Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies
Abstract
:1. Introduction
2. Morphological and Functional Changes of Synapse in Stroke
2.1. Ischemia-Induced Synaptic Plasticity Damage
2.2. Causal Relationship between Neuronal Death, Synaptic Loss, and Transmission Disorder
2.3. The Role of Excitatory Synaptic Transmission for the Ischemic Cascade
3. Excessive Synaptic or Extra-Synaptic Glutamate Release Results in Early Consequence of Cerebral Ischemia
3.1. Targeted the Calcium-Dependent Presynaptic Exocytotic Release of Glutamate
3.1.1. Modulation of Ion Imbalance-Induced Depolarization upon Extracellular Calcium Entry
Sodium Calcium Exchanger (NCX)
Voltage-Gated Calcium Channels (VGCC)
3.1.2. Modulation of Presynaptic Store Calcium from the Endoplasmic Reticulum (ER)
CICR/SOCE Mechanism
Ryanodine Receptor
STIM-Orai1 Pathway
3.2. Targeted the Extra-Synaptic Release of Glutamate
3.2.1. Modulation of Exocytosis from Astrocytes
3.2.2. Modulation of VRAC
3.2.3. Modulation of Reverse Glutamate Transporter
4. Postsynaptic Effect of Glutamate as the Main Mechanism of Neuronal Death
4.1. NMDA Receptor: The Most Effective Neurotoxic Agonist
4.2. NMDAR Mediates the Dual Effects of Neuronal Survival and Death
4.2.1. Neuronal Survival Signal Complex Downstream of NMDAR
PI3K/Akt Complex
PI3K/Akt-GSK3
PI3K/Akt-BDNF
PI3K/Akt-PTEN
PI3K/Akt-APPL1
4.2.2. Neuronal Death-Signaling Complexes Downstream of NMDAR
GluN2B-DAPK1 Complex
GluN2B-PSD95-nNOS Complex
NMDAR-PSD93-SynGAP Complex
NMDAR-TRPM Complex
5. Glutamate Uptake and Metabolic Inhibition Aggravating Synaptotoxicity
5.1. Glutamate Uptake by High-Affinity Transporter
5.2. Glutamate Metabolism by Glutamate–Glutamine–Glutathione Cycle
5.3. Glutamate Grabbing by Blood–Brain Endothelium Regulation
6. Regulation of Glutamatergic Transmission by Inhibitory Synapse
6.1. The Role of GABA Receptors in Ischemic Stroke
6.2. Microbiota–Gut–Brain Axis: A New Target for Intervention of Ischemic Stroke
7. Challenges and Prospects
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Drug/Therapy | Targeting Pathway | Therapeutic Effects/Mechanisms | References | Applications |
---|---|---|---|---|
Dantrolene | Inhibition of Ryanodine receptor | Reducing infarction volume and morphological damage induced by HI and cell death induced by OGD via restraining the intracellular calcium levels, apoptosis, and elevating pro-survival protein levels | [95] | Mice HI/In vitro OGD |
DCPIB | Selective block of VRAC | Attenuating cell death via blocking the decrease in Cl− in PC12 cells OGD model, as well as lessening infarct volume and promoting functional recovery in the mice HI model | [114] | Mice HI/In vitro OGD |
HIP-A | Inhibition of EAAT | Suppressing selectively the reverse transport of glutamate upon the low concentration, thus alleviating ischemic damage | [121] | Rat hippocampal slices/Mice brain cortical cultures |
ifenprodil | Selective block of GluN2B | Improving apoptosis, cytosolic Ca2+ overload, BBB damage, and permeability in HBMEC, resulting in declined neurological deficits, cerebral edema, and death | [136] | Phase IV clinical |
Ro25-6981 | Selective block of GluN2B | Suppressing ischemic brain injury via enhancing the expression of NSE and regulating autophagy-related proteins | [206] | Rat 4-VO/In vitro |
Neu2000 | Selective block of GluN2B | A multi-target neuroprotectant and scavenging for free radicals | [207] | Phase II clinical |
Notoginsenoside R1 | Stimulation of Akt-CREB-BDNF | Activating BDNF/Akt/CREB signaling in the rat MCAO/R model, exerting neuroprotective and pro-neurogenic effects | [153] | Rat MCAO/R |
NA-1 | Selective block of PSD95-nNOS | Combating excitotoxicity via reducing the efficiency of Ca2+-induced excitotoxic NO production both in cortical cells and animal IS models | [170] | Phase III clinical |
Nerinetide | Selective block of PSD95-nNOS | Inhibiting the protein-protein interaction of PSD-95. | [208] | Phase III clinical |
N-Cyclohexylethyl-[A/G]-[D/E]-X-V Peptides | Selective block of nNOS- CAPON | Reducing infarct size in rats via blocking nNOS-CAPON interaction upon cerebral I/R models | [209] | Mice MCAO/R |
Tat-SynGAP | Selective block of PSD93- SynGAP | Attenuating ischemic brain damage in mice | [171] | Mice MCAO/R |
TAT-EE3 | Selective block of NMDAR-TRPM2 | Uncoupling TRPM2-NMDARs interaction, thus alleviating neuron ischemic injury in vitro and in vivo | [173] | Mice MCAO/In vitro OGD |
TwinF/Compound 8/19 | Selective block of NMDAR-TRPM4 | Disrupting the NMDAR-TRPM4 interaction, thereby stripping off the toxicity of extrasynaptic NMDARs | [174] | Mice MCAO/In vitro OGD |
NVP-LDE225 | Inhibition of EAAT2 | Lowering extracellular glutamate via inhibiting the SHH-SMO-GLT-1 pathway, thus reducing infarct volume and ameliorating neurological functions following ischemia | [177] | Mice/Cynomolgus monkeys |
Baicalin | Inhibition of glutamate–glutamine cycle | Suppressing ROS production and protecting GS protein stability via inactivating SDH, promoting the disposal of the glutamate in astrocytes and rat IS models | [183] | Rat MCAO |
hrGOT | Scavenging of Glutamate | Attenuating infarct volume via displacing glutamate homeostasis between different pools | [210] | Rat MCAO |
2’-methoxy-6-methylflavone | Inhibition of GABAA δ | Reducing infarct volume and improving functional recovery via downregulating IL1b, TNFa, and IFg and dampening the IS-induced increase in circulating cytokines | [194] | Mice focal ischemia |
S44819 | Inhibition of GABAA α5 | Improving stroke recovery and increasing peri-infarct cortical excitability | [49] | Phase II clinical |
Edaravone Dexborneol injection | Selective block of PSD95-nNOS and GABA receptors | Exerting good neuroprotective functional outcomes via synergistic effects of antioxidant and anti-inflammatory | [211] | Phase III clinical |
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Wang, F.; Xie, X.; Xing, X.; Sun, X. Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies. Int. J. Mol. Sci. 2022, 23, 9381. https://doi.org/10.3390/ijms23169381
Wang F, Xie X, Xing X, Sun X. Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies. International Journal of Molecular Sciences. 2022; 23(16):9381. https://doi.org/10.3390/ijms23169381
Chicago/Turabian StyleWang, Fan, Xueheng Xie, Xiaoyan Xing, and Xiaobo Sun. 2022. "Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies" International Journal of Molecular Sciences 23, no. 16: 9381. https://doi.org/10.3390/ijms23169381
APA StyleWang, F., Xie, X., Xing, X., & Sun, X. (2022). Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies. International Journal of Molecular Sciences, 23(16), 9381. https://doi.org/10.3390/ijms23169381