scholarly journals Characterization of Neuroprotection from Excitotoxicity by Moderate and Profound Hypothermia in Cultured Cortical Neurons Unmasks a Temperature-Insensitive Component of Glutamate Neurotoxicity

1998 ◽  
Vol 18 (8) ◽  
pp. 848-867 ◽  
Author(s):  
Michael Tymianski ◽  
Rita Sattler ◽  
Joseph M. Zabramski ◽  
Robert F. Spetzler
Keyword(s):  
Nmda Receptors ◽  
Cortical Neurons ◽  
Underlying Mechanism ◽  
The Other ◽  
Glutamate Toxicity ◽  
Protective Effects ◽  
Profound Hypothermia ◽  
Glutamate Neurotoxicity ◽  
Cultured Cortical Neurons

Although profound hypothermia has been used for decades to protect the human brain from hypoxic or ischemic insults, little is known about the underlying mechanism. We therefore report the first characterization of the effects of moderate (30°C) and profound hypothermia (12° to 20°C) on excitotoxicity in cultured cortical neurons exposed to excitatory amino acids (EAA; glutamate, N-methyl-D-aspartate [NMDA], AMPA, or kainate) at different temperatures (12° to 37°C). Cooling neurons to 30°C and 20°C was neuroprotective, but cooling to 12°C was toxic. The extent of protection depended on the temperature, the EAA receptor agonist employed, and the duration of the EAA challenge. Neurons challenged briefly (5 minutes) with all EAA were protected, as were neurons challenged for 60 minutes with NMDA, AMPA, or kainate. The protective effects of hypothermia (20° and 30°C) persisted after rewarming to 37°C, but rewarming from 12°C was deleterious. Surprisingly, however, prolonged (60 minutes) exposures to glutamate unmasked a temperature-insensitive component of glutamate neurotoxicity that was not seen with the other, synthetic EAA; this component was still mediated via NMDA receptors, not by ionotropic or metabotropic non-NMDA receptors. The temperature-insensitivity of glutamate toxicity was not explained by effects of hypothermia on EAA-evoked [Ca2+]i increases measured using high- and low-affinity Ca2+ indicators, nor by effects on mitochondrial production of reactive oxygen species. This first characterization of excitotoxicity at profoundly hypothermic temperatures reveals a previously unnoticed feature of glutamate neurotoxicity unseen with the other EAA, and also suggests that hypothermia protects the brain at the level of neurons by blocking, rather than slowing, excitotoxicity.

scholarly journals Mechanisms of protective effects of cholecystokinin (CCK)-related peptides against glutamate cytotoxicity of cultured cortical neurons

1992 ◽  
Vol 58 ◽  
pp. 183
Author(s):  
Akinori Akaike ◽  
Yutaka Tamura ◽  
Yuko Sato ◽  
Hisako Tanaka ◽  
Mariko Yamashita ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Protective Effects ◽  
Cultured Cortical Neurons

Trapping Channel Block of NMDA-Activated Responses By Amantadine and Memantine

1997 ◽  
Vol 77 (1) ◽  
pp. 309-323 ◽  
Author(s):  
Thomas A. Blanpied ◽  
Faye A. Boeckman ◽  
Elias Aizenman ◽  
Jon W. Johnson
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Cortical Neurons ◽  
Chinese Hamster ◽  
Therapeutic Effects ◽  
Channel Block ◽  
Cultured Cortical Neurons ◽  
Simple Kinetic Model ◽  
Rat Cortical Neurons ◽  
Partial Trapping

Blanpied, Thomas A., Faye Boeckman, Elias Aizenman, and Jon W. Johnson. Trapping channel block of NMDA-activated responses by amantadine and memantine. J. Neurophysiol. 77: 309–323, 1997. We investigated the mechanisms by which the antiparkinsonian and neuroprotective agents amantadine and memantine inhibit responses to N-methyl-d-aspartic acid (NMDA). Whole cell recordings were performed using cultured rat cortical neurons or Chinese hamster ovary (CHO) cells expressing NMDA receptors. Both amantadine and memantine blocked NMDA-activated channels by binding to a site at which they could be trapped after channel closure and agonist unbinding. For neuronal receptors, the IC50s of amantadine and memantine at −67 mV were 39 and 1.4 μM, respectively. When memantine and agonists were washed off after steady-state block, one-sixth of the blocked channels released rather than trapped the blocker; memantine exhibited “partial trapping.” Thus memantine appears to have a lesser tendency to be trapped than do phencyclidine or (5R,10S)-(+)-5m e t h y l - 1 0 , 1 1 - d i h y d r o - 5 H - d i b e n z o [ 1 , d ] c y c l i h e p t e n - 5 , 1 0 - i m i n e(MK-801). We next investigated mechanisms that might underlie partial trapping. Memantine blocked and could be trapped by recombinant NMDA receptors composed of NR1 and either NR2A or NR2B subunits. In these receptors, as in the native receptors, the drug was released from one-sixth of blocked channels rather than being trapped in all of them. The partial trapping we observed therefore was not due to variability in the action of memantine on a heterogeneous population of NMDA receptors in cultured cortical neurons. Amantadine and memantine each noncompetitively inhibited NMDA-activated responses by binding at a second site with roughly 100-fold lower affinity, but this form of inhibition had little effect on the extent to which memantine was trapped. A simple kinetic model of blocker action was used to demonstrate that partial trapping can result if the presence of memantine in the channel affects the gating transitions or agonist affinity of the NMDA receptor. Partial trapping guarantees that during synaptic communication in the presence of blocker, some channels will release the blocker between synaptic responses. The extent to which amantadine and memantine become trapped after channel block thus may influence their therapeutic effects and their modulation of NMDA-receptor-mediated excitatory postsynaptic potentials.

scholarly journals CIRBP Ameliorates Neuronal Amyloid Toxicity via Antioxidative and Antiapoptotic Pathways in Primary Cortical Neurons

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Fang Su ◽  
Shanshan Yang ◽  
Hongcai Wang ◽  
Zhenkui Qiao ◽  
Hong Zhao ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Rna Binding ◽  
Neuronal Loss ◽  
Underlying Mechanism ◽  
Protective Effects ◽  
Neuroprotective Effects ◽  
Primary Cortical Neurons ◽  
Amyloid Toxicity ◽  
Proapoptotic Protein ◽  
Ad Prevention

It is generally accepted that the amyloid β (Aβ) peptide toxicity contributes to neuronal loss and is involved in the initiation and progression of Alzheimer’s disease (AD). Cold-inducible RNA-binding protein (CIRBP) is reported to be a general stress-response protein, which is induced by different stress conditions. Previous reports have shown the neuroprotective effects of CIRBP through the suppression of apoptosis via the Akt and ERK pathways. The objective of this study is to examine the effect of CIRBP against Aβ-induced toxicity in cultured rat primary cortical neurons and attempt to uncover its underlying mechanism. Here, MTT, LDH release, and TUNEL assays showed that CIRBP overexpression protected against both intracellular amyloid β- (iAβ-) induced and Aβ25-35-induced cytotoxicity in rat primary cortical neurons. Electrophysiological changes responsible for iAβ-induced neuronal toxicity, including an increase in neuronal resting membrane potentials and a decrease in K+ currents, were reversed by CIRBP overexpression. Western blot results further showed that Aβ25-35 treatment significantly increased the level of proapoptotic protein Bax, cleaved caspase-3, and cleaved caspase-9 and decreased the level of antiapoptotic factor Bcl-2, but were rescued by CIRBP overexpression. Furthermore, CIRBP overexpression prevented the elevation of ROS induced by Aβ25-35 treatment by decreasing the activities of oxidative biomarker and increasing the activities of key enzymes in antioxidant system. Taken together, our findings suggested that CIRBP exerted protective effects against neuronal amyloid toxicity via antioxidative and antiapoptotic pathways, which may provide a promising candidate for amyloid-based AD prevention or therapy.

scholarly journals Neuroprotective effects of genistein and folic acid on apoptosis of rat cultured cortical neurons induced by β-amyloid 31-35

2009 ◽  
Vol 102 (5) ◽  
pp. 655-662 ◽  
Author(s):  
Huan-Ling Yu ◽  
Li Li ◽  
Xiao-Hong Zhang ◽  
Li Xiang ◽  
Jie Zhang ◽  
...  
Keyword(s):  
Folic Acid ◽  
Cortical Neuron ◽  
Cortical Neurons ◽  
Tail Length ◽  
Underlying Mechanism ◽  
Pcr Analysis ◽  
Neuroprotective Effects ◽  
Regulated Expression ◽  
Cultured Cortical Neurons ◽  
Β Amyloid

Genistein and folic acid have been reported respectively to protect against the development of cognitive dysfunction; however, the underlying mechanism(s) for this protection remain unknown. In this report, the mechanism(s) contributing to the neuroprotective effects of genistein and folic acid were explored using rat cortical neuron cultures. We found that genistein and folic acid, both separately and collaboratively, increased cell viability and mitochondrial membrane potential in β-amyloid (Aβ) 31-35-treated neurons. Furthermore, reduced percentage of comet cells and shortened tail length were observed in the neurons treated with genistein or folic acid. A more significant reduction in tail length of the comet neurons was observed in the co-administered neurons. RT-PCR analysis of the cultured cortical neurons showed down-regulated expression of p53, bax and caspase-3, but up-regulated expression of bcl-2 in the three neuroprotective treatment groups compared with neurons from the Aβ31-35 solo-treated group. In a nuclear dyeing experiment using Hoechst 33342, we found that both genistein and folic acid prevent neuronal apoptosis. Collectively, these findings suggest that the mechanism underlying the neuroprotection of genistein and folic acid singly or in combination observed in cultured cortical neuron studies might be related to their anti-apoptotic properties.

scholarly journals Protective effects of adenosine on apoptotic neuronal cell death in cultured cortical neurons

2000 ◽  
Vol 82 ◽  
pp. 182
Author(s):  
Yutaka Tamura ◽  
Taizo Fukui ◽  
Megumi Kajikawa ◽  
Mikiko Omoto ◽  
Hirohito Shiomi
Keyword(s):  
Cell Death ◽  
Cortical Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Protective Effects ◽  
Cultured Cortical Neurons
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