Anti-Inflammatory and Antioxidant Mechanism of Tangeretin in Activated Microglia

Tangeretin, a flavonoid from citrus fruit peels, has been proven to play an important role in anti-inflammatory responses and neuroprotective effects in several disease models, but further study is necessary for elucidating the detailed mechanisms of these effects. In this study, we examined the anti-inflammatory effect of tangeretin in lipopolysaccharide (LPS)-stimulated microglia. We first observed that tangeretin inhibited LPS-induced production of nitric oxide, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1β, as well as LPS-induced mRNA expression of inducible nitric oxide synthases and cytokines. Additionally, we found that the activities, mRNA levels, and protein levels of matrix metalloproteinase (MMP)-3 and MMP-8 were inhibited, while the expression of tissue inhibitor of metalloproteinase-2 was enhanced by tangeretin in LPS-stimulated microglia. Further mechanistic study showed that tangeretin suppressed LPS-induced phosphorylation of mitogen-activated protein kinases and Akt. Also, tangeretin inhibited nuclear factor-κB by upregulating sirtuin 1 and 5′-adenosine monophosphate-activated protein kinase. We further demonstrated the antioxidant effect of tangeretin by showing that tangeretin inhibited reactive oxygen species production and p47^phox phosphorylation, while enhancing the expression of heme oxygenase-1 and the DNA binding activity of nuclear factor-erythroid 2-related factor 2 to the antioxidant response element in LPS-stimulated microglia. Taken together, the results of the present study demonstrate that tangeretin possesses a potent anti-inflammatory and antioxidant effect in microglia.     

Assessment of DCE–MRI parameters for brain tumors through implementation of physiologically–based pharmacokinetic model approaches for Gd-DOTA

Dynamic-contrast enhanced magnetic resonance imaging (DCE–MRI) is used for detailed characterization of pathology of lesions sites, such as brain tumors, by quantitative analysis of tracer’s data through the use of pharmacokinetic (PK) models. A key component for PK models in DCE–MRI is the estimation of the concentration–time profile of the tracer in a nearby vessel, referred as Arterial Input Function (AIF). The aim of this work was to assess through full body physiologically-based pharmacokinetic (PBPK) model approaches the PK profile of gadoteric acid (Gd-DOTA) and explore potential application for parameter estimation in DCE-MRI based on PBPK-derived AIFs. The PBPK simulations were generated through Simcyp^® platform and the predicted PK parameters for Gd-DOTA were compared with available clinical data regarding healthy volunteers and renal impairment patients. The assessment of DCE-MRI parameters was implemented by utilizing similar virtual profiles based on gender, age and weight to clinical profiles of patients diagnosed with glioblastoma multiforme. The PBPK–derived AIFs were then used to compute DCE-MRI parameters through the Extended Tofts Model and compared with the corresponding ones derived from image-based AIF computation. The comparison involved: (i) image measured AIF of patients vs AIF of in silico profile, and, (ii) population average AIF vs in silico mean AIFs. The results indicate that PBPK–derived AIFs allowed the estimation of comparable imaging biomarkers with those calculated from typical DCE–MRI image analysis. The incorporation of PBPK models and potential utilization of in silico profiles to real patient data, can provide new perspectives in DCE–MRI parameter estimation and data analysis.     

Ventriculostomy-related hemorrhage in patients on antiplatelet therapy for endovascular treatment of acutely ruptured intracranial aneurysms. A meta-analysis

The risk of ventriculostomy-related hemorrhage among patients requiring antiplatelet therapy (AT) for the endovascular treatment of acutely ruptured intracranial aneurysms needed further investigation. The authors performed a systematic review and meta-analysis of the literature examining the EVD-related hemorrhage rate among patients with and without AT (controls). According to PRISMA guidelines, a comprehensive review of studies published between January 1990 and April 2018 was carried out. The authors identified series with > 5 patients reporting the EVD-associated hemorrhage rate among the AT group and the control group. Variables influencing outcomes were analyzed using a random-effects meta-analysis model. We included 13 studies evaluating 516 (with AT) and 647 (without AT) patients requiring ventriculostomy. EVD-related hemorrhage rates were higher among the AT group (125/516 = 20.9%, 95% CI = 11.9–30%, I2 = 90% vs 57/647 = 9%, 95% CI = 5.5–12.5%, I2 = 45.8%) (p < 0.0001). Major EVD-associated hemorrhage rates were low in both the AT and control group (25/480 = 4.4%, 95% CI = 1.7–7.7%, I2 = 53.9% vs 6/647 = 0.7%, 95% CI = 0.03–1.7%, I2 = 0%) (p < 0.0001). Ventriculostomy before embolization and intraprocedural AT were associated with lower rates of EVD-related bleeding (32/230 = 9.6%, 95% CI = 2.1–17.1%, I2 = 75.4% vs 6/24 = 25.1%, 95% CI = 8.8–41%, I2 = 0%) (p < 0.02). The rate of major hemorrhage was higher after dual AT (CP + ASA) compared to single AT (ASA or CP) used as an intraprocedural loading dose (13/173 = 7%, 95% CI = 3.3–10.7%, I2 = 0% vs 6/210 = 1.7%, 95% CI = 0.1–3.4%, I2 = 0%) (p < 0.009). AT during endovascular treatment of acutely ruptured intracranial aneurysms increases the risk of EVD-related hemorrhages, although most of them are small and asymptomatic. When ventriculostomy is performed before endovascular procedures requiring antiplatelet administration, the hemorrhagic risk is minimized. A single antiplatelet therapy is associated with a lower rate of major bleeding than a dual therapy.     

Estimation of phase signal change in neuronal current MRI for evoke response of tactile detection with realistic somatosensory laminar network model

Magnetic field generated by neuronal activity could alter magnetic resonance imaging (MRI) signals but detection of such signal is under debate. Previous researches proposed that magnitude signal change is below current detectable level, but phase signal change (PSC) may be measurable with current MRI systems. Optimal imaging parameters like echo time, voxel size and external field direction, could increase the probability of detection of this small signal change. We simulate a voxel of cortical column to determine effect of such parameters on PSC signal. We extended a laminar network model for somatosensory cortex to find neuronal current in each segment of pyramidal neurons (PN). 60,000 PNs of simulated network were positioned randomly in a voxel. Biot–savart law applied to calculate neuronal magnetic field and additional phase. The procedure repeated for eleven neuronal arrangements in the voxel. PSC signal variation with the echo time and voxel size was assessed. The simulated results show that PSC signal increases with echo time, especially 100/80 ms after stimulus for gradient echo/spin echo sequence. It can be up to 0.1 mrad for echo time = 175 ms and voxel size = 1.48 × 1.48 × 2.18 mm³. With echo time less than 25 ms after stimulus, it was just acquired effects of physiological noise on PSC signal. The absolute value of the signal increased with decrease of voxel size, but its components had complex variation. External field orthogonal to local surface of cortex maximizes the signal. Expected PSC signal for tactile detection in the somatosensory cortex increase with echo time and have no oscillation.     

Partial coherence and frustration in self‐organizing spherical grids

Nearby grid cells have been observed to express a remarkable degree of long‐range order, which is often idealized as extending potentially to infinity. Yet their strict periodic firing and ensemble coherence are theoretically possible only in flat environments, much unlike the burrows which rodents usually live in. Are the symmetrical, coherent grid maps inferred in the lab relevant to chart their way in their natural habitat? We consider spheres as simple models of curved environments and waiting for the appropriate experiments to be performed, we use our adaptation model to predict what grid maps would emerge in a network with the same type of recurrent connections, which on the plane produce coherence among the units. We find that on the sphere such connections distort the maps that single grid units would express on their own, and aggregate them into clusters. When remapping to a different spherical environment, units in each cluster maintain only partial coherence, similar to what is observed in disordered materials, such as spin glasses.     

Deletion of calcineurin from GFAP-expressing astrocytes impairs excitability of cerebellar and hippocampal neurons through astroglial Na+/K+ ATPase

Astrocytes perform important housekeeping functions in the nervous system including maintenance of adequate neuronal excitability, although the regulatory mechanisms are currently poorly understood. The astrocytic Ca²⁺/calmodulin-activated phosphatase calcineurin (CaN) is implicated in the development of reactive gliosis and neuroinflammation, but its roles, including the control of neuronal excitability, in healthy brain is unknown. We have generated a mouse line with conditional knockout (KO) of CaN B1 (CaNB1) in glial fibrillary acidic protein-expressing astrocytes (a stroglial c alcin eurin KO [ACN-KO]). Here, we report that postnatal and astrocyte-specific ablation of CaNB1 did not alter normal growth and development as well as adult neurogenesis. Yet, we found that specific deletion of astrocytic CaN selectively impairs intrinsic neuronal excitability in hippocampal CA1 pyramidal neurons and cerebellar granule cells (CGCs). This impairment was associated with a decrease in after hyperpolarization in CGC, while passive properties were unchanged, suggesting impairment of K⁺ homeostasis. Indeed, blockade of Na⁺/K⁺-ATPase (NKA) with ouabain phenocopied the electrophysiological alterations observed in ACN-KO CGCs. In addition, NKA activity was significantly lower in cerebellar and hippocampal lysates and in pure astrocytic cultures from ACN-KO mice. While no changes were found in protein levels, NKA activity was inhibited by the specific CaN inhibitor FK506 in both cerebellar lysates and primary astroglia from control mice, suggesting that CaN directly modulates NKA activity and in this manner controls neuronal excitability. In summary, our data provide formal evidence for the notion that astroglia is fundamental for controlling basic neuronal functions and place CaN center-stage as an astrocytic Ca²⁺-sensitive switch.