Table 1.
Potential therapies for ischemic stroke targeting synaptic transmission pathway.
| 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 |