scholarly journals Failed Neuroprotection of Combined Inhibition of L-Type and ASIC1a Calcium Channels with Nimodipine and Amiloride

2020 ◽  
Vol 21 (23) ◽  
pp. 8921
Author(s):  
Jonas Ort ◽  
Benedikt Kremer ◽  
Linda Grüßer ◽  
Romy Blaumeiser-Debarry ◽  
Hans Clusmann ◽  
...  
Keyword(s):  
Channel Blocker ◽  
Cell Damage ◽  
Neuroprotective Effect ◽  
Hippocampal Slices ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Glucose Deprivation ◽  
Modern Medicine ◽  
Technical Note

Effective pharmacological neuroprotection is one of the most desired aims in modern medicine. We postulated that a combination of two clinically used drugs—nimodipine (L-Type voltage-gated calcium channel blocker) and amiloride (acid-sensing ion channel inhibitor)—might act synergistically in an experimental model of ischaemia, targeting the intracellular rise in calcium as a pathway in neuronal cell death. We used organotypic hippocampal slices of mice pups and a well-established regimen of oxygen-glucose deprivation (OGD) to assess a possible neuroprotective effect. Neither nimodipine (at 10 or 20 µM) alone or in combination with amiloride (at 100 µM) showed any amelioration. Dissolved at 2.0 Vol.% dimethyl-sulfoxide (DMSO), the combination of both components even increased cell damage (p = 0.0001), an effect not observed with amiloride alone. We conclude that neither amiloride nor nimodipine do offer neuroprotection in an in vitro ischaemia model. On a technical note, the use of DMSO should be carefully evaluated in neuroprotective experiments, since it possibly alters cell damage.

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 Molecular and Pharmacological Modulation of CALHM1 Promote Neuroprotection against Oxygen and Glucose Deprivation in a Model of Hippocampal Slices

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 664 ◽  
Author(s):  
Javier Garrosa ◽  
Iñigo Paredes ◽  
Philippe Marambaud ◽  
Manuela G. López ◽  
María F. Cano-Abad
Keyword(s):  
Neuroprotective Effect ◽  
Hippocampal Slices ◽  
Glucose Deprivation ◽  
Point Of View ◽  
Oxygen And Glucose Deprivation ◽  
Molecular Events ◽  
Vitro Model ◽  
Species Production ◽  
Reperfusion Phase

Calcium homeostasis modulator 1 (CALHM1) is a calcium channel involved in the regulation of cytosolic Ca2+ levels. From a physiological point of view, the open state of CALHM1 depends not only on voltage but also on the extracellular concentration of calcium ([Ca2+]) ions. At low [Ca2+]e or depolarization, the channel is opened, allowing Ca2+ influx; however, high extracellular [Ca2+]e or hyperpolarization promote its resting state. The unique Ca2+ permeation of CALHM1 relates to the molecular events that take place in brain ischemia, such as depolarization and extracellular changes in [Ca2+]e, particularly during the reperfusion phase after the ischemic insult. In this study, we attempted to understand its role in an in vitro model of ischemia, namely oxygen and glucose deprivation, followed by reoxygenation (OGD/Reox). To this end, hippocampal slices from wild-type Calhm1+/+, Calhm1+/−, and Calhm1−/− mice were subjected to OGD/Reox. Our results point out to a neuroprotective effect when CALHM1 is partially or totally absent. Pharmacological manipulation of CALHM1 with CGP37157 reduced cell death in Calhm1+/+ slices but not in that of Calhm1−/− mice after exposure to the OGD/Reox protocol. This ionic protection was also verified by measuring reactive oxygen species production upon OGD/Reox in Calhm1+/+ and Calhm1−/− mice, resulting in a downregulation of ROS production in Calhm1−/− hippocampal slices and increased expression of HIF-1α. Taken together, we can conclude that genetic or pharmacological inhibition of CALHM1 results in a neuroprotective effect against ischemia, due to an attenuation of the neuronal calcium overload and downregulation of oxygen reactive species production.

scholarly journals Neuroprotective Effect of Metaplexis japonica against in vitro Ischemia Model

2019 ◽  
Vol 3 (1) ◽  
pp. 51-55 ◽  
Author(s):  
Nirmala Jamarkattel-Pandit ◽  
Hocheol Kim
Keyword(s):  
Cell Damage ◽  
Neuroprotective Effect ◽  
Ethanol Extract ◽  
Glucose Deprivation ◽  
Ethyl Acetate Fraction ◽  
Perennial Herb ◽  
Oxygen Glucose Deprivation ◽  
In Vitro Ischemia ◽  
Ht22 Cell

Metaplexis japonica (Apocynaceae) is a perennial herb, extensively used in traditional medicinal system for various diseases. The purpose of the study was to evaluate the protective effect of M. japonica against in vitro ischemia. In the present study, 70% ethanol extract of M. japonica was fractionated with different polarity solvents. For in vitro ischemia, oxygen-glucose deprivation followed by reoxygenation (OGD-R) in cells was used to investigate the effects of M. japonica and its fractions. For oxidative stress model, Hydrogen peroxide (H2 O2 ) induced cell death was studied in HT22 cell line. M. japonica and its fractions significantly reduced the HT22 cell damage, which was induced by 4 hrs of OGD followed by 24 hrs of reoxygenation and 24 hrs of H2 O2, respectively. The effectiveness of ethyl acetate fraction was higher than other fractions/crude extract. Our results suggest that M. japonica could be a neuroprotective agent for the treatment of stroke. Key words: Metaplexis japonica, Stroke, Oxygen-glucose deprivation, Neuroprotection

scholarly journals Kaempferol Has Potent Protective and Antifibrillogenic Effects for α-Synuclein Neurotoxicity In Vitro

2021 ◽  
Vol 22 (21) ◽  
pp. 11484
Author(s):  
Masatoshi Inden ◽  
Ayaka Takagi ◽  
Hazuki Kitai ◽  
Taisei Ito ◽  
Hisaka Kurita ◽  
...  
Keyword(s):  
Amyloid Fibril ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Neuronal Cell Death ◽  
Lewy Bodies ◽  
Neuronal Cell ◽  
Therapeutic Agents ◽  
Amyloid Fibril Formation ◽  
Transcription Factor Eb

Aggregation of α-synuclein (α-Syn) is implicated in the pathogenesis of Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Therefore, the removal of α-Syn aggregation could lead to the development of many new therapeutic agents for neurodegenerative diseases. In the present study, we succeeded in generating a new α-Syn stably expressing cell line using a piggyBac transposon system to investigate the neuroprotective effect of the flavonoid kaempferol on α-Syn toxicity. We found that kaempferol provided significant protection against α-Syn-related neurotoxicity. Furthermore, kaempferol induced autophagy through an increase in the biogenesis of lysosomes by inducing the expression of transcription factor EB and reducing the accumulation of α-Syn; thus, kaempferol prevented neuronal cell death. Moreover, kaempferol directly blocked the amyloid fibril formation of α-Syn. These results support the therapeutic potential of kaempferol in diseases such as synucleinopathies that are characterized by α-Syn aggregates.

scholarly journals Optimized-SopungSunkiwon, a Herbal Formula, Attenuates AβOligomer-Induced Neurotoxicity in Alzheimer’s Disease Models

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Jin Gyu Choi ◽  
Sun Yeou Kim ◽  
Jong Woo Kim ◽  
Myung Sook Oh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Damage ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Medicinal Herbs ◽  
Glutathione Depletion ◽  
Age Related

Alzheimer’s disease (AD), the most common form of dementia, is an age-related neurodegenerative disease that is characterized by memory dysfunction, neuronal cell damage, and neuroinflammation. It is believed that AD-related pathology is mostly due to the overproduction of Aβ, especially the oligomeric form (AβO), in the brain. Evidence of the effects of multifunctional medicinal herbs in the treatment of AD has been steadily increasing. Optimized-SopungSunkiwon (OSS), a multiherbal formulation that is composed of six medicinal herbs derived from SopungSunkiwon, is a traditional medicine that is prescribed for neurodegenerative disorders in elderly patients. We previously reported that OSS showed an antiamnesic and memory enhancing effect in mice, but it is unknown whether OSS has a protective effect against AβO neurotoxicity. In this study, we investigated the effects of OSS in AD models induced by AβOin vitroandin vivo. We found that OSS protected neuronal cells and inhibited the generation of nitric oxide and reactive oxygen species against AβO toxicityin vitro. These results were confirmed byin vivodata that oral administration of OSS for 14 days attenuated memory impairments and neuronal cell death by modulating gliosis, glutathione depletion, and synaptic damage in the mouse hippocampus induced by AβO.

Polygalae Radix Extract Protects Cultured Rat Granule Cells Against Damage Induced by NMDA

2004 ◽  
Vol 32 (04) ◽  
pp. 599-610 ◽  
Author(s):  
Hyun Joo Lee ◽  
Ju Yeon Ban ◽  
Sang Bum Koh ◽  
Nak Sul Seong ◽  
Kyung Sik Song ◽  
...  
Keyword(s):  
Cell Death ◽  
Granule Cells ◽  
Cell Damage ◽  
Glutamate Release ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Inhibitory Effect ◽  
Trypan Blue Exclusion ◽  
Trypan Blue Exclusion Test

Polygalae Radix (PR) from Polygala tenuifolia (Polygalaceae) is traditionally used in China and Korea, as this herb has a sedative, anti-inflammatory and antibacterial agent. To extend our understanding of the pharmacological actions of PR in the CNS on the basis of its CNS inhibitory effect, the present study examined whether PR has the neuroprotective action against N-methyl-D-aspartate (NMDA)-induced cell death in primarily cultured rat cerebellar granule neurons. PR, over a concentration range of 0.05 to 5 μg/ml, inhibited NMDA (1 mM)-induced neuronal cell death, which was measured by a trypan blue exclusion test and a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay. PR (0.5 μg/ml) inhibited glutamate release into medium induced by NMDA (1 mM), which was measured by HPLC. Pre-treatment of PR (0.5 μg/ml) inhibited NMDA (1 mM)-induced elevation of intracellular Ca 2+ concentration ([ Ca 2+] i ), which was measured by a fluorescent dye, Fura 2-AM, and generation of reactive oxygen species (ROS). These results suggest that PR prevents NMDA-induced neuronal cell damage in vitro.

scholarly journals Contribution of ginsenosides Rg1, Rb1 to the neuroprotective effect of Panax notoginseng in mouse organotypic hippocampal slice cultures exposed to oxygen and glucose deprivation

2021 ◽  
Vol 63 (2) ◽  
pp. 64-69
Author(s):  
Nguyen Thi Thanh Loan ◽  
◽  
Le Thi Xoan ◽  
Pham Thi Nguyet Hang ◽  
Nguyen Van Tai ◽  
...  
Keyword(s):  
Hippocampal Slice ◽  
Cell Damage ◽  
Neuroprotective Effect ◽  
Neuronal Cell ◽  
Glucose Deprivation ◽  
Panax Notoginseng ◽  
Ginsenoside Rg1 ◽  
Neuroprotective Effects ◽  
Oxygen And Glucose Deprivation ◽  
Mk 801

We previously demonstrated that Panax notoginseng (pNG) root extract treatments exertedneuroprotective effects on brain injuries using middle cerebral artery occlusion in mice. The present study aims to investigate the neuroprotective effects of PNG extract and its ginsenosides Rg1 and Rb1 on ischemic neuronal damage caused by oxygen and glucose deprivation (OGD) in mouse organotypic hippocampal slice cultures (OHSCs). Before the experiments, hippocampal slices collected from 7-day-old Swiss mice were cultured for 7 days. OGD was triggered in OHSCs for 30, 60, or 90 min with the aim of finding the optimal period of OGD for drug testing. PNG extract (10, 30 μg/ml), ginsenosides Rg1 and Rb1 (5, 25 μM), or MK-801 25 μM, a reference drug, was added to the culture medium 24 h before OGD and these treatments were continued for 24 h after the optimum 60-min period of OGD. After 24 h of OGD exposure, the measurement of propidium iodide uptake was analysed in OHSCs to evaluate neuronal cell damage. The results showed that OGD time-dependently increased PI uptake of the OHSCs. PNG 30 μg/ml treatment reduced the OGD-induced neuronal cell damage in OHSCs. Ginsenosides Rg1 25 μM, Rb1 (5, 25 μM), as well as MK-801 (25 μM) significantly inhibited PI uptake 24 h after OGD exposure. However, ginsenoside Rg1 5 μM did not show any significant effects on the OGD-induced neuronal cell damage. These findings indicated that ginsenosides Rg1 and Rb1 contributed to the neuroprotective effects of PNG against ischemic damage in OHSCs and the neuroprotective effect of ginsenoside Rb1 was stronger than that of ginsenoside Rg1.

scholarly journals Inhibition of Tryptophan Catabolism Is Associated With Neuroprotection During Zika Virus Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Fernanda Martins Marim ◽  
Danielle Cunha Teixeira ◽  
Celso Martins Queiroz-Junior ◽  
Bruno Vinicius Santos Valiate ◽  
Jose Carlos Alves-Filho ◽  
...  
Keyword(s):  
Zika Virus ◽  
Ex Vivo ◽  
Neuroprotective Effect ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Kynurenine Pathway ◽  
Pcr Analysis ◽  
The Brain

Zika virus (ZIKV) is an arbovirus belonging to Flaviviridae family that emerged as a global health threat due to its association with microcephaly and other severe neurological complications, including Guillain-Barré Syndrome (GBS) and Congenital Zika Syndrome (CZS). ZIKV disease has been linked to neuroinflammation and neuronal cell death. Neurodegenerative processes may be exacerbated by metabolites produced by the kynurenine pathway, an important pathway for the degradation of tryptophan, which induces neuronal dysfunction due to enhanced excitotoxicity. Here, we exploited the hypothesis that ZIKV-induced neurodegeneration can be rescued by blocking a target enzyme of the kynurenine pathway, the Indoleamine 2,3-dioxygenase (IDO-1). RT-PCR analysis showed increased levels of IDO-1 RNA expression in undifferentiated primary neurons isolated from wild type (WT) mice infected by ZIKV ex vivo, as well as in the brain of ZIKV-infected A129 mice. Pharmacological inhibition of IDO-1 enzyme with 1-methyl-D-tryptophan (1-MT), in both in vitro and in vivo systems, led to significant reduction of ZIKV-induced neuronal death without interfering with the ability of ZIKV to replicate in those cells. Furthermore, in vivo analyses using both genetically modified mice (IDO-/- mice) and A129 mice treated with 1-MT resulted in reduced microgliosis, astrogliosis and Caspase-3 positive cells in the brain of ZIKV-infected A129 mice. Interestingly, increased levels of CCL5 and CXCL-1 chemokines were found in the brain of 1-MT treated-mice. Together, our data indicate that IDO-1 blockade provides a neuroprotective effect against ZIKV-induced neurodegeneration, and this is amenable to inhibition by pharmacological treatment.

scholarly journals MLN4924 Exerts a Neuroprotective Effect against Oxidative Stress via Sirt1 in Spinal Cord Ischemia-Reperfusion Injury

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Sifei Yu ◽  
Lei Xie ◽  
Zhuochao Liu ◽  
Changwei Li ◽  
Yu Liang
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Ischemia Reperfusion Injury ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Sirtuin 1

Oxidative stress is a leading contributor to spinal cord ischemia-reperfusion (SCIR) injury. Recently, MLN4924, a potent and selective inhibitor of the NEDD8-activating enzyme, was shown to exert a neuroprotective effect against oxidative stress in vitro. However, it is unknown whether MLN4924 plays a protective role against SCIR injury. In the present study, we found that MLN4924 treatment significantly attenuated oxidative stress and neuronal cell death induced by H2O2 in SH-SY-5Y neural cells and during rat SCIR injury. Furthermore, MLN4924 administration restored neurological and motor functions in rats with SCIR injury. Mechanistically, we found that MLN4924 protects against H2O2- and SCIR injury-induced neurodegeneration by regulating sirtuin 1 (Sirt1) expression. Collectively, these findings demonstrate the neuroprotective role of MLN4924 against oxidative stress in SCIR injury via Sirt1.

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