sixty-three AIS patients with MCAO. Multivariate logistic analysis revealed the new integrated parameter-both collateral circulation and relative PS (odds ratio, 16.59; 95% confidence interval, 13.09-19.10; P < 0.001) was independent predictor of HT. The area under the curve was 0.85 (95% confidence interval, 0.81-0.89). The sensitivity was 57%, specificity 97% and positive predictive value 92%, negative predictive value 58%. CONCLUSIONS: For AIS patients with MCAO, these with poor collateral circulation on CTA and at the same time with high relative PS on CTP were at high risk for HT.

Modeling and analysis of epidemic spreading on community networks with heterogeneity.

A large number of real world networks exhibit community structure, and different communities may often possess heterogeneity. In this paper, considering the heterogeneity among communities, we construct a new community network model in which the communities show significant differences in average degree. Based on this heterogeneous community network, we propose a novel mathematical epidemic model for each community and study the epidemic dynamics in this network model. We find that the location of the initial infection node only affects the spreading velocity and barely influences the epidemic prevalence. And the epidemic threshold of entire network decreases with the increase of heterogeneity among communities. Moreover, the epidemic prevalence increases with the increase of heterogeneity around the epidemic threshold, while the converse situation holds when the infection rate is much greater than the epidemic threshold.

Predictors of short-term outcome in patients with acute middle cerebral artery occlusion: unsuitability of fluid-attenuated inversion recovery vascular hyperintensity scores.

Fluid-attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) is used to assess leptomeningeal collateral circulation, but clinical outcomes of patients with FVH can be very different. The aim of the present study was to assess a FVH score and explore its relationship with clinical outcomes. Patients with acute ischemic stroke due to middle cerebral artery M1 occlusion underwent magnetic resonance imaging and were followed up at 10 days (National Institutes of Health Stroke Scale) and 90 days (modified Rankin Scale) to determine short-term clinical outcomes. Effective collateral circulation indirectly improved recovery of neurological function and short-term clinical outcome by extending the size of the pial penumbra and reducing infarct lesions. FVH score showed no correlation with 90-day functional clinical outcome and was not sufficient as an independent predictor of short-term clinical outcome.

Abnormal Gray Matter Structural Networks in Idiopathic Normal Pressure Hydrocephalus.

Purpose: Idiopathic normal pressure hydrocephalus (iNPH) is known as a treatable form of dementia. Network analysis is emerging as a useful method to study neurological disorder diseases. No study has examined changes of structural brain networks of iNPH patients. We aimed to investigate alterations in the gray matter (GM) structural network of iNPH patients compared with normal elderly volunteers. Materials and Methods: Structural networks were reconstructed using covariance between regional GM volumes extracted from three-dimensional T1-weighted images of 29 possible iNPH patients and 30 demographically similar normal-control (NC) participants and compared with each other. Results: Global network modularity was significantly larger in the iNPH network (P < 0.05). Global network measures were not significantly different between the two networks (P > 0.05). Regional network analysis demonstrated eight nodes with significantly decreased betweenness located in the bilateral frontal, right temporal, right insula and right posterior cingulate regions, whereas only the left anterior cingulate was detected with significantly larger betweenness. The hubs of the iNPH network were mostly located in temporal areas and the limbic lobe, those of the NC network were mainly located in frontal areas. Conclusions: Network analysis was a promising method to study iNPH. Increased network modularity of the iNPH group was detected here, and modularity analysis should be paid much attention to explore the biomarker to select shunting-responsive patients.

Inhibition of Notch1 Signaling at the Subacute Stage of Stroke Promotes Endogenous Neurogenesis and Motor Recovery After Stroke.

Background and Purpose: It is still not clear whether Notch1 signaling inhibition can promote functional outcomes after stroke, given that it plays time-dependent roles in the sequential process of endogenous neurogenesis. The purpose of this study was to identify the appropriate time frame for Notch1 signaling inhibition according to the temporal evolution of Notch1 signaling activation and the responses of neural stem cells (NSCs), in order to target it for therapeutic intervention and stimulate neurorestorative strategies after stroke. Methods: Sprague-Dawley (SD) rats were subjected to 90-min of middle cerebral artery occlusion (MCAO). Rats were sacrificed before, and at day 1, day 2, day 3, day 4, and day 7 after ischemia for immunohistochemical analysis of the Notch intracellular domain (NICD), Nestin and doublecortin (Dcx). Next, MCAO rats were treated with the γ-secretase inhibitor N-[N-(3,5-di uorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT) or with saline at day 4 after ischemia, and subsequently evaluated with behavioral test analysis and magnetic resonance imaging (MRI). The rat brains were then harvested for immunohistochemical analysis of Dcx, NeuN and myelin basic protein (MBP) at 2, 3, 4, and 8 weeks. Results: Notch1 signaling was maximally activated at day 3 after ischemia in parallel with the temporal evolution of NSCs. Inhibiting Notch1 signaling at day 4 after reperfusion with DAPT further promoted recovery of MRI parameters of the corticospinal tract (CST) and the functional outcomes, concomitantly with an increase in neuroblasts, their migration to the ischemic boundary, and potential differentiation to mature neurons, as well as the amelioration of axonal bundle integrity. Conclusion: Inhibition of Notch1 signaling at the subacute stage of stroke could maximally promote endogenous neurogenesis and axonal reorganization.

Dynamic Evaluation of Notch Signaling-Mediated Angiogenesis in Ischemic Rats Using Magnetic Resonance Imaging.

OBJECTIVE: The Notch signaling pathway is involved in angiogenesis induced by brain ischemia and can be efficiently inhibited by the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butyl ester (DAPT). The aim of the present study was to noninvasively investigate the effect of DAPT treatment on angiogenesis in brain repair after stroke using magnetic resonance imaging (MRI). METHODS: Sprague-Dawley rats (n = 40) were subjected to 90 minutes of transient middle cerebral artery (MCA) occlusion and treated with PBS (n = 20) or DAPT (n = 20) at 72 hours after the onset of ischemia. MRI measurements including T2-weighted imaging (T2WI), susceptibility-weighted imaging (SWI), and cerebral blood flow (CBF) were performed at 24 hours after reperfusion and weekly up to 4 weeks using a 3-Tesla system. Histological measurements were obtained at each time point after MRI scans. RESULTS: SWI showed that DAPT treatment significantly enhanced angiogenesis in the ischemic boundary zone (IBZ) with respect to the control group, with local CBF in the angiogenic area elevated, along with increases in vascular density confirmed by histology. CONCLUSION: Treatment of ischemic stroke with DAPT significantly augments angiogenesis, which promotes poststroke brain remodeling by elevating CBF level, and these processes can be dynamically monitored and evaluated by MRI.

MRI detects protective effects of DAPT treatment with modulation of microglia/macrophages at subacute and chronic stages following cerebral ischemia.

Notch homolog 1 (Notch 1) signaling is regarded as a potential therapeutic target for modulating the inflammatory response and exhibiting neuroprotective effects in cerebral injury following stroke. N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t­butylester (DAPT) efficiently inhibits activation of the Notch 1 signaling pathway in microglia and may protect brain tissue from ischemic damage. However, the temporal proliferation and morphological alterations of microglia/macrophages throughout progression of the disease, as well as the comprehensive alterations of the whole brain following DAPT treatment, remain to be elucidated. The present study evaluated the temporal proliferation and the morphological alterations of microglia/macrophages over the period of the subacute and chronic stages, in addition to dynamic alterations of brain tissue, using the magnetic resonance imaging (MRI) method, following DAPT treatment. Sprague­Dawley rats (n=40) were subjected to 90 min of middle cerebral artery occlusion and were treated with DAPT (n=20) or acted as controls with no treatment (n=20). The two groups of rats underwent MRI scans prior to the induction of stroke symptoms and at 24 h, 7, 14, 21 and 28 days following the stroke. A total of five rats from each group were sacrificed at 7, 14, 21 and 28 days following induction of stroke. Compared with control rats, the MRI data of the ipsilateral striatum in treated rats revealed ameliorated brain edema at the subacute stage and recovered brain tissue at the chronic stage. In addition to this, treatment attenuated the round­shape and promoted a ramified­shape of microglia/macrophages. The present study confirmed the protective effect of DAPT treatment by dynamically monitoring the cerebral alterations and indicated the possibility of DAPT treatment to alter microglial characteristics to induce a protective effect, via inhibition of the Notch signaling pathway.