Effectiveness of electro-acupuncture for cognitive improvement on Alzheimer's disease quantified via PET imaging of sphingosine-1-phosphate receptor 1.

INTRODUCTION: Electro-acupuncture (EA) has demonstrated potential in improving mild-to-moderate dementia in clinics, but the underlying scientific target remains unclear. METHODS: EA was administered to APP/PS1 Alzheimer's disease (AD) mice, with untreated AD, and wild type (WT) mice serving as controls. The efficacy of EA was assessed by the Morris water maze cognitive functional tests. Brain magnetic resonance imaging-positron emission tomography (PET) scans using [18F]TZ4877 targeting sphingosine-1-phosphate receptor 1 (S1PR1) and [18F]AV45 targeting amyloid beta fibrils were conducted. The correlation between regional brain PET quantifications and cognitive functions was analyzed. RESULTS: EA significantly improved cognitive and memory functions of AD (p  = 0.04) and reduced the uptake of [18F]TZ4877 in the cortex (p  = 0.02) and hippocampus (p  = 0.03). Immunofluorescence confirmed colocalizations of S1PR1 with glial fibrillary acidic protein and ionized calcium-binding adaptor molecule-1. Furthermore, immunohistochemistry showed a significant reduction of interleukin 1ß and tumor necrosis factor α after EA treatment. DISCUSSION: EA may reverse AD by suppressing neuroinflammation, and the PET imaging of S1PR1 seemed potent in evaluating the treatment for AD patients HIGHLIGHTS: Electro-acupuncture (EA) was administered to APP/PS1 Alzheimer's disease (AD) mice, with untreated AD, and wild type (WT) mice serving as controls. The efficacy of EA was assessed by the Morris water maze cognitive functional tests and positron emission tomography (PET) imaging quantifications. PET tracer [18F]AV45 was used to detect amyloid beta deposition. An increased uptake of [18F]AV45 was found in AD compared to WT mice, with significance observed only in the cortex and not in the hippocampus. EA treatment exhibited a trend toward reduced [18F]AV45 uptake in AD mouse brains post-treatment. However, statistical difference was not attained in most brain regions. EA "Baihui (DU20) and Sishencong (EX-HN1)" significantly improved cognitive and memory functions of AD (p = 0.04). Brain magnetic resonance imaging p(MRI)-positron emission tomography (PET) quantifications revealed that significantly reduced the uptake of [18F]TZ4877 in the cortex (p = 0.02) and hippocampus (p = 0.03) after EA treatment. The correlation between PET quantifications and cognitive functions was analyzed and the most notable correlations were found between escape latency (reaction cognitive and memory behavior) and volume distribution (VT) quantifications of [18F]TZ4877. VT quantifications of [18F]TZ4877 in key brain regions for cognitive and memory ability, such as the cortex and hippocampus, positively correlated with platform latency (cortex p < 0.01, r = 0.7102; hippocampus p < 0.01, r = 0.6891). Immunofluorescence confirmed colocalizations of S1PR1 with glial fibrillary acidic protein and ionized calcium-binding adaptor molecule-1 in the AD brain. And the EA treatment significantly reduced the signals in the cortex and hippocampus. Immunohistochemistry showed a significant reduction of interleukin 1ß and tumor necrosis factor α after EA treatment. EA reversed AD by suppressing neuroinflammation in the cortex and hippocampus. The S1PR1 targeting PET tracer [18F]TZ4877 showed promise in evaluating the pathological progression of AD in clinical settings.

A novel DPP-4 inhibitor Gramcyclin A attenuates cognitive deficits in APP/PS1/tau triple transgenic mice via enhancing brain GLP-1-dependent glucose uptake.

Enhancing glucagon-like peptide 1 (GLP-1) signaling with a dipeptidyl peptidase IV (DPP-4) inhibitor might exert protective effects on Alzheimer's disease (AD). We found that intragastric administration of Gramcyclin A (10, 20 and 40 mg/kg), a novel DPP-4 inhibitor, for 3 months significantly reversed cognitive decline in APP/PS1/tau triple transgenic mice in a dose-dependent manner. Gramcyclin A treatment markedly reduced Aß plaques as well as the insoluble and soluble forms of Aß40 and Aß42 in the hippocampus of APP/PS1/tau mice. Treatment with Gramcyclin A remarkedly decreased the level of microglia and suppressed neuroinflammation in the hippocampus of APP/PS1/tau mice. Moreover, Gramcyclin A treatment could increase brain glucose uptake in APP/PS1/tau mice, as detected by 18-fluoro-2-deoxyglucose (18 F-FDG) micro-positron emission tomography (micro-PET) imaging. Furthermore, Gramcyclin A significantly increased expression of glucagon-like peptide-1 (GLP-1), GLP-1R, proliferator-activated receptor gamma coactivator (PGC)-1α and glucose transporter 4 (GLUT4), and inhibited insulin receptor (IRS)-1 phosphorylation and tau hyperphosphorylation in the hippocampus of APP/PS1/tau mice. Collectively, Gramcyclin A conferred protective effects against AD via enhancing brain GLP-1-dependent glucose uptake. The DPP-4 inhibitor Gramcyclin A might be a potential therapeutic drug for AD.

In Vivo Evaluation of Brain [18F]F-FDG Uptake Pattern Under Different Anaesthesia Protocols.

BACKGROUND/AIM: Since the use of anaesthetics has the drawback of altering radiotracer distribution, preclinical positron emission tomography (PET) imaging findings of anaesthetised animals must be carefully handled. This study aimed at assessing the cerebral [18F]F-FDG uptake pattern in healthy Wistar rats under four different anaesthesia protocols using microPET/magnetic resonance imaging (MRI) examinations. MATERIALS AND METHODS: Post-injection of 15±1.2 MBq of [18F]F-FDG, either while awake or during the isoflurane-induced incubation phase was applied. Prior to microPET/MRI imaging, one group of the rats was subjected to forane-only anaesthesia while the other group was anaesthetised with the co-administration of forane and dexmedetomidine/Dexdor® Results: While as for the whole brain it was the addition of dexmedetomidine/Dexdor® to the anaesthesia protocol that generated the differences between the radiotracer concentrations of the investigated groups, regarding the cortex, the [18F]F-FDG accumulation was rather affected by the way of incubation. To ensure the most consistent and highest uptake, forane-induced anaesthesia coupled with an awake uptake condition seemed to be most suitable method of anaesthetisation for cerebral metabolic assessment. Diminished whole brain and cortical tracer accumulation detected upon dexmedetomidine/Dexdor® administration highlights the significance of the mechanism of action of different anaesthetics on radiotracer pharmacokinetics. CONCLUSION: Overall, the standardization of PET protocols is of utmost importance to avoid the confounding factors derived from anaesthesia.

Detection of Transdermal Drug Delivery Efficiency by Shock Wave.

OBJECTIVE: This study aimed to observe the drug distribution ex-vivo after transdermal drug delivery (TDD) by Shock Wave (SW) and to explore the different effects of the two types of shock waves. MATERIALS AND METHODS: Nine female Sprague-Dawley (SD) rats were randomly divided into 3 groups: (i) control group; (ii) RESW group (0.35mJ/mm2, 2 Hz, 400 pulse); (iii) FESW group (0.16mJ/mm2, 2 Hz, 400 pulse). Micro positron emission tomography/computed tomography (PET/CT) was used to observe the distribution of [18]F-NaF. Furthermore, 12 SD rats were randomly divided into 4 groups: (i) control group; (ii) FESW group 1 (0.03mJ/mm2, 2 Hz, 400 pulse); (iii) FESW group 2 (0.16mJ/mm2, 2 Hz, 400 pulse); (iv) FESW group 3 (0.35mJ/mm2, 2 Hz, 400 pulse). High-performance liquid chromatography (HPLC) tested diclofenac sodium and glucose percutaneously TDD by FESW. Statistical significance was conducted by analysis of variance of repeated measurement. RESULTS: The micro PET/CT observed FESW could penetrate [18]F-NaF through the skin, while RESW could not. The second study found the higher the energy of the FESW, the more diclofenac sodium and glucose penetration. Repeated measures analysis of variance found a within-subject effect (diclofenac sodium, F = 4.77, p = 0.03), (glucose, F = 8.95, p = 0.006), significant differences between the control group, FESW group 1, and FESW group 2 (p < 0.05). CONCLUSION: The study found that FESW can penetrate [18]F-NaF, sugar and diclofenac sodium into the rat body. FESW has a good indication of drug penetration, which provides new biological evidence for route administration.

Micro-PET imaging of hepatitis C virus NS3/4A protease activity using a protease-activatable retention probe.

Hepatitis C virus (HCV) NS3/4A protease is an attractive target for direct-acting antiviral agents. Real-time tracking of the NS3/4A protease distribution and activity is useful for clinical diagnosis and disease management. However, no approach has been developed that can systemically detect NS3/4A protease activity or distribution. We designed a protease-activatable retention probe for tracking HCV NS3/4A protease activity via positron emission topography (PET) imaging. A cell-penetrating probe was designed that consisted of a cell-penetrating Tat peptide, HCV NS3/4A protease substrate, and a hydrophilic domain. The probe was labeled by fluorescein isothiocyanate (FITC) and 124I in the hydrophilic domain to form a TAT-ΔNS3/4A-124I-FITC probe. Upon cleavage at NS3/4A substrate, the non-penetrating hydrophilic domain is released and accumulated in the cytoplasm allowing PET or optical imaging. The TAT-ΔNS3/4A-FITC probe selectively accumulated in NS3/4A-expressing HCC36 (NS3/4A-HCC36) cells/tumors and HCV-infected HCC36 cells. PET imaging showed that the TAT-ΔNS3/4A-124I-FITC probe selectively accumulated in the NS3/4A-HCC36 xenograft tumors and liver-implanted NS3/4A-HCC36 tumors, but not in the control HCC36 tumors. The TAT-ΔNS3/4A-124I-FITC probe can be used to represent NS3/4 protease activity and distribution via a clinical PET imaging system allowing. This strategy may be extended to detect any cellular protease activity for optimization the protease-based therapies.

Therapeutic Efficacy Evaluation of Pegylated Liposome Encapsulated With Vinorelbine Plus 111In Repeated Treatments in Human Colorectal Carcinoma With Multimodalities of Molecular Imaging.

BACKGROUND/AIM: In precision therapy, liposomal encapsulated chemotherapeutic drugs have been developed to treat cancers by achieving higher drug accumulation in the tumor compared to normal tissues/organs. MATERIALS AND METHODS: We developed a novel chemoradiotherapeutic approach via nanoliposomes conjugated with vinorelbine (VNB) and 111In (111In-VNB-liposome) and examined their pharmacokinetics, biodistribution, maximum tolerance dose, and toxicity in a NOD/SCID mouse model. RESULTS: Pharmacokinetic results showed that the area under the curve (AUC) of PEGylated liposomes was about 17-fold higher than that of the free radioisotope. Tumor growth inhibition by 111In-VNB-liposome was significantly higher than that of the control (p<0.05). CONCLUSION: The tumors in NOD/SCID mice bearing HT-29/tk-luc xenografts were significantly suppressed by 111In-VNB-liposomes. The study proposed repeated treatments with a novel liposome-mediated radiochemotherapy and validation of therapeutic efficacy via imaging.

Micro-PET Imaging Demonstrates 3-O-ß-D-Glucopyranosyl Platycodigenin as an Effective Metabolite Affects Permeability of Cell Membrane and Improves Dosimetry of [18F]-Phillygenin in Lung Tissue.

Platycodon grandiflorum, as a traditional medicinal plant, is commonly used in the treatment of pulmonary disease. Platycodon saponins are proposed as active ingredients. However, the role of secondary saponin metabolites (SSM) in the traditional use of Platycodon has not yet been fully clarified. In this study, [18F]-phillygenin ([18F]-PH) probe was synthesized and thereby used as a tracer for micro-positron emission tomography scanning to explore the effects of platycodon saponins. The membrane permeability with different SSM was evaluated in vitro based on the dye-carrying capacity of fluorescein isothiocyanate. The results showed that total platycodon saponins improved the dosimetry of [18F]-PH in the lung tissue, and an SSM named 3-O-ß-D-glucopyranosyl platycodigenin (GPD682) appreciably changed the distribution of drugs both in vitro and in vivo. We propose that GPD682 could be utilized as an important ingredient to help drug delivery to the lung tissue and improve the treatment of respiratory disease.

Flow perfusion culture of MC3T3-E1 osteogenic cells on gradient calcium polyphosphate scaffolds with different pore sizes.

Calcium polyphosphate is a biodegradable bone substitute. It remains a challenge to prepare porous calcium polyphosphate with desired gradient porous structures. In this study, a modified one-step gravity sintering method was used to prepare calcium polyphosphate scaffolds with desired-gradient-pore-size distribution. The differences of porous structure, mechanical strength, and degradation rate between gradient and homogenous calcium polyphosphate scaffolds were evaluated by micro-computed tomography, scanning electron microscopy, and mechanical testing. Preosteoblastic MC3T3-E1 cells were seeded onto gradient and homogenous calcium polyphosphate scaffolds and cultured in a flow perfusion bioreactor. The distribution, proliferation, and differentiation of the MC3T3-E1 cells were compared to that of homogenous calcium polyphosphate scaffolds. Though no significant difference of cell proliferation was found between the gradient and the homogenous calcium polyphosphate scaffolds, a much higher cell differentiation and mineralization were observed in the gradient calcium polyphosphate scaffolds than that of the homogenous calcium polyphosphate scaffolds, as manifested by increased alkaline phosphatase activity (p < 0.05). The improved distribution and differentiation of cultured cells within gradient scaffolds were further supported by both (18)F-fluorine micro-positron emission tomography scanning and in vitro tetracycline labeling. We conclude that the calcium polyphosphate scaffold with gradient pore sizes enhances osteogenic cell differentiation as well as mineralization. The in vivo performance of gradient calcium polyphosphate scaffolds warrants further investigation in animal bone defect models.

Common and unique mechanisms of Chinese herbal remedies on ischemic stroke mice revealed by transcriptome analyses.

ETHNOPHARMACOLOGICAL RELEVANCE: Four traditional Chinese herbal remedies (CHR) including Buyang Huanwu decoction (BHD), Xuefu Zhuyu decoction (XZD), Tianma Gouteng decoction (TGD) and Shengyu decoction (SYD) are popular used in treating brain-related dysfunction clinically with different syndrome/pattern based on traditional Chinese medicine (TCM) principles, yet their neuroprotective mechanisms are still unclear. MATERIALS AND METHODS: Mice were subjected to an acute ischemic stroke to examine the efficacy and molecular mechanisms of action underlying these CHR. RESULTS: CHR treatment significantly enhanced the survival rate of stroke mice, with BHD being the most effective CHR. All CHR were superior to recombinant tissue-type plasminogen activator (rt-PA) treatment in successfully ameliorating brain function, infarction, and neurological deficits in stroke mice that also paralleled to improvements in blood-brain barrier damage, inflammation, apoptosis, and neurogenesis. Transcriptome analyses reveals that a total of 774 ischemia-induced probe sets were significantly modulated by four CHR, including 52 commonly upregulated genes and 54 commonly downregulated ones. Among them, activation of neurogenesis-associated signaling pathways and down-regulating inflammation and apoptosis pathways are key common mechanisms in ischemic stroke protection by all CHR. Besides, levels of plasma CX3CL1 and S100a9 in patients could be used as biomarkers for therapeutic evaluation before functional recovery could be observed. CONCLUSION: Our results suggest that using CHR, a combinatory cocktail therapy, is a better way than rt-PA for treating cerebral ischemic-associated diseases through modulating a common as well as a specific group of genes/pathways that may partially explain the syndrome differentiation and treatment principle in TCM.

A behavioral and micro positron emission tomography imaging study in a rat model of hypothyroidism.

Hypothyroidism leads to somatic, neuropsychological, and psychiatric changes that are similar to depression. The mechanisms underlying the behavioral abnormalities in adult onset hypothyroidism remain ambiguous. Hypothyroidism was induced in adult male Wistar rats by the maintenance of 0.05% propylthiouracil (PTU) in drinking water for 5 weeks (hypothyroid group; HP group); control rats (CON group) received an equivalent amount of water. The open field and sucrose preference tests were employed, and the link between behavioral changes and brain glucose metabolism was evaluated using micro positron emission tomography imaging. The open field test revealed slightly decreased locomotor activity and significantly reduced rearing and defecation in the hypothyroid group. Hypothyroid rats were also characterized by decreased body weight, sucrose preference, and relative sucrose intake compared to control rats. Hypothyroidism induced reduced brain glucose metabolism in the bilateral motor cortex, the caudate putamen, the cortex cingulate, the nucleus accumbens, and the frontal association cortex. A decreased sucrose preference was positively correlated with metabolic glucose changes in the caudate putamen and the nucleus accumbens. The results indicate that the activity pattern in adult onset hypothyroidism is different from the activity pattern when hypothyroidism is induced in the developmental period of the central nervous system. Decreased sucrose preference in hypothyroid rats may be attributed to anhedonia. Furthermore, these findings suggest there may be a common mechanism underlying adult onset hypothyroidism and depression.