scholarly journals Verapamil/Curcumin treatment attenuates the behavioral alterations observed in Williams Syndrome mice by regulation of MAPK pathway and Microglia overexpression

2021 ◽  
Author(s):  
Paula Ortiz-Romero ◽  
Gustavo Egea ◽  
Luis A Pérez-Jurado ◽  
Victoria Campuzano
Keyword(s):  
Mapk Pathway ◽  
Neurodevelopmental Disorder ◽  
Underlying Mechanism ◽  
Brain Regions ◽  
Mapk Signaling ◽  
Potential Candidate ◽  
Neuroprotective Effects ◽  
Behavioral Deficits ◽  
Activated Microglia ◽  
Beneficial Effects

AbstractWilliams-Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there currently are not any effective treatments. We investigated the progression of behavioral deficits present in CD (complete deletion) mice, a rodent model of WBS, after chronic treatment with curcumin, verapamil and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism in CD mice. Behavioral improvement correlates with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation with the control of synaptic transmission. Moreover, CD mice showed an increased activated microglia density in different brain regions, which was prevented by treatment. Therefore, results show that treatment prevented behavioral deficits by recovering altered gene expression in cortex of CD mice, reducing activated microglia and normalizing Bdnf expression levels. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice, and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients.

scholarly journals Co-Treatment With Verapamil and Curcumin Attenuates the Behavioral Alterations Observed in Williams–Beuren Syndrome Mice by Regulation of MAPK Pathway and Microglia Overexpression

2021 ◽  
Vol 12 ◽  
Author(s):  
Paula Ortiz-Romero ◽  
Alejandro González-Simón ◽  
Gustavo Egea ◽  
Luis A. Pérez-Jurado ◽  
Victoria Campuzano
Keyword(s):  
Mapk Pathway ◽  
Neurodevelopmental Disorder ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Potential Candidate ◽  
Behavioral Alterations ◽  
Neuroprotective Effects ◽  
Behavioral Deficits ◽  
Activated Microglia ◽  
Beneficial Effects

Williams–Beuren syndrome (WBS) is a rare neurodevelopmental disorder characterized by a distinctive cognitive phenotype for which there are currently no effective treatments. We investigated the progression of behavioral deficits present in WBS complete deletion (CD) mice, after chronic treatment with curcumin, verapamil, and a combination of both. These compounds have been proven to have beneficial effects over different cognitive aspects of various murine models and, thus, may have neuroprotective effects in WBS. Treatment was administered orally dissolved in drinking water. A set of behavioral tests demonstrated the efficiency of combinatorial treatment. Some histological and molecular analyses were performed to analyze the effects of treatment and its underlying mechanism. CD mice showed an increased density of activated microglia in the motor cortex and CA1 hippocampal region, which was prevented by co-treatment. Behavioral improvement correlated with the molecular recovery of several affected pathways regarding MAPK signaling, in tight relation to the control of synaptic transmission, and inflammation. Therefore, the results show that co-treatment prevented behavioral deficits by recovering altered gene expression in the cortex of CD mice and reducing activated microglia. These findings unravel the mechanisms underlying the beneficial effects of this novel treatment on behavioral deficits observed in CD mice and suggest that the combination of curcumin and verapamil could be a potential candidate to treat the cognitive impairments in WBS patients.

scholarly journals Anti–Na+/K+-ATPase immunotherapy ameliorates α-synuclein pathology through activation of Na+/K+-ATPase α1–dependent autophagy

2021 ◽  
Vol 7 (5) ◽  
pp. eabc5062
Author(s):  
Lei Cao ◽  
Siping Xiong ◽  
Zhiyuan Wu ◽  
Lei Ding ◽  
Yebo Zhou ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tyrosine Hydroxylase ◽  
Neurodegenerative Diseases ◽  
Motor Function ◽  
Therapeutic Strategy ◽  
Underlying Mechanism ◽  
Behavioral Tests ◽  
Behavioral Deficits ◽  
Cellular Homeostasis ◽  
Beneficial Effects

Na+/K+-ATPase (NKA) plays important roles in maintaining cellular homeostasis. Conversely, reduced NKA activity has been reported in aging and neurodegenerative diseases. However, little is known about the function of NKA in the pathogenesis of Parkinson’s disease (PD). Here, we report that reduction of NKA activity in NKAα1+/− mice aggravates α-synuclein–induced pathology, including a reduction in tyrosine hydroxylase (TH) and deficits in behavioral tests for memory, learning, and motor function. To reverse this effect, we generated an NKA-stabilizing monoclonal antibody, DR5-12D, against the DR region (897DVEDSYGQQWTYEQR911) of the NKAα1 subunit. We demonstrate that DR5-12D can ameliorate α-synuclein–induced TH loss and behavioral deficits by accelerating α-synuclein degradation in neurons. The underlying mechanism for the beneficial effects of DR5-12D involves activation of NKAα1-dependent autophagy via increased AMPK/mTOR/ULK1 pathway signaling. Cumulatively, this work demonstrates that NKA activity is neuroprotective and that pharmacological activation of this pathway represents a new therapeutic strategy for PD.

scholarly journals Sirtuin 3 Mediates Neuroprotection of Ketones against Ischemic Stroke

2015 ◽  
Vol 35 (11) ◽  
pp. 1783-1789 ◽  
Author(s):  
Junxiang Yin ◽  
Pengcheng Han ◽  
Zhiwei Tang ◽  
Qingwei Liu ◽  
Jiong Shi
Keyword(s):  
Ischemic Stroke ◽  
Ketone Bodies ◽  
Infarct Volume ◽  
Field Tests ◽  
Underlying Mechanism ◽  
Sirtuin 3 ◽  
Neuroprotective Effects ◽  
Beneficial Effects ◽  
Beta Hydroxybutyrate

Stroke is one of the leading causes of death. Growing evidence indicates that ketone bodies have beneficial effects in treating stroke, but their underlying mechanism remains unclear. Our previous study showed ketone bodies reduced reactive oxygen species by using NADH as an electron donor, thus increasing the NAD+/NADH ratio. In this study, we investigated whether mitochondrial NAD+-dependent Sirtuin 3 (SIRT3) could mediate the neuroprotective effects of ketone bodies after ischemic stroke. We injected mice with either normal saline or ketones (beta-hydroxybutyrate and acetoacetate) at 30 minutes after ischemia induced by transient middle cerebral artery (MCA) occlusion. We found that ketone treatment enhanced mitochondria function, reduced oxidative stress, and therefore reduced infarct volume. This led to improved neurologic function after ischemia, including the neurologic score and the performance in Rotarod and open field tests. We further showed that ketones' effects were achieved by upregulating NAD+-dependent SIRT3 and its downstream substrates forkhead box O3a (FoxO3a) and superoxide dismutase 2 (SOD2) in the penumbra region since knocking down SIRT3 in vitro diminished ketones' beneficial effects. These results provide us a foundation to develop novel therapeutics targeting this SIRT3-FoxO3a-SOD2 pathway.

Immunoregulatory Neuroprotection of Cerebral Ischaemia by Haematopoietic Stem and Precursor Cells

2009 ◽  
Vol 4 (2) ◽  
pp. 42
Author(s):  
Sönke Schwarting ◽  
Harald Neumann ◽  
◽  
Keyword(s):  
Immune System ◽  
Cerebral Ischaemia ◽  
Therapeutic Option ◽  
Underlying Mechanism ◽  
Brain Regions ◽  
Precursor Cells ◽  
Neuroprotective Effects ◽  
Immune System Activation ◽  
Ischaemic Brain ◽  
Stem Cell Treatment

Cerebral ischaemia leads to early immune system activation followed by delayed immunosuppression. Post-ischaemic inflammation contributes to neurodegeneration. Although experimental approaches using adult stem or precursor cells have repeatedly demonstrated neuroprotective effects in cerebral ischaemia, the underlying mechanism of cell-mediated neuroprotection is still debated. It was suggested that stem or precursor cells invade ischaemic brain regions and act locally. However, recent data demonstrate that systemically transplanted stem or precursor cells have strong immunoregulatory effects leading to reduced post-ischaemic brain tissue inflammation. This article argues that the systemic balance of the immune system might explain the reduced neurodegeneration observed after stem cell treatment in cerebral ischaemia. Consequently, systemic immunoregulatory neuroprotection using stem and precursor cells should be considered an important therapeutic option to prevent post-ischaemic neurodegeneration in cerebral ischaemia.

scholarly journals Metformin Treatment Attenuates Brain Inflammation and Rescues Pacap/Vip Neuropeptide Alterations in Mice Fed a High-Fat Diet

2021 ◽  
Vol 22 (24) ◽  
pp. 13660
Author(s):  
Mawj Mandwie ◽  
Jocelyn Karunia ◽  
Aram Niaz ◽  
Kevin A. Keay ◽  
Giuseppe Musumeci ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Underlying Mechanism ◽  
Brain Regions ◽  
Brain Inflammation ◽  
Low Grade ◽  
Metformin Treatment ◽  
High Fat ◽  
Activation Markers ◽  
Beneficial Effects ◽  
Therapeutic Activities

High-fat diet (HFD)-induced comorbid cognitive and behavioural impairments are thought to be the result of persistent low-grade neuroinflammation. Metformin, a first-line medication for the treatment of type-2 diabetes, seems to ameliorate these comorbidities, but the underlying mechanism(s) are not clear. Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) are neuroprotective peptides endowed with anti-inflammatory properties. Alterations to the PACAP/VIP system could be pivotal during the development of HFD-induced neuroinflammation. To unveil the pathogenic mechanisms underlying HFD-induced neuroinflammation and assess metformin’s therapeutic activities, (1) we determined if HFD-induced proinflammatory activity was present in vulnerable brain regions associated with the development of comorbid behaviors, (2) investigated if the PACAP/VIP system is altered by HFD, and (3) assessed if metformin rescues such diet-induced neurochemical alterations. C57BL/6J male mice were divided into two groups to receive either standard chow (SC) or HFD for 16 weeks. A further HFD group received metformin (HFD + M) (300 mg/kg BW daily for 5 weeks) via oral gavage. Body weight, fasting glucose, and insulin levels were measured. After 16 weeks, the proinflammatory profile, glial activation markers, and changes within the PI3K/AKT intracellular pathway and the PACAP/VIP system were evaluated by real-time qPCR and/or Western blot in the hypothalamus, hippocampus, prefrontal cortex, and amygdala. Our data showed that HFD causes widespread low-grade neuroinflammation and gliosis, with regional-specific differences across brain regions. HFD also diminished phospho-AKT(Ser473) expression and caused significant disruptions to the PACAP/VIP system. Treatment with metformin attenuated these neuroinflammatory signatures and reversed PI3K/AKT and PACAP/VIP alterations caused by HFD. Altogether, our findings demonstrate that metformin treatment rescues HFD-induced neuroinflammation in vulnerable brain regions, most likely by a mechanism involving the reinstatement of PACAP/VIP system homeostasis. Data also suggests that the PI3K/AKT pathway, at least in part, mediates some of metformin’s beneficial effects.

scholarly journals Caveolin 3-mediated integrin β1 signaling is required for the proliferation of folliculostellate cells in rat anterior pituitary gland under the influence of extracellular matrix

2011 ◽  
Vol 210 (1) ◽  
pp. 29-36 ◽  
Author(s):  
Kotaro Horiguchi ◽  
Ken Fujiwara ◽  
Cimi Ilmiawati ◽  
Motoshi Kikuchi ◽  
Takehiro Tsukada ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Pituitary Gland ◽  
Signaling Pathway ◽  
Anterior Pituitary ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Anterior Pituitary Gland ◽  
Potential Candidate ◽  
Integrin Β1 ◽  
Functional Changes

Folliculostellate (FS) cells in the anterior pituitary gland are believed to have multifunctional properties. Using transgenic rats that express green fluorescent protein (GFP) specifically in FS cells in the anterior pituitary gland (S100b-GFP rats), we recently revealed that FS cells in primary culture exhibited marked proliferation in the presence of laminin, an extracellular matrix (ECM) component of the basement membrane. In a process referred to as matricrine action, FS cells receive ECM as a signal through their receptors, which results in morphological and functional changes. In this study, we investigated matricrine signaling in FS cells and observed that the proliferation of FS cells is mediated by integrin β1, which is involved in various signaling pathways for cell migration and proliferation in response to ECM. Then, we analyzed downstream events of the integrin β1 signaling pathway in the proliferation of FS cells and identified caveolin 3 as a potential candidate molecule. Caveolin 3 is a membrane protein that binds cholesterol and a number of signaling molecules that interact with integrin β1. Using specific small interfering RNA of caveolin 3, the proliferation of FS cells was inhibited. Furthermore, caveolin 3 drove activation of the mitogen-activated protein kinase (MAPK) signaling cascades, which resulted in upregulation of cyclin D1 in FS cells. These findings suggest that matricrine signaling in the proliferation of FS cells was transduced by a caveolin 3-mediated integrin β1 signaling pathway and subsequent activation of the MAPK pathway.

scholarly journals Neuroprotective Effects and Therapeutic Potential of Transcorneal Electrical Stimulation for Depression

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2492
Author(s):  
Wing-Shan Yu ◽  
So-Hyun Kwon ◽  
Stephen Kugbere Agadagba ◽  
Leanne-Lai-Hang Chan ◽  
Kah-Hui Wong ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Therapeutic Potential ◽  
Brain Regions ◽  
Neuroprotective Effects ◽  
Transcorneal Electrical Stimulation ◽  
Beneficial Effects ◽  
Non Invasive ◽  
Antidepressant Treatments ◽  
Antidepressant Effects ◽  
Apoptosis And Inflammation

Transcorneal electrical stimulation (TES) has emerged as a non-invasive neuromodulation approach that exerts neuroprotection via diverse mechanisms, including neurotrophic, neuroplastic, anti-inflammatory, anti-apoptotic, anti-glutamatergic, and vasodilation mechanisms. Although current studies of TES have mainly focused on its applications in ophthalmology, several lines of evidence point towards its putative use in treating depression. Apart from stimulating visual-related structures and promoting visual restoration, TES has also been shown to activate brain regions that are involved in mood alterations and can induce antidepressant-like behaviour in animals. The beneficial effects of TES in depression were further supported by its shared mechanisms with FDA-approved antidepressant treatments, including its neuroprotective properties against apoptosis and inflammation, and its ability to enhance the neurotrophic expression. This article critically reviews the current findings on the neuroprotective effects of TES and provides evidence to support our hypothesis that TES possesses antidepressant effects.

scholarly journals Methylphenidate Attenuates the Cognitive and Mood Alterations Observed in Mbnl2 Knockout Mice and Reduces Microglia Overexpression

2018 ◽  
Vol 29 (7) ◽  
pp. 2978-2997 ◽  
Author(s):  
Carla Ramon-Duaso ◽  
Thomas Gener ◽  
Marta Consegal ◽  
Cristina Fernández-Avilés ◽  
Juan José Gallego ◽  
...  
Keyword(s):  
Cognitive Deficits ◽  
Potential Candidate ◽  
Mrna Levels ◽  
Drd2 Gene ◽  
Cellular Mechanisms ◽  
Multisystem Disorder ◽  
Behavioral Deficits ◽  
Beneficial Effects ◽  
Neural Spiking

Abstract Myotonic dystrophy type 1 (DM1) is a multisystem disorder affecting muscle and central nervous system (CNS) function. The cellular mechanisms underlying CNS alterations are poorly understood and no useful treatments exist for the neuropsychological deficits observed in DM1 patients. We investigated the progression of behavioral deficits present in male and female muscleblind-like 2 (Mbnl2) knockout (KO) mice, a rodent model of CNS alterations in DM1, and determined the biochemical and electrophysiological correlates in medial prefrontal cortex (mPFC), striatum and hippocampus (HPC). Male KO exhibited more cognitive impairment and depressive-like behavior than female KO mice. In the mPFC, KO mice showed an overexpression of proinflammatory microglia, increased transcriptional levels of Dat, Drd1, and Drd2, exacerbated dopamine levels, and abnormal neural spiking and oscillatory activities in the mPFC and HPC. Chronic treatment with methylphenidate (MPH) (1 and 3 mg/kg) reversed the behavioral deficits, reduced proinflammatory microglia in the mPFC, normalized prefrontal Dat and Drd2 gene expression, and increased Bdnf and Nrf2 mRNA levels. These findings unravel the mechanisms underlying the beneficial effects of MPH on cognitive deficits and depressive-like behaviors observed in Mbnl2 KO mice, and suggest that MPH could be a potential candidate to treat the CNS deficiencies in DM1 patients.

scholarly journals Neuroprotective Effects of Baicalein, Wogonin, and Oroxylin A on Amyloid Beta-Induced Toxicity via NF-κB/MAPK Pathway Modulation

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5087
Author(s):  
Yeongseon Ji ◽  
Jin Han ◽  
Nayoung Lee ◽  
Jeong-Hyun Yoon ◽  
Kumju Youn ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Neuronal Apoptosis ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Ros Generation ◽  
Oroxylin A ◽  
Neuroprotective Effects ◽  
Cycle Arrest ◽  
Tnf Α ◽  
Apoptosis And Inflammation

Amyloid beta (Aβ) peptide, one of the most important pathogenic traits of Alzheimer’s disease (AD), invokes a cascade of oxidative damage and eventually leads to neuronal death. In the present study, baicalein, wogonin, and oroxylin A, main active flavones in Scutellaria baicalensis, were evaluated for their neuroprotective effects against Aβ25–35-stimulated damage. All tested compounds decreased Aβ25–35-induced ROS generation and cell cycle arrest. In particular, baicalein exhibited the strongest antioxidant activity. In addition, these compounds suppressed apoptosis by attenuating mitochondrial dysfunction such as loss of membrane potential, Ca2+ accumulation and Bax/Bcl-2 ratio. Furthermore, all tested flavones inhibited the expression of iNOS and COX-2, which resulted in suppressing inflammatory cytokines including TNF-α, NO, and PGE2. Noticeably, all compounds exhibited the anti-inflammatory effects through downregulating NF-κB/MAPK pathway. Especially, oroxylin A was effective against both p65 and IκBα, while wogonin and baicalein were suppressed phospho-p65 and phospho-IκBα, respectively. Taken together, baicalein, wogonin, and oroxylin A can effectively relieve Aβ25–35-stimulated neuronal apoptosis and inflammation in PC12 cells via downregulating NF-κB/MAPK signaling pathway.

Dietary Quercetin Alleviated DSS-induced Colitis in Mice Through Several Possible Pathways by Transcriptome Analysis

2020 ◽  
Vol 21 (15) ◽  
pp. 1666-1673 ◽  
Author(s):  
Yuanyang Dong ◽  
Jiaqi Lei ◽  
Bingkun Zhang
Keyword(s):  
Antioxidant Capacity ◽  
Underlying Mechanism ◽  
Control Group ◽  
Sequencing Analysis ◽  
Colon Tissue ◽  
Beneficial Effects ◽  
Intestinal Integrity ◽  
Inflammatory Bowel ◽  
Vegetables And Fruits ◽  
Key Pathways

Background: The prevalence of inflammatory bowel disease is rapidly increasing around the world. Quercetin is a flavonoid commonly found in vegetables and fruits and has been reported to exert numerous pharmacological activities such as enhancing antioxidant capacity or suppressing inflammation. Objective: We aimed to explore whether quercetin was effective for IBD and the underlying mechanism of quercetin for the ameliorative effects on the DSS-induced colitis in mice. Methods: Thirty-six mice were randomly assigned to three treatments, including the control group (Ctr), DSS-induced colitis group (DSS) and DSS-induced colitis supplemented with 500 ppm quercetin (DQ500). Colitis was induced by DSS intake, and body weight was recorded every day. After six days administration of DSS, intestinal permeability was measured, and the liver was taken for antioxidant enzyme tests. Colonic tissue was taken for the histopathlogical score and RNA-sequencing analysis. Results: In this experiment, dietary quercetin for 500ppm alleviated the DSS-induced colitis, possibly by strengthening intestinal integrity, liver antioxidant capacity. Based on the results of the transcriptome of colon tissue, several key genes were modulated by quercetin. ERK1/2-FKBP pathway and RXR-STAT3 pathway were involved in the development of IBD, furthermore, in the down-regulation of S100a8/9, FBN2 contributed to lowering the risk of colongenesis. Conclusion: We demonstrated that dietary quercetin alleviated the DSS-induced colitis in mice. This is most likely due to its beneficial effects on intestinal integrity and modulation of several key pathways. Based on our research, quercetin was a promising candidate for IBD and its pharmaceutical effects on both IBD and colongenesis need further research.

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