Microcirculatory Impairment and Cerebral Injury in Hydrocephalus and the Effects of Cerebrospinal Fluid Diversion.

BACKGROUND AND OBJECTIVES: Hydrocephalus is characterized by progressive enlargement of cerebral ventricles, resulting in impaired microvasculature and cerebral hypoperfusion. This study aimed to demonstrate the microvascular changes in hydrocephalic rats and the effects of cerebrospinal fluid (CSF) release on cerebral blood flow (CBF). METHODS: On postnatal day 21 (P21), male Wistar rats were intracisternally injected with either a kaolin suspension or saline. On P47, Evan's ratio (ER) was measured using MRI. On P49, the arteriolar diameter and vascular density of the pia were quantified using a capillary video microscope. The CBF was measured using laser Doppler flowmetry. The expressions of NeuN and glial fibrillary acidic protein determined by immunochemical staining were correlated with the ER. The CBF and rotarod test performance were recorded before and after CSF release. The expressions of 4-hydroxynonenal (4-HNE) and c-caspase-3 were studied on P56. RESULTS: Ventriculomegaly was induced to varying degrees, resulting in the stretching and abnormal narrowing of pial arterioles, which regressed with increasing ER. Quantitative analysis revealed significant decreases in the arteriolar diameter and vascular density in the hydrocephalic group compared with those in the control group. In addition, the CBF in the hydrocephalic group decreased to 30%-50% of that in the control group. In hydrocephalus, the neurons appear distorted, and the expression of 4-HNE and reactive astrogliosis increase in the cortex. After CSF was released, improvements in the CBF and rotarod test performance were inversely associated with the ER. In addition, the levels of 4-HNE and c-caspase-3 were further elevated. CONCLUSION: Rapid ventricular dilatation is associated with severe microvascular distortion, vascular regression, cortical hypoperfusion, and cellular changes that impair the recovery of CBF and motor function after CSF release. Moreover, CSF release may induce reperfusion injury. This pathophysiology should be taken into account when treating hydrocephalus.

Recombinant soluble form of receptor for advanced glycation end products ameliorates microcirculation impairment and neuroinflammation after subarachnoid hemorrhage.

Impaired cerebral microcirculation after subarachnoid hemorrhage (SAH) has been shown to be related to delayed ischemic neurological deficits (DIND). We previously demonstrated the involvement of the receptor for advanced glycation end products (RAGE) in the pathogenesis of SAH related neuronal death. In the present study, we aimed to investigate the therapeutic effects of a recombinant soluble form of RAGE (sRAGE) on microcirculation impairment following SAH. Intrathecal injection of autologous blood in rats, mixed primary astrocyte and microglia cultures exposed to hemolysates and endothelial cells â€‹(ECs) from human brain microvascular exposed to glia-conditioned medium or SAH patient's CSF were used as experimental SAH models in vivo and in vitro. The results indicated that intrathecal administration of recombinant sRAGE significantly ameliorated the vasoconstriction of cortical arterioles and associated perfusion impairment, brain edema, reduced cell death, endothelial dysfunction, and improved motor performance at 24 and 48 â€‹h after SAH induction in rats. The in vitro results further showed that recombinant sRAGE significantly reduced astrocyte swelling and microglia activation, in parallel with decreased mRNA expression levels of pro-inflammatory cytokines including interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) in vitro. Moreover, the in vitro model of SAH-induced p-eNOS and eNOS suppression, along with stress fiber formation in brain microvascular ECs, was effectively reversed by sRAGE treatment and led to a decrease in cleaved-caspase 3 expression. In summary, recombinant sRAGE effectively lessened microcirculation impairment and vascular injury after SAH via the mechanism of anti-inflammation, which may provide a potential therapeutic strategy for SAH.

Dental Pulp Stem Cell-Derived Conditioned Medium Alleviates Subarachnoid Hemorrhage-Induced Microcirculation Impairment by Promoting M2 Microglia Polarization and Reducing Astrocyte Swelling.

Aneurysmal subarachnoid hemorrhage (SAH) can cause severe neurological deficits and high mortality. Early brain edema following SAH contributes to the initiation of microcirculation impairment and may further lead to delayed ischemic neurologic deficit (DIND). This study aimed to investigate whether dental pulp stem cell conditioned medium (DPSC-CM) ameliorates SAH-induced microcirculation impairment and the underlying mechanisms. SAH was induced via intrathecal injection of fresh autologous blood in Wistar male adult rat. DPSC-CM or DPSC-CM + insulin growth factor-1 (IGF-1) antibody was randomly administered by intrathecal route 5 min after SAH induction. To evaluate the underlying mechanisms of DPSC-CM in the treatment of SAH, primary rat astrocyte and microglia co-cultures were challenged with hemolysate or SAH-patient CSF in the presence or absence of DPSC-CM. The results showed that in vivo, DPSC-CM treatment decreased the brain water content, improved microcirculation impairment and enhanced functional recovery at 24 h post-SAH. DPSC-CM treatment also alleviated the expressions of water channel protein aquaporin-4 (AQP4) and pro-inflammatory cytokines, and enhanced the expressions of anti-inflammatory factors in the cortical region. However, all the beneficial effects of DPSC-CM were abrogated after treatment with IGF-1 neutralizing antibody. The in vitro results further showed that DPSC-CM treatment reduced hemolysate/SAH-patient CSF-induced astrocyte swelling and promoted M2 microglia polarization, partially through IGF-1/AKT signaling. The data suggested that DPSC-CM significantly reduced brain edema and rescued microcirculation impairment with concomitant anti-inflammatory benefits after SAH, and may potentially be developed into a novel therapeutic strategy for SAH.

Erratum: Chen, Y.-R., et al. Improvement of Impaired Motor Functions by Human Dental Exfoliated Deciduous Teeth Stem Cell-Derived Factors in a Rat Model of Parkinson's Disease. Int. J. Mol. Sci. 2020, 21, 3807.

The authors regret to have made a mistake in publishing this paper [...].

Improvement of Impaired Motor Functions by Human Dental Exfoliated Deciduous Teeth Stem Cell-Derived Factors in a Rat Model of Parkinson's Disease.

Parkinson's disease (PD) is a long-term degenerative disease of the central nervous system (CNS) that primarily affects the motor system. So far there is no effective treatment for PD, only some drugs, surgery, and comprehensive treatment can alleviate the symptoms of PD. Stem cells derived from human exfoliated deciduous teeth (SHED), mesenchymal stem cells derived from dental pulp, may have promising potential in regenerative medicine. In this study, we examine the therapeutic effect of SHED-derived conditioned medium (SHED-CM) in a rotenone-induced PD rat model. Intravenous administration of SHED-CM generated by standardized procedures significantly improved the PD symptoms accompanied with increased tyrosine hydroxylase amounts in the striatum, and decreased α-synuclein levels in both the nigra and striatum, from rotenone-treated rats. In addition, this SHED-CM treatment decreased both Iba-1 and CD4 levels in these brain areas. Gene ontology analysis indicated that the biological process of genes affected by SHED-CM was primarily implicated in neurodevelopment and nerve regeneration. The major constituents of SHED-CM included insulin-like growth factor binding protein-6 (IGFBP-6), tissue inhibitor of metalloproteinase (TIMP)-2, TIMP-1, and transforming growth factor 1 (TGF-1). RNA-sequencing (RNA-seq) and Ingenuity Pathway Analysis (IPA) revealed that these factors may ameliorate PD symptoms through modulating the cholinergic synapses, calcium signaling pathways, serotoninergic synapses, and axon guidance. In conclusion, our data indicate that SHED-CM contains active constituents that may have promising efficacy to alleviate PD.

Synthesis and evaluation of ortho-[18F] fluorocelecoxib for COX-2 cholangiocarcinoma imaging.

BACKGROUND: An 18F-tagged NSAID analog was prepared for use as a probe for COX-2 expression, which is associated with tumor development. METHODS: The in vivo uptake of celecoxib was monitored with ortho-[18F]fluorocelecoxib using positron emission tomography (PET). The binding affinity of ortho-[18F]fluorocelecoxib to COX-1 and COX-2 enzymes were assessed using the competitor celecoxib. RESULTS: The IC50 values were 0.039 µM and 0.024 µM, respectively. A selectivity index of 1.63 was obtained (COX-2 vs COX-1). COX-2 overexpressed cholangiocarcinoma (CCA) murine cells took up more ortho-[18F]fluorocelecoxib than that by usual CCA cells from 10 to 60 minutes post incubation. Competitive inhibition (blocking) of the tracer uptake of ortho-[18F]fluorocelecoxib in the presence of celecoxib by the COX-2 overexpressed CCA cells and the usual CCA cells gave the IC50 values of 0.5 µM and 46.5 µM, respectively. Based on the in vitro accumulation data and in vivo metabolism half-life (30 min), PET scanning was performed 30-60 min after the administration of ortho-[18F]fluorocelecoxib through the tail vein. Study of ortho-[18F]F-celecoxib in the CCA rats showed a tumor to normal ratio (T/N) of 1.38±0.23 and uptake dose of 1.14±0.25 (%ID/g). CONCLUSION: The inferior in vivo blocking results of 1.48±0.20 (T/N) and 1.18±0.22 (%ID/g) suggests that the nonspecificity is associated with the complex role of peroxidase or the binding to carbonic anhydrase.

Dataset on the synthesis and characterization of boron fenbufen and its F-18 labeled homolog.

The data presented in this article are related to the research article entitled "Synthesis and Characterization of Boron Fenbufen and its F-18 Labeled Homolog for Boron Neutron Capture Therapy of COX-2 Overexpressed Cholangiocarcinoma". The contents of the data article include 1) the set up for performing in vitro binding assay, 2) 1H-, 13C- and 19F-NMR of compounds described in main text, 3) HPLC chromatogram of the fluorination mixtures, 4) data of in vitro stability test, cell survival assay, western blot and PCR analysis, 5) the modules for fixing the two CCA rats for BNCT, and 6) bar diagram for tumor reduction using [18F]FDG-PET 24 h post treatment with BNCT.

Synthesis and characterization of boron fenbufen and its F-18 labeled homolog for boron neutron capture therapy of COX-2 overexpressed cholangiocarcinoma.

Boron neutron capture therapy (BNCT) is a binary therapy that employs neutron irradiation on the boron agents to release high-energy helium and alpha particles to kill cancer cells. An optimal response to BNCT depends critically on the time point of maximal 10B accumulation and highest tumor to normal ratio (T/N) for performing the neutron irradiation. The aggressive cholangiocarcinoma (CCA) representing a liver cancer that overexpresses COX-2 enzyme is aimed to be targeted by COX-2 selective boron carrier, fenbufen boronopinacol (FBPin). Two main works were performed including: 1) chemical synthesis of FBPin as the boron carrier and 2) radiochemical labeling with F-18 to provide the radiofluoro congener, m-[18F]fluorofenbufen ester boronopinacol (m-[18F]FFBPin), to assess the binding affinity, cellular accumulation level and distribution profile in CCA rats. FBPin was prepared from bromofenbufen via 3 steps with 82% yield. The binding assay employed [18F]FFBPin to compete FBPin for binding to COX-1 (IC50=0.91±0.68µM) and COX-2 (IC50=0.33±0.24µM). [18F]FFBPin-derived 60-min dynamic PET scans predict the 10B-accumulation of 0.8-1.2ppm in liver and 1.2-1.8ppm in tumor and tumor to normal ratio=1.38±0.12. BNCT was performed 40-55min post intravenous administration of FBPin (20-30mg) in the CCA rats. CCA rats treated with BNCT display more tumor reduction than that by NCT with respect of 2-[18F]fluoro-2-deoxy glucose uptake in the tumor region of interest, 20.83±3.00% (n=12) vs. 12.83±3.79% (n=10), P=0.05. The visualizing agent [18F]FFBPin resembles FBPin to generate the time-dependent boron concentration profile. Optimal neutron irradiation period is thus determinable for BNCT. A boron-substituted agent based on COX-2-binding features has been prepared. The moderate COX-2/COX-1 selectivity index of 2.78 allows a fair tumor selectivity index of 1.38 with a mild cardiovascular effect. The therapeutic effect from FBPin with BNCT warrants a proper COX-2 targeting of boron NSAIDs.