scholarly journals Potential therapeutic effects of Nrf2 activators on intracranial hemorrhage

2021 ◽  
pp. 0271678X2098456
Author(s):  
Takahiko Imai ◽  
Hirofumi Matsubara ◽  
Hideaki Hara
Keyword(s):  
Brain Injury ◽  
Animal Models ◽  
Intracranial Hemorrhage ◽  
Therapeutic Potential ◽  
Heme Oxygenase 1 ◽  
Therapeutic Effects ◽  
Secondary Brain Injury ◽  
Pathological Conditions ◽  
Poor Outcomes ◽  
Effective Drugs

Intracranial hemorrhage (ICH) is a devastating disease which induces high mortality and poor outcomes including severe neurological dysfunctions. ICH pathology is divided into two types: primary brain injury (PBI) and secondary brain injury (SBI). Although there are numerous preclinical studies documenting neuroprotective agents in experimental ICH models, no effective drugs have been developed for clinical use due to complicated ICH pathology. Oxidative and inflammatory stresses play central roles in the onset and progression of brain injury after ICH, especially SBI. Nrf2 is a crucial transcription factor in the anti-oxidative stress defense system. Under normal conditions, Nrf2 is tightly regulated by the Keap1. Under ICH pathological conditions, such as overproduction of reactive oxygen species (ROS), Nrf2 is translocated into the nucleus where it up-regulates the expression of several anti-oxidative phase II enzymes such as heme oxygenase-1 (HO-1). Recently, many reports have suggested the therapeutic potential of Nrf2 activators (including natural or synthesized compounds) for treating neurodegenerative diseases. Moreover, several Nrf2 activators attenuate ischemic stroke-induced brain injury in several animal models. This review summarizes the efficacy of several Nrf2 activators in ICH animal models. In the future, Nrf2 activators might be approved for the treatment of ICH patients.

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.

scholarly journals HMGB1 a-Box Reverses Brain Edema and Deterioration of Neurological Function in a Traumatic Brain Injury Mouse Model

2018 ◽  
Vol 46 (6) ◽  
pp. 2532-2542 ◽  
Author(s):  
Lijun Yang ◽  
Feng Wang ◽  
Liang Yang ◽  
Yunchao Yuan ◽  
Yan Chen ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Brain Edema ◽  
Therapeutic Potential ◽  
High Mobility ◽  
Neurological Injury ◽  
Secondary Brain Injury ◽  
Cell Degeneration ◽  
Injured Brain ◽  
Walking Tests

Background/Aims: Traumatic brain injury (TBI) is a complex neurological injury in young adults lacking effective treatment. Emerging evidences suggest that inflammation contributes to the secondary brain injury following TBI, including breakdown of the blood brain barrier (BBB), subsequent edema and neurological deterioration. High mobility group box-1 (HMGB1) has been identified as a key cytokine in the inflammation reaction following TBI. Here, we investigated the therapeutic efficacy of HMGB1 A-box fragment, an antagonist competing with full-length HMGB1 for receptor binding, against TBI. Methods: TBI was induced by controlled cortical impact (CCI) in adult male mice. HMGB1 A-box fragment was given intravenously at 2 mg/kg/day for 3 days after CCI. HMGB1 A-box-treated CCI mice were compared with saline-treated CCI mice and sham mice in terms of BBB disruption evaluated by Evan’s blue extravasation, brain edema by brain water content, cell death by propidium iodide staining, inflammation by Western blot and ELISA assay for cytokine productions, as well as neurological functions by the modified Neurological Severity Score, wire grip and beam walking tests. Results: HMGB1 A-box reversed brain damages in the mice following TBI. It significantly reduced brain edema by protecting integrity of the BBB, ameliorated cell degeneration, and decreased expression of pro-inflammatory cytokines released in injured brain after TBI. These cellular and molecular effects were accompanied by improved behavioral performance in TBI mice. Notably, HMGB1 A-box blocked IL-1β-induced HMGB1 release, and preferentially attenuated TLR4, Myd88 and P65 in astrocyte cultures. Conclusion: Our data suggest that HMGB1 is involved in CCI-induced TBI, which can be inhibited by HMGB1 A-box fragment. Therefore, HMGB1 A-box fragment may have therapeutic potential for the secondary brain damages in TBI.

scholarly journals Saikosaponin D Ameliorates Mechanical Hypersensitivity in Animal Models of Neuropathic Pain

2020 ◽  
Vol 07 (04) ◽  
pp. e145-e149
Author(s):  
Gyeongbeen Lee ◽  
Yeon-Ju Nam ◽  
Woo Jung Kim ◽  
Bo Hye Shin ◽  
Jong Suk Lee ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Animal Models ◽  
Oral Administration ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Receptor Potential ◽  
Repeated Administration ◽  
Therapeutic Effects ◽  
Mechanical Hypersensitivity ◽  
Pain Outcomes

AbstractWe have previously identified saikosaponins as transient receptor potential ankyrin 1 antagonists and showed that saikosaponin D improves neuropathic pain induced by the anticancer drug vincristine in mice. In order to gain more insight into the therapeutic effects of saikosaponin D, we tested saikosaponin D in animal models of neuropathic pain induced by either streptozotocin, which mimics diabetes, or paclitaxel, a commonly used chemotherapy treatment. Our findings indicate that although saikosaponin D improved pain outcomes in neuropathic pain models, the mechanisms underlying the therapeutic effects of saikosaponin D appear to differ between streptozotocin- and paclitaxel-induced pain. Streptozotocin-induced neuropathic pain was significantly alleviated 30 minutes after oral administration of saikosaponin D, while 1-day oral administration of saikosaponin D had little effect on paclitaxel-induced mechanical hypersensitivity. Attenuation of paclitaxel-induced mechanical hypersensitivity was evident only after repeated administration of saikosaponin D. Although the mechanisms underlying the therapeutic effects of saikosaponin D remain to be elucidated, our results shed new light on the therapeutic potential of saikosaponin D in the management of neuropathic pain caused by diabetes or chemotherapy.

The role of caspase family in acute brain injury: the potential therapeutic targets in the future

2021 ◽  
Vol 19 ◽  
Author(s):  
Anke Zhang ◽  
Zeyu Zhang ◽  
Yibo Liu ◽  
Cameron Lenahan ◽  
Houshi Xu ◽  
...  
Keyword(s):  
Brain Injury ◽  
Biological Function ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Acute Brain Injury ◽  
Therapeutic Effects ◽  
Caspase Inhibitors ◽  
Caspase Family ◽  
Translational Strategies

: The caspase family is commonly involved in the pathophysiology of acute brain injury (ABI) through complex apoptotic, pyroptotic, and inflammatory pathways. Current translational strategies for caspase modulation in ABI primarily focus on caspase inhibitors. Because there are no caspase-inhibiting drugs approved for clinical use on the market, the development of caspase inhibitors remains an attractive challenge for researchers and clinicians. Therefore, we conducted the present review with the aim of providing a comprehensive introduction of caspases in ABI. In this review, we summarized the available evidence and potential mechanisms regarding the biological function of caspases. We also reviewed the therapeutic effects of caspase inhibitors on ABI and its subsequent complications. However, various important issues remain unclear, prompting further verification of the efficacy and safety regarding clinical application of caspase inhibitors. We believe that our work will be helpful to further understand the critical role of the caspase family, and will provide novel therapeutic potential for ABI treatment.

scholarly journals Co-Expression Network Analysis of MicroRNAs and Proteins in Severe Traumatic Brain Injury: A Systematic Review

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2425
Author(s):  
Claire Osgood ◽  
Zubair Ahmed ◽  
Valentina Di Pietro
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Therapeutic Potential ◽  
Psychosocial Problems ◽  
Bioinformatic Analysis ◽  
Healthcare Services ◽  
Secondary Brain Injury ◽  
Mortality And Morbidity ◽  
Severe Tbi ◽  
Novel Target

Traumatic brain injury (TBI) represents one of the leading causes of mortality and morbidity worldwide, placing an enormous socioeconomic burden on healthcare services and communities around the world. Survivors of TBI can experience complications ranging from temporary neurological and psychosocial problems to long-term, severe disability and neurodegenerative disease. The current lack of therapeutic agents able to mitigate the effects of secondary brain injury highlights the urgent need for novel target discovery. This study comprises two independent systematic reviews, investigating both microRNA (miRNA) and proteomic expression in rat models of severe TBI (sTBI). The results were combined to perform integrated miRNA-protein co-expression analyses with the aim of uncovering the potential roles of miRNAs in sTBI and to ultimately identify new targets for therapy. Thirty-four studies were included in total. Bioinformatic analysis was performed to identify any miRNA–protein associations. Endocytosis and TNF signalling pathways were highlighted as common pathways involving both miRNAs and proteins found to be differentially expressed in rat brain tissue following sTBI, suggesting efforts to find novel therapeutic targets that should be focused here. Further high-quality investigations are required to ascertain the involvement of these pathways and their miRNAs in the pathogenesis of TBI and other CNS diseases and to therefore uncover those targets with the greatest therapeutic potential.

Central 5-HT2 antagonists: A preclinical evaluation of a therapeutic potential

1990 ◽  
Vol 2 (4) ◽  
pp. 101-109 ◽  
Author(s):  
T.F. Meert ◽  
F. Awouters
Keyword(s):  
Animal Models ◽  
Negative Symptoms ◽  
Tricyclic Antidepressants ◽  
Therapeutic Potential ◽  
Test Procedure ◽  
Therapeutic Effects ◽  
Preclinical Evaluation ◽  
Animal Models Of Depression ◽  
Animal Models Of Anxiety ◽  
Positive And Negative Symptoms

SummaryA preclinical evaluation is presented of the serotonin 5-HT2 antagonists ritanserin and risperidone. Whereas ritanserin is a relative selective 5-HT2 antagonist, risperidone is a potent 5-HT2 and catecholamine antagonist. The pharmacological differences between both drugs are also observed in the drug discrimination test procedure. Using DOM, d-amphetamine and cocaine. Ritanserin was found active in animal models of anxiety using natural aversive stimuli; and in animal models of depression. Clear differences were observed between ritanserin and the benzodiazepines and between ritanserin and the tricyclic antidepressants. Risperidone was active in animal models of psychosis. Risperidone has, as opposed to classical neuroleptics such as haloperidol, less risks of inducing a dopamine D2 overblockade. Clinically, ritanserin is described as a thymostenic agent.Risperidone is an antipsychotic with therapeutic effects on both the positive and negative symptoms of schizophrenia and with a reduced risk of extrapyramidal side-effects.

scholarly journals Identification of hub genes and small-molecule compounds related to intracerebral hemorrhage with bioinformatics analysis

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7782 ◽  
Author(s):  
Zhendong Liu ◽  
Ruotian Zhang ◽  
Xin Chen ◽  
Penglei Yao ◽  
Tao Yan ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Small Molecule ◽  
Rat Model ◽  
Therapeutic Potential ◽  
Receptor Interaction ◽  
Therapeutic Effects ◽  
Secondary Brain Injury ◽  
Ppi Network ◽  
Hub Genes ◽  
Brain Tissues

Background Because of the complex mechanisms of injury, conventional surgical treatment and early blood pressure control does not significantly reduce mortality or improve patient prognosis in cases of intracerebral hemorrhage (ICH). We aimed to identify the hub genes associated with intracerebral hemorrhage, to act as therapeutic targets, and to identify potential small-molecule compounds for treating ICH. Methods The GSE24265 dataset, consisting of data from four perihematomal brain tissues and seven contralateral brain tissues, was downloaded from the Gene Expression Omnibus (GEO) database and screened for differentially expressed genes (DEGs) in ICH, with a fold change (FC) value of (|log2FC|) > 2 and a P-value of <0.05 set as cut-offs. The functional annotation of DEGs was performed using Gene Ontology (GO) resources, and the cell signaling pathway analysis of DEGs was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG), with a P-value of <0.05 set as the cut-off. We constructed a protein-protein interaction (PPI) network to clarify the interrelationships between the different DEGs and to select the hub genes with significant interactions. Next, the DEGs were analyzed using the CMap tool to identify small-molecule compounds with potential therapeutic effects. Finally, we verified the expression levels of the hub genes by RT-qPCR on the rat ICH model. Result A total of 59 up-regulated genes and eight down-regulated genes associated with ICH were identified. The biological functions of DEGs associated with ICH are mainly involved in the inflammatory response, chemokine activity, and immune response. The KEGG analysis identified several pathways significantly associated with ICH, including but not limited to HIF-1, TNF, toll-like receptor, cytokine-cytokine receptor interaction, and chemokine molecules. A PPI network consisting of 57 nodes and 373 edges was constructed using STRING, and 10 hub genes were identified with Cytoscape software. These hub genes are closely related to secondary brain injury induced by ICH. RT-qPCR results showed that the expression of ten hub genes was significantly increased in the rat model of ICH. In addition, a CMap analysis of three small-molecule compounds revealed their therapeutic potential. Conclusion In this study we obtained ten hub genes, such as IL6, TLR2, CXCL1, TIMP1, PLAUR, SERPINE1, SELE, CCL4, CCL20, and CD163, which play an important role in the pathology of ICH. At the same time, the ten hub genes obtained through PPI network analysis were verified in the rat model of ICH. In addition, we obtained three small molecule compounds that will have therapeutic effects on ICH, including Hecogenin, Lidocaine, and NU-1025.

scholarly journals Biologic Effect of Hydrogen Sulfide and Its Role in Traumatic Brain Injury

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Jiaxin Zhang ◽  
Shaoyi Zhang ◽  
Haiyan Shan ◽  
Mingyang Zhang
Keyword(s):  
Traumatic Brain Injury ◽  
Hydrogen Sulfide ◽  
Brain Injury ◽  
Therapeutic Potential ◽  
Long Term Potentiation ◽  
Secondary Brain Injury ◽  
Term Potentiation ◽  
Great Hope ◽  
Biologic Effects ◽  
Physiological Dose

Ever since endogenous hydrogen sulfide (H2S) was found in mammals in 1989, accumulated evidence has demonstrated that H2S functions as a novel neurological gasotransmitter in brain tissues and may play a key role in traumatic brain injury. It has been proved that H2S has an antioxidant, anti-inflammatory, and antiapoptosis function in the neuron system and functions as a neuroprotective factor against secondary brain injury. In addition, H2S has other biologic effects such as regulating the intracellular concentration of Ca2+, facilitating hippocampal long-term potentiation (LTP), and activating ATP-sensitive K channels. Due to the toxic nature of H2S when exceeding the physiological dose in the human body, only a small amount of H2S-related therapies was applied to clinical treatment. Therefore, it has huge therapeutic potential and has great hope for recovering patients with traumatic brain injury.

scholarly journals Therapeutic Potential of Pluripotent Stem Cell-derived Dopaminergic Progenitors in Parkinson's Disease: A Systematic Review Protocol

2020 ◽  
Author(s):  
Aliasghar Karimi ◽  
Mitra Elmi ◽  
Zahra Shiri ◽  
Hossein Baharvand
Keyword(s):  
Systematic Review ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Models ◽  
Therapeutic Potential ◽  
Experimental Studies ◽  
Risk Of Bias ◽  
Substantia Nigra Pars Compacta ◽  
Therapeutic Effects ◽  
Promising Alternative

Abstract Background: Parkinson's disease (PD) is the second most common age-dependent neurodegenerative disease that causes motor and cognitive disabilities. This disease is associated with a loss of dopamine content within the putamen, which stems from the degeneration of dopaminergic (DA) neurons in the Substantia Nigra pars Compacta (SNc). Several approved drugs are available that can effectively treat symptoms of PD. However, long-term medical management is often complicated and does not delay or halt disease progression. Alternatively, cell replacement strategies can address these shortcomings and provide dopamine where it is needed. Although using human pluripotent stem cells (hPSCs) for treatment of PD is a promising alternative, no consensus in the literature pertains to efficacy concerns of hPSC-based therapy for PD. This systematic review aims to investigate the efficacy of hPSC-derived DA progenitor transplantation to treat PD in preclinical animal models.Methods: This is a systematic review of preclinical studies in animal models of PD. We intend to use the following databases as article sources: MEDLINE (via PubMed), Web of Science, and SCOPUS without any restrictions on language or publication status for all related articles published until the end of 2019. Rescue of motor deficits is defined as the primary outcome, while histological and imaging data comprise the secondary outcomes. Two independent reviewers will select the titles and abstracts, extract data from qualifying studies, and assess the risk of bias by using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool and the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist. The standardized mean difference (SMD) will be calculated to determine the efficacy of the treatment, with 95% confidence intervals (95% CI). The heterogeneity between studies will be calculated by "I2 inconsistency of values and Cochran's Q statistical test", where I2 > 50% and/or p < 0.10 suggest high heterogeneity. Meta-analyses of random effects will be run when appropriate.Discussion: This study will present an overview of preclinical research on hPSCs and their therapeutic effects in PD animal models. This systematic review will point out the strengths and limitations of studies in the current literature while encouraging the funding of new studies by public health managers and governmental bodies.

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