scholarly journals Perampanel Reduces Hyperthermia-Induced Seizures in Dravet Syndrome Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Shih-Yin Ho ◽  
Li Lin ◽  
I-Chun Chen ◽  
Che-Wen Tsai ◽  
Fang-Chia Chang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Model Potential ◽  
Temperature Tolerance ◽  
Epileptic Activity ◽  
Dravet Syndrome ◽  
Therapeutic Effects ◽  
Discharge Duration ◽  
Spontaneous Recurrent Seizures

Treatment options for Dravet syndrome are limited. The aim of this study was to evaluate the antiepileptic effect of the AMPA receptor antagonist perampanel (PER) on a mouse model of Dravet syndrome (Scn1aE1099X/+). We report here that the PER (2 mg/kg) treatment inhibited the spontaneous recurrent seizures and attenuated epileptic activity in Scn1aE1099X/+ mice. In the hyperthermia-induced seizure experiment, PER clearly increased temperature tolerance and significantly ameliorated seizure frequency and discharge duration. PER also demonstrated antiepileptic effects in a cross-over study and a synergistic effect for attenuating heat-induced seizure when given in combination with stiripentol or valproic acid. The results showed that PER effectively decreased the occurrence of spontaneous recurrent seizures and showed significant therapeutic potential for hyperthermia-induced seizures with regard to both susceptibility and severity in a Dravet syndrome mouse model. Potential therapeutic effects of PER for treatment of Dravet syndrome were demonstrated.

scholarly journals Therapeutic Effects of Intravitreously Administered Bacteriophage in a Mouse Model of Endophthalmitis Caused by Vancomycin-Sensitive or -Resistant Enterococcus faecalis

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Tatsuma Kishimoto ◽  
Waka Ishida ◽  
Ken Fukuda ◽  
Isana Nakajima ◽  
Takashi Suzuki ◽  
...  
Keyword(s):  
Mouse Model ◽  
Enterococcus Faecalis ◽  
Structural Integrity ◽  
Vision Loss ◽  
Therapeutic Potential ◽  
Therapeutic Effects ◽  
Myeloperoxidase Activity ◽  
Content Type ◽  
Viable Bacteria ◽  
Vancomycin Resistant

ABSTRACT Endophthalmitis due to infection with Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Given that the frequency of this condition caused by vancomycin-resistant Enterococcus faecalis has been increasing, the development of novel therapeutics is urgently required. We have demonstrated the therapeutic potential of bacteriophage ΦEF24C-P2 in a mouse model of endophthalmitis caused by vancomycin-sensitive (EF24) or vancomycin-resistant (VRE2) strains of E. faecalis. Phage ΦEF24C-P2 induced rapid and pronounced bacterial lysis in turbidity reduction assays with EF24, VRE2, and clinical isolates derived from patients with E. faecalis-related postoperative endophthalmitis. Endophthalmitis was induced in mice by injection of EF24 or VRE2 (1 × 104 cells) into the vitreous. The number of viable bacteria in the eye increased to >1 × 107 CFU, and neutrophil infiltration into the eye was detected as an increase in myeloperoxidase activity at 24 h after infection. A clinical score based on loss of visibility of the fundus as well as the number of viable bacteria and the level of myeloperoxidase activity in the eye were all significantly decreased by intravitreous injection of ΦEF24C-P2 6 h after injection of EF24 or VRE2. Whereas histopathologic analysis revealed massive infiltration of inflammatory cells and retinal detachment in vehicle-treated eyes, the number of these cells was greatly reduced and retinal structural integrity was preserved in phage-treated eyes. Our results thus suggest that intravitreous phage therapy is a potential treatment for endophthalmitis caused by vancomycin-sensitive or -resistant strains of E. faecalis.

scholarly journals Development of an imaging toolbox to assess the therapeutic potential and biodistribution of macrophages in a mouse model of multiple organ dysfunction

2018 ◽  
Author(s):  
Jack Sharkey ◽  
Lorenzo Ressel ◽  
Nathalie Brillant ◽  
Bettina Wilm ◽  
B. Kevin Park ◽  
...  
Keyword(s):  
Liver Function ◽  
Mouse Model ◽  
Organ Dysfunction ◽  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Multiple Organ ◽  
Therapeutic Effects ◽  
M2 Macrophages ◽  
Optoacoustic Tomography ◽  
Kidney Liver

AbstractCell-based regenerative medicine therapies require robust preclinical safety, efficacy, biodistribution and engraftment data prior to clinical testing. To address these challenges, we have developed an imaging toolbox comprising multi-spectral optoacoustic tomography and ultrasonography, which allows the degree of kidney, liver and cardiac injury and the extent of functional recovery to be assessed non-invasively in a mouse model of multi-organ dysfunction. This toolbox allowed us to determine the therapeutic effects of adoptively transferred M2 macrophages. Using bioluminescence imaging, we could then investigate the association between amelioration and biodistribution. Macrophage therapy improved kidney and liver function to a limited extent, but did not ameliorate histological damage. No improvement in cardiac function was observed. Biodistribution analysis showed that macrophages homed and persisted in the injured kidneys and liver, but did not populate the heart. Our data suggest that the limited improvement observed in kidney and liver function could be mediated by M2 macrophages.

scholarly journals Insights into Multifunctional Nanoparticle-Based Drug Delivery Systems for Glioblastoma Treatment

Molecules ◽  
2021 ◽  
Vol 26 (8) ◽  
pp. 2262
Author(s):  
Mohd Khan ◽  
Subuhi Sherwani ◽  
Saif Khan ◽  
Sultan Alouffi ◽  
Mohammad Alam ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Delivery Systems ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Survival Rates ◽  
Delivery Systems ◽  
Chemotherapeutic Agents ◽  
Membrane Receptors ◽  
Therapeutic Effects ◽  
Microvascular Proliferation

Glioblastoma (GB) is an aggressive cancer with high microvascular proliferation, resulting in accelerated invasion and diffused infiltration into the surrounding brain tissues with very low survival rates. Treatment options are often multimodal, such as surgical resection with concurrent radiotherapy and chemotherapy. The development of resistance of tumor cells to radiation in the areas of hypoxia decreases the efficiency of such treatments. Additionally, the difficulty of ensuring drugs effectively cross the natural blood–brain barrier (BBB) substantially reduces treatment efficiency. These conditions concomitantly limit the efficacy of standard chemotherapeutic agents available for GB. Indeed, there is an urgent need of a multifunctional drug vehicle system that has potential to transport anticancer drugs efficiently to the target and can successfully cross the BBB. In this review, we summarize some nanoparticle (NP)-based therapeutics attached to GB cells with antigens and membrane receptors for site-directed drug targeting. Such multicore drug delivery systems are potentially biodegradable, site-directed, nontoxic to normal cells and offer long-lasting therapeutic effects against brain cancer. These models could have better therapeutic potential for GB as well as efficient drug delivery reaching the tumor milieu. The goal of this article is to provide key considerations and a better understanding of the development of nanotherapeutics with good targetability and better tolerability in the fight against GB.

scholarly journals Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

2021 ◽  
Author(s):  
Jiqing Yang ◽  
Zunyue Zhang ◽  
Zhenrong Xie ◽  
Ling Bai ◽  
Pu Xiong ◽  
...  
Keyword(s):  
Mouse Model ◽  
Gut Microbiota ◽  
Relative Abundance ◽  
Therapeutic Potential ◽  
Withdrawal Symptoms ◽  
Anxiety And Depression ◽  
Therapeutic Effects ◽  
List Type ◽  
Psychiatric Manifestations ◽  
Behavioural Deficits

ABSTRACTObjectiveMetformin exhibits therapeutic potential in behavioural deficits induced by methamphetamine (METH) in rats. Emerging studies suggest gut microbiota may impact psychiatric symptoms, but there is no direct evidence supporting metformin’s participation in the pathophysiology of withdrawal symptoms via modulation of gut microbiota.MehodsIn order to define the functional contributions by gut microbiota and metformin to the behavioural deficits during METH withdrawal, we utilized a combination of fecal microbiota transplantation (FMT), high-throughput sequencing, and untargeted metabolomics technologies.ResultsFirst, METH addicts exhibited higher α diversity and distinct microbial structures compared to heathy controls. In particular, the relative abundance of Rikenellaceae was positively correlated with the severity of anxiety and depression. Second, both human-to-mouse and mouse-to-mouse FMTs confirmed that METH-altered-microbiota transplantation is sufficient to promote anxiety and depression-like behaviours in recipient germ-free mice, and these behavioural disturbances could be ameliorated by metformin. In-depth analysis revealed that METH significantly altered the bacterial composition and structure as well as relative abundance of several bacterial taxa and metabolites, including Rikenellaceae and inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and depression-like behaviours in mice.DiscussionThis study demonstrates that METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model. The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota-derived metabolites, highlighting the role of the gut microbiota in substance use disorders and the pathophysiology of withdrawal symptoms.Study HighlightsWhat is known?There are no targeted therapies for substance withdrawal syndrome, but there is considerable evidence that withdrawal-associated psychiatric manifestations contribute to the poor adherence to rehabilitation treatment as well as the relapse rates.Metformin has shown its therapeutic potential against METH-induced neurobehavioural changes and neurodegeneration in rats through CREB/BDNF and Akt/GSK3 signaling pathways in the anxiety-related brain nuclei.What is new here?METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model.The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota derived metabolites.Inosine complementation could restore METH withdrawal-induced anxiety and depression-like behaviours.

scholarly journals A Noninvasive Imaging Toolbox Indicates Limited Therapeutic Potential of Conditionally Activated Macrophages in a Mouse Model of Multiple Organ Dysfunction

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Jack Sharkey ◽  
Lorenzo Ressel ◽  
Nathalie Brillant ◽  
Lauren Scarfe ◽  
Bettina Wilm ◽  
...  
Keyword(s):  
Regenerative Medicine ◽  
Liver Function ◽  
Mouse Model ◽  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Multiple Organ ◽  
Therapeutic Effects ◽  
Optoacoustic Tomography ◽  
Multiple Organs ◽  
Kidney Liver

Cell-based regenerative medicine therapies require robust preclinical safety, efficacy, biodistribution, and engraftment data prior to clinical testing. To address these challenges, we have developed an imaging toolbox comprising multispectral optoacoustic tomography and ultrasonography, which allows the degree of kidney, liver, and cardiac injury and the extent of functional recovery to be assessed noninvasively in a mouse model of multiorgan dysfunction. This toolbox allowed us to determine the therapeutic effects of adoptively transferred macrophages. Using bioluminescence imaging, we could then investigate the association between amelioration and biodistribution. Macrophage therapy provided limited improvement of kidney and liver function, although not significantly so, without amelioration of histological damage. No improvement in cardiac function was observed. Biodistribution analysis showed that macrophages homed and persisted in the injured kidneys and liver but did not populate the heart. Our data suggest that the limited improvement observed in kidney and liver function could be mediated by M2 macrophages. More importantly, we demonstrate here the utility of the imaging toolbox for assessing the efficacy of potential regenerative medicine therapies in multiple organs.

L-Citrulline supplementation during pregnancy improves perinatal and postpartum maternal vascular function in a mouse model of preeclampsia

2021 ◽  
Author(s):  
Mary Gemmel ◽  
Elizabeth F Sutton ◽  
Judith Brands ◽  
Lauren Burnette ◽  
Marcia J Gallaher ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Mouse Model ◽  
Vascular Function ◽  
Ex Vivo ◽  
Treatment Options ◽  
Late Pregnancy ◽  
Therapeutic Effects ◽  
Specific Syndrome ◽  
Increased Risk ◽  
Pregnancy And Postpartum

Preeclampsia is a spontaneously occurring pregnancy complication diagnosed by new onset hypertension and end-organ dysfunction with or without proteinuria. This pregnancy-specific syndrome contributes to maternal morbidity and mortality and can have detrimental effects on fetal outcome. Preeclampsia is also linked to increased risk of maternal cardiovascular disease throughout life. Despite intense investigation of this disorder, few treatment options are available. The aim of this study was to investigate the potential therapeutic effects of maternal L-citrulline supplementation on pregnancy-specific vascular dysfunction in the ♀ C57BL/6J x ♂ C57BL/6J C1q-/- preeclampsia-like mouse model. L-citrulline is a non-essential amino acid that is converted to L-arginine to promote smooth muscle and blood vessel relaxation and improve nitric oxide (NO) mediated vascular function. To model a preeclampsia-like pregnancy, female C57BL/6J mice were mated to C1q-/- male mice, and a subset of dams were supplemented with L-citrulline throughout pregnancy. Blood pressure, systemic vascular glycocalyx, and ex-vivo vascular function were investigated in late pregnancy, and postpartum at 6 and 10 months of age. Main findings show that L-citrulline reduced blood pressure, increased vascular glycocalyx volume and rescued ex-vivo vascular function at gestation day 17.5 in this preeclampsia-like model. The vascular benefit of L-citrulline also extended postpartum, with improved vascular function and glycocalyx measures at 6 and 10 months of age. L-citrulline mediated vascular improvements appear, in part, attributable to NO pathway signaling. Taken together, L-citrulline supplementation during pregnancy appears to have beneficial effects on maternal vascular health which may have translational implications for improved maternal cardiovascular health.

Effects of Extracellular Vesicles Derived from Mesenchymal Stem/Stromal Cells on Liver Diseases

2019 ◽  
Vol 14 (5) ◽  
pp. 442-452 ◽  
Author(s):  
Wenjie Zheng ◽  
Yumin Yang ◽  
Russel Clive Sequeira ◽  
Colin E. Bishop ◽  
Anthony Atala ◽  
...  
Keyword(s):  
Regenerative Medicine ◽  
Extracellular Vesicles ◽  
Stromal Cells ◽  
Liver Diseases ◽  
Therapeutic Potential ◽  
Mechanisms Of Action ◽  
Therapeutic Effects ◽  
Chronic Liver Injury ◽  
Mediated Effects ◽  
Therapeutic Benefits

Therapeutic effects of Mesenchymal Stem/Stromal Cells (MSCs) transplantation have been observed in various disease models. However, it is thought that MSCs-mediated effects largely depend on the paracrine manner of secreting cytokines, growth factors, and Extracellular Vesicles (EVs). Similarly, MSCs-derived EVs also showed therapeutic benefits in various liver diseases through alleviating fibrosis, improving regeneration of hepatocytes, and regulating immune activity. This review provides an overview of the MSCs, their EVs, and their therapeutic potential in treating various liver diseases including liver fibrosis, acute and chronic liver injury, and Hepatocellular Carcinoma (HCC). More specifically, the mechanisms by which MSC-EVs induce therapeutic benefits in liver diseases will be covered. In addition, comparisons between MSCs and their EVs were also evaluated as regenerative medicine against liver diseases. While the mechanisms of action and clinical efficacy must continue to be evaluated and verified, MSCs-derived EVs currently show tremendous potential and promise as a regenerative medicine treatment for liver disease in the future.

Therapeutic Potential of Amniotic Fluid Derived Mesenchymal Stem Cells Based on their Differentiation Capacity and Immunomodulatory Properties

2019 ◽  
Vol 14 (4) ◽  
pp. 327-336 ◽  
Author(s):  
Carl R. Harrell ◽  
Marina Gazdic ◽  
Crissy Fellabaum ◽  
Nemanja Jovicic ◽  
Valentin Djonov ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Animal Models ◽  
Amniotic Fluid ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Therapeutic Effects ◽  
Differentiation Potential ◽  
Differentiation Capacity ◽  
Cell Based Therapy

Background: Amniotic Fluid Derived Mesenchymal Stem Cells (AF-MSCs) are adult, fibroblast- like, self-renewable, multipotent stem cells. During the last decade, the therapeutic potential of AF-MSCs, based on their huge differentiation capacity and immunomodulatory characteristics, has been extensively explored in animal models of degenerative and inflammatory diseases. Objective: In order to describe molecular mechanisms responsible for the therapeutic effects of AFMSCs, we summarized current knowledge about phenotype, differentiation potential and immunosuppressive properties of AF-MSCs. Methods: An extensive literature review was carried out in March 2018 across several databases (MEDLINE, EMBASE, Google Scholar), from 1990 to present. Keywords used in the selection were: “amniotic fluid derived mesenchymal stem cells”, “cell-therapy”, “degenerative diseases”, “inflammatory diseases”, “regeneration”, “immunosuppression”. Studies that emphasized molecular and cellular mechanisms responsible for AF-MSC-based therapy were analyzed in this review. Results: AF-MSCs have huge differentiation and immunosuppressive potential. AF-MSCs are capable of generating cells of mesodermal origin (chondrocytes, osteocytes and adipocytes), neural cells, hepatocytes, alveolar epithelial cells, insulin-producing cells, cardiomyocytes and germ cells. AF-MSCs, in juxtacrine or paracrine manner, regulate proliferation, activation and effector function of immune cells. Due to their huge differentiation capacity and immunosuppressive characteristic, transplantation of AFMSCs showed beneficent effects in animal models of degenerative and inflammatory diseases of nervous, respiratory, urogenital, cardiovascular and gastrointestinal system. Conclusion: Considering the fact that amniotic fluid is obtained through routine prenatal diagnosis, with minimal invasive procedure and without ethical concerns, AF-MSCs represents a valuable source for cell-based therapy of organ-specific or systemic degenerative and inflammatory diseases.

The therapeutic potential of resveratrol in a mouse model of melanoma lung metastasis

2020 ◽  
Vol 88 ◽  
pp. 106905 ◽  
Author(s):  
Amirhossein Davoodvandi ◽  
Maryam Darvish ◽  
Sarina Borran ◽  
Majid Nejati ◽  
Samaneh Mazaheri ◽  
...  
Keyword(s):  
Mouse Model ◽  
Lung Metastasis ◽  
Therapeutic Potential
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