mcao

Piclozotan (anhydrous), a 5-HT1A receptor agonist, demonstrated significant neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model, ameliorating motor complications in patients with advanced Parkinson's disease.

Dihydrocapsaicin (CCRIS1589) is isolated from Capsicum fruit. Capsaicin is the primary active component of the heat and pain-eliciting lipid soluble fraction of the Capsicum pepper. Like capsaicin, dihydrocapsaicin is an irritant. Capsaicin is found in natural hot pepper extracts along with a number of impurities, including dihydrocapsaicin and several lesser impurities. Separation by HPLC is required in order to obtain pure dihydrocapsaicin. Dihydrocapsaicin represents about 10% of the compound present in commercial preparations purporting to be pure capsaicin, but it has about the same pungency as capsaicin. VR1 (vanilloid receptor 1) is a heat activated calcium ion channel which functions as a part of the normal nociceptive pain pathway. Capsaicin elicits a sensation of burning pain by activation of VR1 on small, non-myelinated polymodal C-type nociceptive nerve fibers. The potency of dihydrocapsaicin at VR1 appears equivalent to capsaicin. Antioxidant. Reduces oxidation of serum lipids. Mutagenic. Dihydrocapsaicin is an activator of VR1.

Desmethylanethol trithione (ADT-OH) is a derivative of anethole dithiolethione (ADT) and synthetic hydrogen sulfide (H2S) donor. In the in vitro glucose-oxygen deprivation (OGD) model, Desmethylanethol trithione markedly attenuated tPA-enhanced Akt activation and VEGF expression in brain microvascular endothelial cells. Finally, Desmethylanethol trithione improved functional outcomes in mice subjected to MCAO and tPA infusion. H2S donors reduced tPA-induced cerebral hemorrhage by possibly inhibiting the Akt-VEGF-MMP9 cascade. Administration of H2S donors has potential as a novel modality to improve the safety of tPA following the stroke.

MTP 131 is a mitochondria-targeted peptide antioxidant.1,2It localizes to the mitochondria and reducestert-butyl hydroperoxide-induced lipid peroxidation and apoptosis in SH-SY5Y cells when used at concentrations ranging from 0.001 to 1 nM.1MTP 131 (2 mg kg) reduces infarct volume, hemispheric swelling, and glutathione (GSH) depletion in a mouse model of acute cerebral ischemia induced by middle cerebral artery occlusion (MCAO).2It increases survival, improves motor function, and decreases degeneration of the lumbar spinal cord in a superoxide dismutase 1 mutant (SOD1G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS) when administered at a dose of 5 mg kg. MTP 131 reduces albuminuria, urinary hydrogen peroxide levels, and mesangial matrix accumulation, as well as preserves superoxide production, in adb dbmouse model of diabetic nephropathy.3 1.Zhao, K., Luo, G., Giannelli, S., et al.Mitochondria-targeted peptide prevents mitochondrial depolarization and apoptosis induced by tert-butyl hydroperoxide in neuronal cell linesBiochem. Pharmacol.70(12)1796-1806(2005) 2.Szeto, H.H.Mitochondria-targeted peptide antioxidants: Novel neuroprotective agentsAAPS J.8(3)E521-E531(2006) 3.Miyamoto, S., Zhang, G., Hall, D., et al.Restoring mitochondrial superoxide levels with elamipretide (MTP-131) protects db db mice against progression of diabetic kidney diseaseJ. Biol. Chem.295(21)7249-7260(2020)

Tat-M2NX, a peptide antagonist of transient receptor potential melastatin 2 (TRPM2), blocks hydrogen peroxide-induced calcium influx in HEK293 cells expressing human TRPM2 at concentrations between 25 to 100 µM. In male mice models of stroke caused by middle cerebral artery occlusion (MCAO), Tat-M2NX (20 mg/kg) demonstrates efficacy in reducing brain infarct volume when applied before or 3 hours-post occlusion, yet it shows no such effect in female mice.

Tat-CBD3 is a chemical compound inhibiting the interaction between the N-type voltage-gated calcium channel Cav2.2 and collapsin response mediator protein 2 (CRMP2), as well as the interaction between CRMP2 and the NMDA receptor NR2B subunit. At a concentration of 10 µM, Tat-CBD3 reduces the Cav2.2-CRMP2 interaction by 43% in cell-free assays and impedes the NMDA receptor NR2B subunit-CRMP2 interaction in immunoprecipitation assays. It lowers voltage-induced calcium currents by about 60% in primary rat dorsal root ganglion (DRG) neurons and decreases glutamate-induced cytosolic calcium level rises in primary rat hippocampal neurons. When administered at 20 mg/kg, Tat-CBD3 lessens infarct volume in a rat model of cerebral ischemia following middle cerebral artery occlusion (MCAO). Additionally, intrathecal delivery of Tat-CBD3 at a dose of 20 µg/5 µl mitigates carrageenan-induced thermal hypersensitivity in rats.

Tat-Gap 19, a peptide inhibitor of connexin43 (Cx43) hemichannels, is derived from the HIV-1 Tat protein transduction domain fused with a nine-amino acid sequence from Cx43 residues 128-136. This compound, at a concentration of 10 µM, effectively suppresses glutamate-induced ATP release in primary rat hepatocytes, indicating inhibition of Cx43 hemichannel activity. Furthermore, Tat-Gap 19 demonstrates therapeutic potential by significantly reducing infarct volume in a mouse cerebral ischemia-reperfusion injury model following middle cerebral artery occlusion (MCAO) at a dosage of 25 mg/kg. Moreover, its intraperitoneal administration at 1 mg/kg per day ameliorates fibrosis and decreases the area of hepatic stellate cells, the precursors to myofibroblasts, expressing α-smooth muscle actin (α-SMA), in a model of thioacetamide-induced liver damage. Additionally, it enhances superoxide dismutase (SOD) activity in hepatic cells from the treated mice, indicating its antioxidative benefits.

NMDAR/TRPM4-IN-2 is a potent interfacial inhibitor of NMDAR/TRPM4 interaction.NMDAR/TRPM4-IN-2 protects against MCAO-induced brain damage and NMDA-induced retinal ganglion cell loss in mice.NMDAR/TRPM4-IN-2 has neuroprotective activity against NMDA-induced hippocampal neuronal cell death and mitochondrial dysfunction. NMDAR/TRPM4-IN-2 showed neuroprotective activity against NMDA-induced cell death and mitochondrial dysfunction in hippocampal neurons with an IC50 value of 2.1 μM.

Bumetanide (PF 1593) is a potent sulfamoylanthranilic acid derivative belonging to the class of loop diuretics. In the brain, bumetanide may prevent seizures in neonates by blocking the bumetanide-sensitive sodium-potassium-chloride cotransporter (NKCC1), thereby inhibiting chloride uptake thus, decreasing the internal chloride concentration in neurons and may block the excitatory effect of GABA in neonates.

Tat-CIRP, a peptide inhibitor, impedes the protein-protein interaction between myeloid differentiation 2 (MD-2), also known as lymphocyte antigen 96 (LY96), and cold-inducible RNA binding protein (CIRP) by binding to MD-2. This disrupts the MD-2 and CIRP interaction as confirmed in co-immunoprecipitation assays. Notably, in vivo studies reveal that Tat-CIRP, at dosages of 10 and 20 mg/kg, significantly reduces infarct volume in both a mouse model of middle cerebral artery occlusion (MCAO) and a rhesus monkey model of thrombosis-induced stroke. Additionally, it improves motor function, evidenced by decreased time to manipulate and withdraw food with the affected arm in the primate model.

KUS121 is a valosin-containing protein (VCP) modulator that inhibits VCP ATPase activity (IC50= 330 nM).1It inhibits cell death, ATP depletion, and upregulation of C/EBP-homologous protein (CHOP) induced by tunicamycin, an inducer of ER stress, in HeLa cells when used at concentrations of 20, 50, and 50 μM, respectively. KUS121 (100 μM) inhibits ATP depletion and cell death induced by oxygen-glucose deprivation (OGD) in rat primary cortical neurons in anin vitromodel of cerebral ischemia.2It reduces infarction volume and increases the latency to fall in an accelerating rotarod test in a mouse model of focal cerebral ischemia induced by transient distal middle cerebral artery occlusion (MCAO) when administered at a dose of 100 mg/kg immediately following occlusion and again at 50 mg/kg following reperfusion. KUS121 (50 mg/kg) inhibits thinning of the retinal outer nuclear layer and preserves visual function in an rd10 mouse model of retinitis pigmentosa.1 1.Ikeda, H.O., Sasaoka, N., Koike, M., et al.Novel VCP modulators mitigate major pathologies of rd10, a mouse model of retinitis pigmentosaSci. Rep.45970(2014) 2.Kinoshita, H., Maki, T., Yasuda, K., et al.KUS121, a valosin-containing protein modulator, attenuates ischemic stroke via preventing ATP depletionSci. Rep.9(1)11519(2019)

Tat-NTS peptide, a cell-penetrating compound, comprises the HIV-1 Tat protein transduction domain fused with a 10-amino acid sequence (residues 228-237) from the repeat III domain of annexin A1, serving as a nuclear translocation signal (NTS). This peptide hinders the interaction between annexin A1 and importin β, obstructing annexin A1's nuclear entry in primary mouse hippocampal neurons. Tat-NTS effectively prevents apoptosis triggered by glucose-oxygen deprivation and reperfusion in these neurons. When administered in vivo at a dosage of 10 mg/kg, it significantly reduces infarct size, minimizes neuronal apoptosis, and improves navigation performance in the Morris water maze test for mice subjected to ischemia-reperfusion injury via middle cerebral artery occlusion (MCAO).

Trofinetide, derived from the neuroprotective tripeptide Gly-Pro-Glu (an N-terminal sequence of insulin-like growth factor-1, IGF-1), shows promise in various neuroprotective models. At a concentration of 10 nM, it mitigates cell death in primary rat embryonic striatal neurons caused by okadaic acid. Additionally, Trofinetide reduces the expression of pro-inflammatory markers (IL-1β, TNF-α, IL-6, and E-selectin) in a rat model simulating neuroinflammation from penetrating ballistic-like brain injuries. In cases of brain injury induced by middle cerebral artery occlusion (MCAO), administration of Trofinetide at 30 and 60 mg/kg reduces the area of cortical and striatal infarct. Furthermore, a daily dose of 100 mg/kg reverses social recognition and contextual fear conditioning deficits, diminishes the number of dendritic spines, and decreases testicular weight gain in an fmr1-/- knockout mouse model of fragile X syndrome. Trofinetide formulations have been employed in treating Rett syndrome, highlighting its versatility across various neurological conditions.

Monomethyl lithospermate (Lithospermic acid monomethyl ester) has potential antiviral activity, alleviating ischemic stroke injury in vivo in middle cerebral artery occlusion mice by activating PI5K Akt signaling and protecting oxygen-glucose deprivation reoxygenation-induced SHSY-3Y cells in vitro. Monomethyl lithospermate could improve the viability of SHSY-5Y cells, inhibit mitochondrial membrane potential (MMOP) collapse, and inhibit cell apoptosis. Monomethyl lithospermate also reduced the level of oxidative stress in the brain tissue of middle artery occlusion (MCAO) rats and improved nerve damage in ischemic stroke (IS) rats.

Myelin oligodendrocyte glycoprotein (MOG) peptide, a truncated form of MOG located on the extracellular myelin sheath surface, interacts with antigen serotype HLA-DR2 to mitigate effects of ischemic stroke induced by middle cerebral artery occlusion (MCAO) in mice. In female mice, it notably reduces cortical and striatal infarct volumes, lessens sensorimotor deficits as observed in tube- and corner turn tests, enhances engagement with novel odors, and prolongs the duration of cage mate-directed vocalizations, without exhibiting similar outcomes in male mice.

LAU-0901, a platelet-activating factor (PAF) receptor antagonist, demonstrates efficacy in reducing infarct volume and enhancing neurological function in rats subjected to middle cerebral artery occlusion (MCAO)-induced cerebral ischemia, at doses of 30, 60, and 90 mg/kg. Furthermore, it diminishes microglial infiltration while promoting astrocytic and neuronal survival in the same model. Additionally, at a dose of 30 mg/kg, LAU-0901, either alone or combined with atorvastatin, shows a capability to inhibit tumor growth in a U87MG glioblastoma mouse orthotopic tumor model.