A new underlying mechanism for the neuroprotective effect of bosutinib: Reverting toxicity‐induced PARylation in SIN1‐mediated neurotoxicity

Neuropathic pain remains as the most frequent cause of suffering and disability around the world. The isomers paeoniflorin (PF) and albiflorin (AF) are major constituents extracted from the roots ofPaeonia (P.) lactifloraPall. Neuroprotective effect of PF has been demonstrated in animal models of neuropathologies. However, only a few studies are related to the biological activities of AF and no report has been published on analgesic properties of AF about neuropathic pain to date. The aim of this study was to compare the effects of AF and PF against CCI-induced neuropathic pain in rat and explore the underlying mechanism. We had found that both PF and AF could inhibit the activation of p38 mitogen-activated protein kinase (p38 MAPK) pathway in spinal microglia and subsequent upregulated proinflammatory cytokines (interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α)). AF further displayed remarkable effects on inhibiting the activation of astrocytes, suppressing the overelevated expression of phosphorylation of c-Jun N-terminal kinases (p-JNK) in astrocytes, and decreasing the content of chemokine CXCL1 in the spinal cord. These results suggest that both PF and AF are potential therapeutic agents for neuropathic pain, which merit further investigation.

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Quetiapine Attenuates the Neuroinflammation and Executive Function Deficit in Streptozotocin-Induced Diabetic Mice

Mediators of Inflammation ◽

10.1155/2019/1236082 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Kexin Wang ◽

Feng Song ◽

Hongxing Wang ◽

Jun-hui Wang ◽

Yu Sun

Keyword(s):

Cognitive Deficit ◽

Neuroprotective Effect ◽

Underlying Mechanism ◽

Diabetic Mouse ◽

Diabetic Patients ◽

Diabetic Mice ◽

Protein Loss ◽

Monocyte Chemoattractant Protein 1 ◽

Beneficial Effects ◽

Increased Risk

Diabetic patients are at increased risk for developing memory and cognitive deficit. Prior studies indicate that neuroinflammation might be one important underlying mechanism responsible for this deficit. Quetiapine (QTP) reportedly exerts a significant neuroprotective effect in animal and human studies. Here, we investigated whether QTP could prevent memory deterioration and cognitive impairment in a streptozotocin- (STZ-) induced diabetic mouse model. In this study, we found that STZ significantly compromised the behavioral performance of mice in a puzzle box test, but administering QTP effectively attenuated this behavioral deficit. Moreover, our results showed that QTP could significantly inhibit the activation of astrocytes and microglia in these diabetic mice and reduce the generation and release of two cytokines, tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1). Meanwhile, QTP also prevented the protein loss of the synaptic protein synaptophysin (SYP) and myelin basic protein (MBP). Here, our results indicate that QTP could inhibit neuroinflammatory response from glial cells and block the injury of released cytokines to neurons and oligodendrocytes in diabetic mice (DM). These beneficial effects could protect diabetic mice from the memory and cognitive deficit. QTP may be a potential treatment compound to handle the memory and cognitive dysfunction in diabetic patients.

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Sildenafil (Viagra) Protective Effects on Neuroinflammation: The Role of iNOS/NO System in an Inflammatory Demyelination Model

Mediators of Inflammation ◽

10.1155/2013/321460 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 32

Author(s):

Catarina Raposo ◽

Ana Karolina de Santana Nunes ◽

Rayana Leal de Almeida Luna ◽

Shyrlene Meiry da Rocha Araújo ◽

Maria Alice da Cruz-Höfling ◽

...

Keyword(s):

Neuroprotective Effect ◽

Underlying Mechanism ◽

Protective Effects ◽

Wild Type ◽

Glutathione S Transferase ◽

Cox 2 ◽

Inflammatory Regulation ◽

Inos Inhibition ◽

Inflammatory Effect

We recently demonstrated that sildenafil reduces the expression of cytokines, COX-2, and GFAP in a demyelinating model induced in wild-type (WT) mice. Herein, the understandings of the neuroprotective effect of sildenafil and the mediation of iNOS/NO system on inflammatory demyelination induced by cuprizone were investigated. The cerebella of iNOS−/−mice were examined after four weeks of treatment with cuprizone alone or combined with sildenafil. Cuprizone increased GFAP, Iba-1, TNF-α, COX-2, IL-1β, and IFN-γexpression, decreased expression of glutathione S-transferase pi (GSTpi), and damaged myelin in iNOS−/−mice. Sildenafil reduced Iba-1, IFN-γ, and IL-1βlevels but had no effect on the expression of GFAP, TNF-α, and COX-2 compared to the cuprizone group. Sildenafil elevated GSTpi levels and improved the myelin structure/ultrastructure. iNOS−/−mice suffered from severe inflammation following treatment with cuprizone, while WT mice had milder inflammation, as found in the previous study. It is possible that inflammatory regulation through iNOS-feedback is absent in iNOS−/−mice, making them more susceptible to inflammation. Sildenafil has at least a partial anti-inflammatory effect through iNOS inhibition, as its effect on iNOS−/−mice was limited. Further studies are required to explain the underlying mechanism of the sildenafil effects.

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1,3,4-Oxadiazole Derivative Attenuates Chronic Constriction Injury Induced Neuropathic Pain: A Computational, Behavioral, and Molecular Approach

Brain Sciences ◽

10.3390/brainsci10100731 ◽

2020 ◽

Vol 10 (10) ◽

pp. 731

Author(s):

Muhammad Faheem ◽

Syed Hussain Ali ◽

Abdul Waheed Khan ◽

Mahboob Alam ◽

Umair Ilyas ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Sciatic Nerve ◽

Pain Perception ◽

Chronic Constriction Injury ◽

Neuroprotective Effect ◽

Underlying Mechanism ◽

Contributing Factors ◽

Neuroprotective Effects ◽

In Silico Studies

The production and up-regulation of inflammatory mediators are contributing factors for the development and maintenance of neuropathic pain. In the present study, the post-treatment of synthetic 1,3,4 oxadiazole derivative (B3) for its neuroprotective potential in chronic constriction injury-induced neuropathic pain was applied. In-silico studies were carried out through Auto Dock, PyRx, and DSV to obtain the possible binding and interactions of the ligands (B3) with COX-2, IL-6, and iNOS. The sciatic nerve of the anesthetized rat was constricted with sutures 3/0. Treatment with 1,3,4-oxadiazole derivative was started a day after surgery and continued until the 14th day. All behavioral studies were executed on day 0, 3rd, 7th, 10th, and 14th. The sciatic nerve and spinal cord were collected for further molecular analysis. The interactions in the form of hydrogen bonding stabilizes the ligand target complex. B3 showed three hydrogen bonds with IL-6. B3, in addition to correcting paw posture/deformation induced by CCI, attenuates hyperalgesia (p < 0.001) and allodynia (p < 0.001). B3 significantly raised the level of GST and GSH in both the sciatic nerve and spinal cord and reduced the LPO and iNOS (p < 0.001). B3 attenuates the pathological changes induced by nerve injury, which was confirmed by H&E staining and IHC examination. B3 down-regulates the over-expression of the inflammatory mediator IL-6 and hence provides neuroprotective effects in CCI-induced pain. The results demonstrate that B3 possess anti-nociceptive and anti-hyperalgesic effects and thus minimizes pain perception and inflammation. The possible underlying mechanism for the neuroprotective effect of B3 probably may be mediated through IL-6.

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Isoform-Specific Effects of Apolipoprotein E on Hydrogen Peroxide-Induced Apoptosis in Human Induced Pluripotent Stem Cell (iPSC)-Derived Cortical Neurons

International Journal of Molecular Sciences ◽

10.3390/ijms222111582 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11582

Author(s):

Huiling Gao ◽

Wei Zheng ◽

Cheng Li ◽

He Xu

Keyword(s):

Hydrogen Peroxide ◽

Cortical Neurons ◽

Neuronal Apoptosis ◽

Neuroprotective Effect ◽

Induced Pluripotent Stem Cell ◽

Mechanistic Explanation ◽

Underlying Mechanism ◽

Neuroprotective Effects ◽

Apoe Isoforms ◽

Induced Apoptosis

Hydrogen peroxide (H2O2)-induced neuronal apoptosis is critical to the pathology of Alzheimer’s disease (AD) as well as other neurodegenerative diseases. The neuroprotective effects of apolipoprotein (ApoE) isoforms against apoptosis and the underlying mechanism remains controversial. Here, we have generated human cortical neurons from iPSCs and induced apoptosis with H2O2. We show that ApoE2 and ApoE3 pretreatments significantly attenuate neuronal apoptosis, whereas ApoE4 has no neuroprotective effect and higher concentrations of ApoE4 even display toxic effect. We further identify that ApoE2 and ApoE3 regulate Akt/FoxO3a/Bim signaling pathway in the presence of H2O2. We propose that ApoE alleviates H2O2-induced apoptosis in human iPSC-derived neuronal culture in an isoform specific manner. Our results provide an alternative mechanistic explanation on how ApoE isoforms influence the risk of AD onset as well as a promising therapeutic target for diseases involving neuronal apoptosis in the central nervous system.

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Blocking PSD-93-CX3CL1 Interaction Promotes the Phenotypic Transformation of Microglia During Acute Ischemic Stroke

10.21203/rs.3.rs-687096/v1 ◽

2021 ◽

Author(s):

qingxiu zhang ◽

xiaowei cao ◽

hui yang ◽

xiaomei Liu ◽

shiying Lou ◽

...

Keyword(s):

Ischemic Stroke ◽

White Matter ◽

Acute Ischemic Stroke ◽

Neuroprotective Effect ◽

Underlying Mechanism ◽

White Matter Injury ◽

Tetrazolium Chloride ◽

Stroke Treatment ◽

Microglial Polarization ◽

M1 Type

Abstract BackgroundPostsynaptic density 93 (PSD-93) plays an important role in ischemic brain injury by mediating neurotoxicity and neuroinflammation. Different photypes of microglia perform an important role in ischemic crerbral injury and repair. Blocking the combination of PSD-93 and CX3C chemokine ligand 1 (CX3CL1) is beneficial in acute ischemic stroke, but the underlying mechanism remains unclear. MethodsMiddle cerebral artery occlusion (MCAO) model was established in male C57BL/6 mice. The peptide Tat-CX3CL1 (357-395aa) which disturbing the interaction of PSD-93 and CX3CL1 was used in this study to explore the mechanism of its neuroprotective effect. The production and secretion of cytokines associated with M1 and M2 type of microglia was detected by PCR and ELISA, respectively. Neurologic damage was evaluated by behavior, triphenyl tetrazolium chloride staining, and brain water content. MBP and SMI32 double immunostaining were used to detect white matter injury and double staining for Iba1 and CD68 to assess M1 type microglia polarization. ResultsThe cytokines level of M1 phenotype cytokines was increased at 6 h after stroke and peaked at 24 h after perfusion. However, the cytokines level of M2 phenotype was decreased at 6 h and 24 h following reperfusion. The Tat-CX3CL1 (357-395aa) facilitated microglial polarization from M1 type to M2 type by reducing the production of soluble CX3CL1. Furthermore, ADAM17 inhibitor GW280264x could restrain the polarization of microglia from M1 to M2 via reducing soluble CX3CL1 formation. Moreover, Tat-CX3CL1 (357-395aa) attenuated long-term cognitive deficits and improved white matter integrity. ConclusionsBlocking the binding between CX3CL1 and PSD-93 by Tat-CX3CL1 (357-395aa) could facilitate the functional recovery after ischemic stroke by promoting M1 to M2 microglial polarization transformation. Tat-CX3CL1 (357-395aa) may be a potent agent for ischemic stroke treatment.

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Echinacoside exhibits antidepressant-like effects through AMPAR–Akt/ERK–mTOR pathway stimulation and BDNF expression in mice

Chinese Medicine ◽

10.1186/s13020-021-00549-5 ◽

2022 ◽

Vol 17 (1) ◽

Author(s):

Han-Wen Chuang ◽

Tse-Yen Wang ◽

Chih-Chia Huang ◽

I-Hua Wei

Keyword(s):

Depressive Disorders ◽

Neuroprotective Effect ◽

Underlying Mechanism ◽

Mtor Pathway ◽

Antidepressant Effect ◽

Bdnf Expression ◽

Echinacea Angustifolia ◽

Extracellular Signal ◽

Wide Range ◽

Swimming Test

Abstract Background Several natural products have been demonstrated to be effective in the treatment of depressive disorders. Echinacoside, a naturally occurring phenol extracted from Cistanche tubulosa, Echinacea angustifolia, and Cistanche spp, has a wide range of physiological effects, such as antioxidation, neuroprotection, anti-inflammatory, and immunoregulation, which are closely related to depression. In addition, echinacoside can activate protein kinase B (Akt), extracellular signal–regulated kinase (ERK), and brain-derived neurotrophic factor (BDNF) in the brain. A key downstream event of the Akt, ERK, and BDNF signaling pathways, namely mechanistic target of rapamycin (mTOR) signaling, plays a crucial role in generating an rapid antidepressant effect. Thus, echinacoside is a promising therapeutic agent for depression. However, research regarding the role of echinacoside in antidepressant effect and brain mTOR activation remains lacking. Materials and methods The forced swimming test and Western blot analysis in C57BL/6 mice was used to investigate the antidepressant-like activities of echinacoside and the underlying mechanism involved inα-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)–Akt/ERK–mTOR pathway. Results We confirmed the suggestions by previous reports that echinacoside activates Akt/ERK signaling and further demonstrated that echinacoside could provide antidepressant-like effects in mice via the activation of AMPAR–Akt/ERK–mTOR pathway in the hippocampus. Conclusions To the best of our knowledge, our study is the first to reveal that echinacoside is a potential treatment for depressive disorders. Moreover, the present study suggests a mechanism for the neuroprotective effect of echinacoside.

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Phytosome Loading the Combined Extract of Mulberry Fruit and Ginger Protects against Cerebral Ischemia in Metabolic Syndrome Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/5305437 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15

Author(s):

Nut Palachai ◽

Jintanaporn Wattanathorn ◽

Supaporn Muchimapura ◽

Wipawee Thukham-mee

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Ischemic Stroke ◽

Cerebral Ischemia ◽

Brain Damage ◽

Neurological Deficit ◽

Neuroprotective Effect ◽

Underlying Mechanism ◽

Neurological Deficit Score ◽

Mulberry Fruit

The prevalence of ischemic stroke in metabolic syndrome (MetS) is continually increasing and produces a great impact on both qualities of life and annual healthcare budget. Due to the efficiency limitation of the current therapeutic strategy, the poor availability of polyphenol substances induced by the first pass effect and the beneficial effects of mulberry fruit and ginger on brain and MetS-related diseases together with the synergistic concept, the neuroprotective effect against ischemic stroke in MetS condition of phytosome containing the combined extract of mulberry fruit and ginger (PMG) has been considered. To explore the neuroprotective effect and possible underlying mechanism of PMG on brain damage in cerebral ischemic rat with MetS, male Wistar rats were induced MetS by high-carbohydrate high-fat diet (HCHF) for 16 weeks and subjected to the cerebral ischemia/reperfusion injury (CIRI) at the right middle cerebral artery (Rt. MCAO). PMG at doses of 50, 100, and 200 mg/kg were orally fed with for 21 days, and they were assessed brain damage, neurological deficit score, and the changes of oxidative stress markers, inflammatory markers, PPARγ expression, and epigenetic modification via DNMT-1 were performed. All doses of PMG significantly improved brain infarction, brain edema, and neurological deficit score. In addition, the reduction in DNMT-1, MDA level, NF-κB, TNFα, and C-reactive protein together with the increase in SOD, CAT, and GPH-Px activities, and PPARγ expression in the lesion brain were also observed. The current data clearly revealed the neuroprotective effect against cerebral ischemia with MetS condition. The possible underlying mechanism might occur partly via the suppression of DNMT-1 giving rise to the improvement of signal transduction via PPARγ resulting in the decreasing of inflammation and oxidative stress. In conclusion, PMG is the potential neuroprotectant candidate against ischemic stroke in the MetS condition. However, the clinical trial is still essential.

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Punicalagin alleviates brain injury and inflammatory responses, and regulates HO-1/Nrf-2/ARE signaling in rats after experimental intracerebral haemorrhage

Tropical Journal of Pharmaceutical Research ◽

10.4314/tjpr.v19i4.8 ◽

2020 ◽

Vol 19 (4) ◽

pp. 727-737

Author(s):

Fuchi Zhang ◽

Kang Wu ◽

Xiaolin Wu ◽

Can Xin ◽

Minghui Zhou ◽

...

Keyword(s):

Brain Injury ◽

Signaling Pathway ◽

Intracerebral Haemorrhage ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Cell Damage ◽

Neuroprotective Effect ◽

Serum Levels ◽

Underlying Mechanism ◽

Sprague Dawley

Purpose: To investigate the effect of punicalagin, an ellagitannin present in pomegranates, on intracerebral haemorrhage (ICH)-induced inflammatory responses and oxidative stress, and also unravel the underlying mechanism(s) of action. Methods: Collagenase type IV (0.2 U) was used to induce ICH in adult male Sprague-Dawley rats. Punicalagin was given to the rats at doses of 25, 50, and 75 mg/kg body weight via oral gavage for 15 days before ICH induction. The animals were sacrificed 24h following induction of ICH, and their brains were excised immediately and used for analysis. Histological changes were determined with Haematoxylin and Eosin (H&E) staining. Permeability to blood-brain barrier (BBB) was determined by quantifying the extent of extravasation of Evan Blue (EB). Protein expressions of HO-1/Nrf-2/ARE and NF-κB signaling were assayed using immunoblotting and RT-PCR. Levels of reactive oxygen species (ROS) and serum levels of cytokines were also determined. Results: Punicalagin treatment reduced inflammatory cell infiltration and cell damage, improved brain tissue architecture and BBB integrity. The punicalagin treatment increased the activities of antioxidant enzymes, and enhanced antioxidant status via activation of Nrf-2/ARE/HO-1 signaling pathway (p < 0.05). The treatment upregulated the expressions of HO-1 to 174 %, relative to 127 % in ICH control rats. Furthermore, it enhanced NF-κB levels and reversed the ICH injury-induced upregulations of IL-6, IL-18 and IL-1β. Conclusion: These findings indicate that punicalagin exerts neuroprotective effect in rats after experimental ICH through regulation of theHO-1/Nrf-2/ARE signaling pathway. Thus, punicalagin has therapeutic potential for ICH. Keywords: Brain injury, Haemoxygenase-1, Intracerebral haemorrhage, Inflammatory responses, Nrf2/ARE signalling, Punicalagin

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Ganoderma lucidumProtects Dopaminergic Neuron Degeneration through Inhibition of Microglial Activation

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nep075 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 16

Author(s):

Ruiping Zhang ◽

Shengli Xu ◽

Yanning Cai ◽

Ming Zhou ◽

Xiaohong Zuo ◽

...

Keyword(s):

Microglial Activation ◽

Neuroprotective Effect ◽

Mrna Level ◽

Underlying Mechanism ◽

Dependent Manner ◽

Chinese Medicinal Herb ◽

Neuroprotective Effects ◽

Promising Therapeutic Target ◽

Progressive Neurodegeneration ◽

Dose Dependent

Abundant evidence has suggested that neuroinflammation participates in the pathogenesis of Parkinson's disease (PD). The emerging evidence has supported that microglia may play key roles in the progressive neurodegeneration in PD and might be a promising therapeutic target.Ganoderma lucidum(GL), a traditional Chinese medicinal herb, has been shown potential neuroprotective effects in our clinical trials that make us to speculate that it might possess potent anti-inflammatory and immunomodulating properties. To test this hypothesis, we investigated the potential neuroprotective effect of GL and possible underlying mechanism of action through protecting microglial activation using co-cultures of dopaminergic neurons and microglia. The microglia is activated by LPS and MPP+-treated MES 23.5 cell membranes. Meanwhile, GL extracts significantly prevent the production of microglia-derived proinflammatory and cytotoxic factors [nitric oxide, tumor necrosis factor-α(TNF-α), interlukin 1β(IL-1β)] in a dose-dependent manner and down-regulate the TNF-αand IL-1βexpressions on mRNA level as well. In conclusion, our results support that GL may be a promising agent for the treatment of PD through anti-inflammation.

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