scholarly journals Neuroprotective Effect of Clobenpropit against Lipopolysaccharide-Induced Cognitive Deficits via Attenuating Neuroinflammation and Enhancing Mitochondrial Functions in Mice

2021 ◽  
Vol 11 (12) ◽  
pp. 1617
Author(s):  
Vasudevan Mani ◽  
Minhajul Arfeen ◽  
Hussein M. Ali ◽  
Abdel-Moneim Hafez Abdel-Moneim ◽  
Maha Aldubayan ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Cognitive Deficits ◽  
Neuroprotective Effect ◽  
Neuronal Cell ◽  
Chain Complex ◽  
Neuronal Necrosis ◽  
Memory Error ◽  
Mitochondrial Respiratory Chain Complex ◽  
Mitochondrial Functions ◽  
Tgf Β1

Clobenpropit (CLO), an antagonist on histamine H3 receptors (HH3R), has been shown to protect NMDA-induced neuronal necrosis in cortical neuronal cell culture from rats. In this work, we explored its potential on lipopolysaccharide (LPS)-induced memory deficits, neuroinflammation, and mitochondrial dysfunction in mice. CLO (1 and 3 mg/kg, p.o.) was treated continually for 30 days, and neurotoxicity was induced by four doses of LPS (250 µg/kg, i.p.). The radial arm maze (RAM) was used to access memory behaviors. After the REM test, brain tissue was collected from each mouse to estimate pro-inflammatory cytokines (TNFα and IL6), anti-inflammatory cytokines (TGF-β1 and IL-10), cyclooxygenase-2 (COX 2), and mitochondrial respiratory chain complex (MRCC- I, II and IV) enzymes. CLO treatment reversed the LPS-induced behavioral deficits by a significant reduction in time taken to consume all five bites (TTB), working memory error (WME), and reference memory error (REM) in the REM test. Regarding neuroinflammation, it attenuated the release of COX, TNF-α, and IL-6, and augmented TGF-β1 and IL-10 levels in the brain. Reversal of LPS-induced brain MRCC (I, II, and IV) levels also resulted with CLO treatment. From these findings, CLO promises neuroprotection against LPS-induced cognitive deficits by ameliorating neuroinflammation and restoring the MRCC enzymes in mice.

scholarly journals Neuroprotective Effects of Chrysin Mediated by Estrogenic Receptors Following Cerebral Ischemia and Reperfusion in Male Rats

2021 ◽  
Vol 12 (1) ◽  
pp. 149-162
Author(s):  
Maryam Khombi Shooshtari ◽  
◽  
Yaghoob Farbood ◽  
Seyed Mohammad Taghi Mansouri ◽  
Mohammad Badavi ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Cognitive Deficits ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Male Rats ◽  
Neuroprotective Effects ◽  
Necrosis Factor Alpha ◽  
Male Wistar Rats

Introduction: Ischemic stroke is one of the leading causes of morbidity and mortality worldwide. Neuroprotective strategies were reported to attenuate cognitive deficits after ischemic incidents. Here we studied the neuroprotective potential of chrysin in a rat model of cerebral Ischemia/Reperfusion (I/R) in the presence or absence of Estrogen Receptors (ERs). Methods: Adult male Wistar rats were pretreated with chrysin (CH) (CH; 30 mg/kg; gavage; for 21 consecutive days) alone or with selective ERs antagonists (ERα antagonist MPP; ERβ antagonist PHTPP; IP) or nonselective ERs antagonist (ICI182780; IP). Then, the bilateral common carotid arteries were occluded for 20 min, which was followed by 72 h reperfusion. Subsequently, cognitive performance was evaluated by Morris Water Maze (MWM) and shuttle box tasks, and afterward, their hippocampi were removed for ELISA assays and H&E staining. Oxidative indicators Malondialdehyde (MDA) and Glutathione Peroxidase (GPx), as well as inflammation mediators interleukin (IL)-1β and tumor necrosis factor-alpha (TNFα), were measured using commercial kits. Results: Results of the current study showed that the anti-oxidative and anti-inflammatory properties of CH are possible mechanisms that could improve cognitive deficits and prevent neuronal cell death following I/R (P<0.001). These effects were reversed by ICI182780 (P>0.05). Furthermore, when chrysin was co-treated with ERβ antagonist, PHTPP showed a weak neuroprotective effect in I/R rats. However, these parameters were not significantly different when chrysin was combined with ERα antagonist MPP. Conclusion: Our data confirm that chrysin could potentially serve as a neuroprotective agent against devastating effects of cerebral I/R injury, which may be mediated via its interaction with ERs, especially ERβ.

scholarly journals Quercetin attenuates the reduction of parvalbumin in middle cerebral artery occlusion animal model

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Dong-Ju Park ◽  
Ju-Bin Kang ◽  
Fawad-Ali Shah ◽  
Phil-Ok Koh
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Neuroprotective Effect ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Male Rats ◽  
Neurological Deficits ◽  
Glutamate Toxicity ◽  
Cerebral Artery Occlusion

Abstract Background Calcium is a critical factor involved in modulation of essential cellular functions. Parvalbumin is a calcium buffering protein that regulates intracellular calcium concentrations. It prevents rises in calcium concentrations and inhibits apoptotic processes during ischemic injury. Quercetin exerts potent antioxidant and anti-apoptotic effects during brain ischemia. We investigated whether quercetin can regulate parvalbumin expression in cerebral ischemia and glutamate toxicity-induced neuronal cell death. Adult male rats were treated with vehicle or quercetin (10 mg/kg) 30 min prior to middle cerebral artery occlusion (MCAO) and cerebral cortical tissues were collected 24 h after MCAO. We used various techniques including Western blot, reverse transcription-PCR, and immunohistochemical staining to elucidate the changes of parvalbumin expression. Results Quercetin ameliorated MCAO-induced neurological deficits and behavioral changes. Moreover, quercetin prevented MCAO-induced a decrease in parvalbumin expression. Conclusions These findings suggest that quercetin exerts a neuroprotective effect through regulation of parvalbumin expression.

Curcumin Reduces Neuroinflammation and Improves the Impairments of Anesthetics on Learning and Memory by Regulating the Expression of miR-181a-5p

2021 ◽  
pp. 1-9
Author(s):  
Guizhen Liu ◽  
Yuchuan Sun ◽  
Fei Liu
Keyword(s):  
Cognitive Impairment ◽  
Protective Effect ◽  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Inflammatory Cytokines ◽  
Neuroprotective Effect ◽  
Morris Water Maze Test ◽  
Sprague Dawley ◽  
Protein Levels ◽  
Sprague Dawley Rats

<b><i>Objective:</i></b> The purpose of this study was to explore the role of curcumin (Cur) in isoflurane (ISO)-induced learning and memory dysfunction in Sprague-Dawley rats and further elucidate the mechanism of the protective effect produced by Cur. <b><i>Methods:</i></b> Rat models of cognitive impairment were established by inhaling 3% ISO. The Morris water maze test was used to assess the cognitive function of rats. ELISA and qRT-PCR were used to analyze the protein levels of pro-inflammatory cytokines and expression levels of miR-181a-5p, respectively. <b><i>Results:</i></b> Cur significantly improved the ISO-induced cognitive dysfunction in rats and alleviated the ISO-induced neuroinflammation. miR-181a-5p was overexpressed in ISO-induced rats, while Cur treatment significantly reduced the expression of miR-181a-5p. Overexpression of miR-181a-5p promoted the cognitive impairment and the release of inflammatory cytokines and reversed the neuroprotective effect of Cur. <b><i>Conclusion:</i></b> Cur has a protective effect on ISO-induced cognitive dysfunction, which may be achieved by regulating the expression of miR-181a-5p.

scholarly journals AIF3 splicing switch triggers neurodegeneration

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Shuiqiao Liu ◽  
Mi Zhou ◽  
Zhi Ruan ◽  
Yanan Wang ◽  
Calvin Chang ◽  
...  
Keyword(s):  
Cell Death ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Nuclear Translocation ◽  
Chromatin Condensation ◽  
Neuronal Cell ◽  
Adult Brain ◽  
Postmortem Brain ◽  
Mitochondrial Functions

Abstract Background Apoptosis-inducing factor (AIF), as a mitochondrial flavoprotein, plays a fundamental role in mitochondrial bioenergetics that is critical for cell survival and also mediates caspase-independent cell death once it is released from mitochondria and translocated to the nucleus under ischemic stroke or neurodegenerative diseases. Although alternative splicing regulation of AIF has been implicated, it remains unknown which AIF splicing isoform will be induced under pathological conditions and how it impacts mitochondrial functions and neurodegeneration in adult brain. Methods AIF splicing induction in brain was determined by multiple approaches including 5′ RACE, Sanger sequencing, splicing-specific PCR assay and bottom-up proteomic analysis. The role of AIF splicing in mitochondria and neurodegeneration was determined by its biochemical properties, cell death analysis, morphological and functional alterations and animal behavior. Three animal models, including loss-of-function harlequin model, gain-of-function AIF3 knockin model and conditional inducible AIF splicing model established using either Cre-loxp recombination or CRISPR/Cas9 techniques, were applied to explore underlying mechanisms of AIF splicing-induced neurodegeneration. Results We identified a nature splicing AIF isoform lacking exons 2 and 3 named as AIF3. AIF3 was undetectable under physiological conditions but its expression was increased in mouse and human postmortem brain after stroke. AIF3 splicing in mouse brain caused enlarged ventricles and severe neurodegeneration in the forebrain regions. These AIF3 splicing mice died 2–4 months after birth. AIF3 splicing-triggered neurodegeneration involves both mitochondrial dysfunction and AIF3 nuclear translocation. We showed that AIF3 inhibited NADH oxidase activity, ATP production, oxygen consumption, and mitochondrial biogenesis. In addition, expression of AIF3 significantly increased chromatin condensation and nuclear shrinkage leading to neuronal cell death. However, loss-of-AIF alone in harlequin or gain-of-AIF3 alone in AIF3 knockin mice did not cause robust neurodegeneration as that observed in AIF3 splicing mice. Conclusions We identified AIF3 as a disease-inducible isoform and established AIF3 splicing mouse model. The molecular mechanism underlying AIF3 splicing-induced neurodegeneration involves mitochondrial dysfunction and AIF3 nuclear translocation resulting from the synergistic effect of loss-of-AIF and gain-of-AIF3. Our study provides a valuable tool to understand the role of AIF3 splicing in brain and a potential therapeutic target to prevent/delay the progress of neurodegenerative diseases.

scholarly journals BDMC protects AD in vitro via AMPK and SIRT1

2020 ◽  
Vol 11 (1) ◽  
pp. 319-327
Author(s):  
Chenlin Xu ◽  
Zijian Xiao ◽  
Heng Wu ◽  
Guijuan Zhou ◽  
Duanqun He ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Neuroprotective Effect ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Activity Measurement ◽  
Therapeutic Approaches ◽  
Cell Viability Assay ◽  
Viability Assay ◽  
Compound C

AbstractBackgroundAlzheimer’s disease (AD) is a common neurodegenerative disorder without any satisfactory therapeutic approaches. AD is mainly characterized by the deposition of β-amyloid protein (Aβ) and extensive neuronal cell death. Curcumin, with anti-oxidative stress (OS) and cell apoptosis properties, plays essential roles in AD. However, whether bisdemethoxycurcumin (BDMC), a derivative of curcumin, can exert a neuroprotective effect in AD remains to be elucidated.MethodsIn this study, SK-N-SH cells were used to establish an in vitro model to investigate the effects of BDMC on the Aβ1–42-induced neurotoxicity. SK-N-SH cells were pretreated with BDMC and with or without compound C and EX527 for 30 min after co-incubation with rotenone for 24 h. Subsequently, western blotting, cell viability assay and SOD and GSH activity measurement were performed.ResultsBDMC increased the cell survival, anti-OS ability, AMPK phosphorylation levels and SIRT1 in SK-N-SH cells treated with Aβ1–42. However, after treatment with compound C, an AMPK inhibitor, and EX527, an SIRT1inhibitor, the neuroprotective roles of BDMC on SK-N-SH cells treated with Aβ1–42 were inhibited.ConclusionThese results suggest that BDMC exerts a neuroprotective role on SK-N-SH cells in vitro via AMPK/SIRT1 signaling, laying the foundation for the application of BDMC in the treatment of neurodegenerative diseases related to AMPK/SIRT1 signaling.

scholarly journals NMDA Receptor-Mediated Neuroprotective Effect of theScutellaria baicalensisGeorgi Extract on the Excitotoxic Neuronal Cell Death in Primary Rat Cortical Cell Cultures

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Jinsong Yang ◽  
Xiaohong Wu ◽  
Haogang Yu ◽  
Xinbiao Liao ◽  
Lisong Teng
Keyword(s):  
Cell Death ◽  
Nmda Receptor ◽  
Cell Cultures ◽  
Neuroprotective Effect ◽  
Neuronal Cell Death ◽  
Cortical Cell ◽  
Neuronal Cell ◽  
Ethanol Extract ◽  
Phytochemical Analysis ◽  
Cortical Cell Cultures

The objective of the current research work was to evaluate the neuroprotective effect of the ethanol extract ofScutellaria baicalensis(S.B.) on the excitotoxic neuronal cell death in primary rat cortical cell cultures. The inhibitory effects of the extract were qualitatively and quantitatively estimated by phase-contrast microscopy and lactate dehydrogenase (LDH) assays. The extract exhibited a potent and dose-dependent inhibition of the glutamate-induced excitotoxicity in the culture media. Further, using radioligand binding assays, it was observed that the inhibitory effect of the extract was more potent and selective for the N-methyl-D-aspartate (NMDA) receptor-mediated toxicity. The S.B. ethanol extract competed with [3H] MDL 105,519 for the specific binding to the NMDA receptor glycine site with 50% inhibition occurring at 35.1 μg/mL. Further, NMDA receptor inactivation by the S.B. ethanol extract was concluded from the decreasing binding capability of [3H]MK-801 in the presence of the extract. Thus, S.B. extract exhibited neuroprotection against excitotoxic cell death, and this neuroprotection was mediated through the inhibition of NMDA receptor function by interacting with the glycine binding site of the NMDA receptor. Phytochemical analysis of the bioactive extract revealed the presence of six phytochemical constituents including baicalein, baicalin, wogonin, wogonoside, scutellarin, and Oroxylin A.

Abstract 2357: Src Kinase Inhibition Blocks Thrombin-induced Brain Injuries without Cognitive Side Effects

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Da-Zhi Liu ◽  
Bradley P Ander ◽  
Ali Izadi ◽  
Ken Van ◽  
Xinhua Zhan ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cognitive Deficits ◽  
Neuronal Cell ◽  
Thrombin Injection ◽  
Cell Cycle Reentry ◽  
Cell Cycle Inhibition ◽  
Mature Neurons ◽  
Cognitive Side Effects

Intracerebral hemorrhage (ICH) activates thrombin, a potent mitogen. Thrombin triggers mitosis by modulating several intracellular mitogenic molecules including Src family kinases. These molecules regulate mitogen-activated protein kinases (MAPKs) and cell cycle proteins such as cyclin-dependent kinases (Cdks); and play critical roles in mitogenic signaling pathways and cell cycle progression. Since aberrant cell cycle reentry results in death of mature neurons, cell cycle inhibition appears to be a candidate strategy for the treatment of neurological diseases including ICH. However, this can also block cell cycle (proliferation) of neural progenitor cells (NPCs) and thus impair brain neurogenesis leading to cognitive deficits. We hypothesized that inhibition of cell cycle by blocking mitogenic signaling molecules (i.e., Src family kinase members) blocks cell cycle reentry of mature neurons without injuring NPCs, which will avoid cognitive side effects during cell cycle inhibition treatment for ICH. Our data shows: (1) Thrombin 30U/ml results in apoptosis of mature neurons via neuronal cell cycle reentry in vitro ; (2) PP2 (Src family kinase inhibitor) 0.3 µM attenuates the thrombin-induced neuronal apoptosis via blocking neuronal cell cycle reentry, but does not affect the viability of NPCs at the same doses in vitro ; (3) Intracerebral ventricular thrombin injection (20U, i.c.v.) results in neuron loss in hippocampus and cognitive deficits 5 weeks after thrombin injection in vivo ; (4) PP2 (1mg/kg, i.p.), given immediately after thrombin injection (i.c.v.), blocks the thrombin-induced neuron loss in hippocampus and cognitive deficits, whereas PP2 on its own at the same doses does not affect normal cognition in vivo . These suggest that Src kinase inhibition prevents hippocampal neuron death via blocking neuronal cell cycle reentry after ICH, but does not affect survival of NPCs.

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