CTX-471 is a monoclonal antibody targeting CD137 for cancer research
**Background**
CD137 (4-1BB) is a potent costimulatory molecule expressed on the surface of activated T cells and natural killer (NK) cells. Activation of CD137 provides critical signals that enhance the proliferation, survival, and effector functions of these immune cells, making it a highly attractive target for immunomodulation and cancer therapy. While agonistic antibodies targeting CD137 have shown promise in stimulating antitumor immunity, many candidates have been limited by severe dose-limiting hepatotoxicity. Consequently, there is a significant need for differentiated antibodies that can maintain potent antitumor efficacy without inducing hepatic inflammation. In this context, we will introduce a fully human monoclonal antibody targeting CD137 – CTX-471.
**Definition**
CTX-471 is a fully human IgG4 kappa monoclonal antibody that binds to a unique epitope on CD137. According to the CTX-471 description, it exhibits high binding affinity for recombinant human and cynomolgus macaque CD137, with $K_d$ values of 50 nM and 61 nM, respectively.
**In Vitro and In Vivo Studies**
The CTX-471 in vitro profile demonstrates that the antibody binds to human, cynomolgus macaque, and mouse CD137 with $K_d$ values of 50 nM, 61 nM, and 748 nM, respectively. Furthermore, CTX-471 (0.1-100 nM; 1, 10 μg/mL; 3 days) increases IFN-$\gamma$ production by human T cells in an Fc$\gamma$ receptor-dependent (Fc$\gamma$R-dependent) manner. Regarding CTX-471 In Vivo activity, the antibody (150 μg; i.p.) exhibits curative monotherapy activity across various syngeneic tumor models in BALB/c mice, demonstrating a unique ability to eradicate very large tumors. Additionally, CTX-471 (10-80 mg/kg; i.v. on days 0, 7, 14, and 21) is well tolerated and does not induce hepatic toxicity even at high doses. The efficacy of the antibody is dependent on the engagement of T cells, NK cells, and Fc$\gamma$R. For researchers seeking detailed CTX-471 technical information, it is noted that the antibody’s molecular weight is 144.5 kDa. In conclusion, CTX-471 is a differentiated agonistic antibody that provides potent antitumor activity in CTX-471 Cancer research without the associated risk of hepatotoxicity.
Keywords
CTX-471, 2377152-49-1, CTX471, CTX 471, Interleukin Related, IL, TNF receptor superfamily (TNFRSF), Cell surface glycoprotein CD137, immune receptors, tumor, monoclonal antibody, immunomodulation, Inhibitor, inhibitor, inhibit
References
**Background**
Skin aging is a complex biological process characterized by the degradation of the extracellular matrix, loss of elasticity, and the formation of wrinkles. A significant contributor to the appearance of facial wrinkles is the repetitive contraction of facial muscles, which is mediated by the release of the neurotransmitter acetylcholine at the neuromuscular junction. By modulating this neurotransmitter release, it is possible to reduce muscle tension and alleviate the formation of expression lines. Consequently, the development of non-toxic, skin-permeable peptides that can mimic the effects of botulinum toxin without its systemic risks has become a primary focus in cosmetic and biomedical research. In this context, we will introduce an anti-wrinkle peptide – Argireline.
**Definition**
Argireline (Acetyl hexapeptide-3) is a non-toxic, skin-permeable, anti-wrinkle peptide with the sequence Ac-Glu-Glu-Met-Gln-Arg-Arg-NH2. According to the Argireline description, it functions by significantly inhibiting Ca2+ dependent neurotransmitter release (acetylcholine) at the neuromuscular junction.
**In Vitro and In Vivo Studies**
The Argireline biological activity has been extensively evaluated across various models. In terms of Argireline in vitro studies, the peptide demonstrated dose-dependent antiproliferative effects when incubated for 48 hours with human embryonic kidney HEK-293 cells (IC50 of 34.862 μM) and neuroblastoma IMR-32 cells (IC50 of 68.458 μM). Similarly, Argireline exhibited a dose-dependent antiproliferative effect on human skin fibroblasts (HSF), although cellular proliferation remained unaffected at low concentrations.
Regarding Argireline In Vivo research, the peptide was applied to aged mice twice daily for a period of 6 weeks. The results indicated a significant improvement in the histological structure of the skin tissue. Specifically, there was an increase in the amount of type I collagen fibers and a decrease in type III collagen fibers, suggesting that the peptide can rejuvenate aging skin and improve overall tissue architecture. In conclusion, Argireline is a potent anti-aging peptide that effectively reduces wrinkles by inhibiting neurotransmitter release and improving skin collagen composition.
Keywords
Argireline, 616204-22-9, Acetyl hexapeptide-3, Acetyl hexapeptide-8, Acetyl hexapeptide3, Acetyl hexapeptide 3, Acetyl hexapeptide8, Acetyl hexapeptide 8, Calcium Channel, Ca2+ channels, Ca channels, Antiwrinkle, anti-aging, non-toxic
References
[1] Blanes-Mira C, et al. A synthetic hexapeptide (Argireline) with antiwrinkle activity. Int J Cosmet Sci. 2002 Oct;24(5):303-10.
[2] Grosicki M, et al. The study of cellular cytotoxicity of argireline – an anti-aging peptide. Acta Biochim Pol. 2014;61(1):29-32.
[3] Wang Y, et al. The anti-wrinkle efficacy of Argireline. J Cosmet Laser Ther. 2013 Aug;15(4):237-41.
**Background**
Major depressive disorder and anxiety are complex neurological conditions often associated with the dysregulation of monoamine neurotransmitters, including serotonin (5-HT), norepinephrine, and dopamine. The modulation of serotonin receptors and the inhibition of monoamine transporters are primary strategies in the development of antidepressant and anxiolytic therapies. Specifically, targeting the 5-HT receptor subtypes and organic cation transporters can help restore neurochemical balance in the brain. Given its ability to cross the blood-brain barrier and its multi-target profile, trimipramine has been extensively studied for its therapeutic potential. In this context, we will introduce a potent 5-HT receptor antagonist and transporter inhibitor – Trimipramine.
**Definition**
Trimipramine is a 5-HT receptor antagonist and a selective inhibitor of human noradrenaline (hNAT), serotonin (hSERT), and organic cation transporters (hOCT1, hOCT2), with hSERT IC50 values of 2.11 μM.
**In Vitro and In Vivo Studies**
According to the Trimipramine description, this compound exhibits distinct binding affinities for various serotonin receptors, with pKi values of 8.10, 6.39, and 4.66 for 5-HT2, 5-HT1C, and 5-HT1A, respectively. Trimipramine in vitro studies using HEK293 cells demonstrated that it acts as a moderate inhibitor of human NAT (IC50 = 4.99 μM) and SERT (IC50 = 2.11 μM), suggesting that these transporters are key targets for its antidepressant effects.
Regarding Trimipramine in vivo activity, chronic administration (5 mg/kg/day for 14 days) via subcutaneous osmotic minipumps in male Wistar rats (220-250 g) resulted in significant neurochemical changes. The treatment increased the concentration of regional 5-HT, particularly in the hippocampus and frontal cortex, and elevated the levels of monoamines and their metabolites, indicating an increased synthesis rate for dopamine (DA) and 5-HT. Furthermore, this chronic treatment led to an adaptive downregulation, decreasing the number of 5-HT2 receptors in the frontal cortex and DA D2 receptors in the striatum, effectively blocking the uptake of 5-HT and dopamine. In conclusion, Trimipramine is a multi-target agent with potent vascular activity and anxiolytic efficacy.
Keywords
Trimipramine, 521-78-8, 5-HT Receptor, Bacterial, Serotonin Receptor, 5-hydroxytryptamine Receptor, antidepressants, 5-HT, 5-hydroxytryptamine, serotonin, 5-HTlc receptors, 5-HTIA receptors, dopamine, DA, DA D2 receptor, 5-HT1C, 5-HT2, 5-HT1A, anxiolytic, neurological disease, noradrenaline, hNAT, hSERT, hDAT, human organic cation transporters, hOCT1, hOCT2, hOCT3
References
[1] Jenck F, et al. Evidence for a role of 5-HT1C receptors in the antiserotonergic properties of some antidepressant drugs. Eur J Pharmacol. 1993 Feb 9;231(2):223-9.
[2] Juorio AV, et al. The effects of chronic trimipramine treatment on biogenic amine metabolism and on dopamine D2, 5-HT2 and tryptamine binding sites in rat brain. Gen Pharmacol. 1990;21(5):759-62.
[3] Haenisch B, et al. Inhibitory potencies of trimipramine and its main metabolites at human monoamine and organic cation transporters. Psychopharmacology (Berl). 2011 Sep. 217(2):289-95.
**Background**
Liver diseases, including nonalcoholic fatty liver disease (NAFLD) and hepatocarcinoma, remain significant global health challenges due to their progression toward inflammation and fibrosis. The liver’s susceptibility to oxidative stress and lipid accumulation necessitates the development of agents with potent antioxidant and anti-inflammatory properties. In the search for natural therapeutic compounds, flavonolignans have gained attention for their ability to modulate cellular apoptosis and protect hepatic tissues from chemical and metabolic injury. Silybin, a primary active component of silymarin, has demonstrated a broad spectrum of pharmacological effects, including the inhibition of tumor growth and the reduction of hepatic steatosis. Therefore, we will introduce a potent flavonolignan with diverse biological activities – Silybin.
**Definition**
Silybin is a flavonolignan isolated from milk thistle (Silybum marianum) seeds that exhibits hepatoprotective, antioxidant, anti-inflammatory, and anti-cancer activity.
**In Vitro and In Vivo Studies**
The Silybin biological activity has been extensively documented across various cell lines and animal models. Silybin in vitro studies using HepG2 cells demonstrated growth inhibition in a time- and dose-dependent manner (0-200 mM; 72 h) with an IC50 of 68 μM. Specifically, treatment with 68 μM Silybin for 72 hours induced apoptosis in 60% of cells, increased the G1-phase population by approximately 22%, decreased the S-phase population by 47%, and induced AKT activity inhibition. Furthermore, Silybin has shown antiproliferative effects against human DU145 cells (IC50 = 93.34 μM) and HCT-116 cells (IC50 = 50 μM), while exhibiting neuroprotective activity in mouse HT22 cells (EC50 > 10 μM). In terms of hepatoprotection, it inhibited CCl4-induced toxicity in HepG2 cells (EC50 = 45 μM) and D-galactosamine/TNF-alpha-induced cytotoxicity in mouse hepatocytes (IC50 = 15-82.4 μM).
Regarding Silybin In Vivo applications, research using male C57BL/6J mice with nonalcoholic fatty liver disease (NAFLD) showed that intragastric administration of Silybin (50, 100 mg/kg/day) for the last 4 weeks significantly lowered both serum and hepatic lipid accumulation. These findings highlight the compound’s potential in treating metabolic liver disorders. For researchers seeking Silybin technical information or high-quality reagents, utilizing a reliable Silybin supplier ensures consistent experimental results. In conclusion, Silybin is a versatile flavonolignan that serves as a powerful tool for studying Silybin Cancer research and hepatoprotective mechanisms.
Keywords
Silybin, 802918-57-6, Silibinin, Apoptosis, milk, thistle, hepatoprotective, antioxidant, anti-inflammatory, anti-cancer, HepG2, G1-phase, S-phase, AKT, Inhibitor
References
[1] Silvia Zappavigna, et al. Silybin-Induced Apoptosis Occurs in Parallel to the Increase of Ceramides Synthesis and miRNAs Secretion in Human Hepatocarcinoma Cells. Int J Mol Sci. 2019 May 3;20(9):2190.
[2] Runbin Sun, et al. Silybin ameliorates hepatic lipid accumulation and modulates global metabolism in an NAFLD mouse model. Biomed Pharmacother. 2020 Mar;123:109721.
**Background**
The sigma-1 receptor ($\sigma_1$R) is a unique chaperone protein located primarily at the mitochondria-associated endoplasmic reticulum membrane (MAM). It plays a critical role in modulating calcium signaling, protein folding, and cellular stress responses. Due to its widespread expression in the central and peripheral nervous systems, $\sigma_1$R has become a significant target for treating various neurological and respiratory disorders. Specifically, agonists of this receptor are often explored for their potential to modulate cough reflexes and smooth muscle tone. In the context of respiratory health, agents that can inhibit bronchial interceptors and reduce airway resistance are of high therapeutic value. Therefore, we will introduce a potent sigma-1 receptor agonist – Pentoxyverine.
**Definition**
Pentoxyverine (also known as Carbetapentane) is an orally active sigma-1 receptor agonist and muscarinic antagonist. According to the Pentoxyverine technical information, it exhibits $K_i$ values of 41 nM for $\sigma_1$, 894 nM for $\sigma_2$, and 75 nM for guinea-pig brain membrane $\sigma_1$.
**In Vitro and In Vivo Studies**
The Pentoxyverine description highlights its utility as a potent antitussive, anticonvulsant, and spasmolytic agent. In vitro studies have demonstrated its antiproliferative activity; specifically, Pentoxyverine in vitro assays showed an $EC_{50}$ of 28.16 $\mu$M against mouse astrocyte cells and 2.083 $\mu$M against mouse medulloblastoma cells harboring heterozygous ptch1 genes, both measured by MTT assay. Additionally, it inhibits human OCT1 expressed in HEK293 cells with an $IC_{50}$ of 1.55 $\mu$M.
Regarding Pentoxyverine In Vivo activity, the compound has been extensively tested in mouse models. In female wild-type mice (25-30 g), subcutaneous administration of Pentoxyverine (0.5, 1, 2, 4, 8, 16, 32 mg/kg) 30 minutes prior to intraplantar capsaicin administration dose-dependently potentiated the sensitizing effect of capsaicin to mechanical stimuli. Notably, a dose of 16 mg/kg showed strong potentiation of capsaicin-induced secondary mechanical allodynia. Furthermore, when used as a positive control at 50 mg/kg orally for 7 days, Pentoxyverine increased the latent period of aqueous ammonia-induced cough by 121.72% and inhibited cough frequency by 45.45%. In conclusion, Pentoxyverine is a versatile $\sigma_1$ receptor agonist with significant applications in respiratory and nociceptive research.
Keywords
Pentoxyverine, 77-23-6, Carbetapentane, Sigma Receptor, mAChR, Muscarinic acetylcholine receptor, sigma-1 receptor, σ1, σ2, muscarinic, antitussive, anticonvulsant, spasmolytic, bronchial interceptor, cough reflex
References
[1] Mohamed SH, et, al. Extraction-free spectrophotometric assay of the antitussive drug pentoxyverine citrate using sulfonephthalein dyes. Spectrochim Acta A Mol Biomol Spectrosc. 2019 Nov 5;222:117186.
[2] Calderon SN, et, al. Novel 1-phenylcycloalkanecarboxylic acid derivatives are potent and selective sigma 1 ligands. J Med Chem. 1994 Jul 22;37(15):2285-91.
[3] Brown C, et, al. Antitussive activity of sigma-1 receptor agonists in the guinea-pig. Br J Pharmacol. 2004 Jan;141(2):233-40.
[4] J M Entrena, et al. Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin. Sci Rep. 2016 Nov 25:6:37835. doi: 10.1038/srep37835.
[5] Yuebin Ge, et al. In Vivo Evaluation of the Antiasthmatic, Antitussive, and Expectorant Activities and Chemical Components of Three Elaeagnus Leaves. Evid Based Complement Alternat Med. 2015:2015:428208.
**Background**
Bacterial infections remain a significant global health challenge, necessitating the continuous development and study of potent antimicrobial agents. Macrolide antibiotics are a critical class of drugs used to treat a wide spectrum of pathogens by inhibiting bacterial protein synthesis. These compounds typically bind to the 50S subunit of the bacterial ribosome, thereby preventing the elongation of the polypeptide chain. Understanding the binding kinetics and pharmacokinetic profiles of these agents is essential for optimizing therapeutic efficacy and overcoming antimicrobial resistance. In this context, we will introduce a macrolide antibiotic – Josamycin.
**Definition**
Josamycin is an orally active macrolide antibiotic that exhibits antimicrobial activity against a wide spectrum of pathogens. It targets the bacterial ribosome with a dissociation constant (Kd) of 5.5 nM.
**In Vitro and In Vivo Studies**
According to the Josamycin description, this compound is derived from the microorganism Streptomyces narbonensis and possesses a molecular weight of 827.99 with the Josamycin Formula $\text{C}_{42}\text{H}_{69}\text{NO}_{15}$. Regarding Josamycin biological activity, the compound demonstrates high affinity for the ribosome, which is central to its antibacterial mechanism. In terms of Josamycin in vivo studies, the pharmacokinetics were evaluated in rabbits following oral administration at a dose of 200 mg/kg. The results indicated that tissue levels of the drug are generally much higher than blood levels. Specifically, three hours after administration, while blood levels had become very low, tissue levels remained relatively high, exceeding the levels observed one hour post-dose. Notably, one hour after medication, the concentration in the lungs was found to be the highest among all examined tissues. In conclusion, Josamycin is a potent macrolide antibiotic with favorable tissue distribution, particularly in pulmonary research.
Keywords
Josamycin, 16846-24-5, EN-141, EN141, EN 141, Bacterial, Antibiotic, Inhibitor, inhibitor, inhibit
References
[1] Lovmar M, et al. Kinetics of macrolide action: the Josamycin and erythromycin cases. J Biol Chem. 2004 Dec 17;279(51):53506-15.
[2] Osono T, et al. Pharmacokinetics of macrolides, lincosamides and streptogramins. J Antimicrob Chemother. 1985 Jul;16 Suppl A:151-66.
**Background**
Glycogen synthase kinase-3 beta (GSK-3β) is a multifunctional serine/threonine kinase that plays a critical role in various cellular processes, including metabolism, signal transduction, and cell proliferation. One of its most prominent roles is the negative regulation of the Wnt signaling pathway, where it facilitates the degradation of β-catenin. In the context of endocrine health, the expansion and proliferation of pancreatic beta cells are essential for maintaining glucose homeostasis and treating metabolic disorders such as diabetes. Because GSK-3β acts as a brake on beta-cell proliferation, its inhibition represents a promising therapeutic strategy to stimulate the regeneration of insulin-producing cells. In this context, we will introduce a selective GSK-3β inhibitor – GSK-3β inhibitor 8.
**Definition**
GSK-3β inhibitor 8 is a thiophenacil derivative that serves as an effective and selective inhibitor of GSK-3β, exhibiting an IC50 value of 64 nM.
**In Vitro Studies**
According to the GSK-3β inhibitor 8 description, this compound negatively regulates the Wnt signaling pathway to stimulate the proliferation of beta cells. In terms of GSK-3β inhibitor 8 in vitro activity, studies demonstrated that the compound (1 nM-100 μM; 7 d) stimulates β-cell proliferation in a dose-dependent manner with an EC50 value of 1.41 μM. Furthermore, treatment with GSK-3β inhibitor 8 (2 μM; 72 h) was found to increase the replication of R7T1 β cells approximately 2-fold. The compound also induces the activation of the Super (8X) TOPFlash reporter (1 nM-100 μM; 24 h) with an EC50 value of 1.25 μM. Additionally, GSK-3β inhibitor 8 (2 μM; 72 h) stimulates the translocation of β-catenin into the nucleus in HEK293 cells, confirming its role in activating the Wnt pathway. For researchers requiring specific GSK-3β inhibitor 8 technical information regarding its chemical properties, the compound has a molecular weight of 413.92 and a molecular formula of C20H20ClN5OS. In conclusion, GSK-3β inhibitor 8 is a potent thiophenacil derivative that promotes pancreatic beta-cell expansion through the inhibition of GSK-3β and the subsequent activation of the Wnt/β-catenin signaling pathway.
Keywords
GSK-3β inhibitor 8, 1139875-74-3, Wnt, GSK-3, Glycogen synthase kinase-3, Glycogen synthase kinase 3, Inhibitor, inhibitor, inhibit
References
**Background**
Cancer and malaria remain significant global health challenges, requiring the continuous discovery of potent small molecules with minimal toxicity. In cancer research, the regulation of apoptosis is a primary therapeutic strategy, often focusing on the balance between pro-apoptotic proteins like Bax and anti-apoptotic proteins like Bcl-2. Similarly, the search for novel anti-malarial agents is critical to combat resistant strains of Plasmodium falciparum. Beyond these areas, the activation of p38 MAPK pathways has been linked to myogenic differentiation and anti-inflammatory responses. Given these diverse pharmacological potentials, there is a growing interest in natural isoquinoline alkaloids. In this context, we will introduce a versatile alkaloid with potent biological activities – Dehydrocorydaline.
**Definition**
Dehydrocorydaline (13-Methylpalmatine) is an isoquinoline alkaloid that exhibits strong anti-malarial effects with an IC50 of 38 nM against the P. falciparum 3D7 strain.
**In Vitro and In Vivo Studies**
The Dehydrocorydaline biological activity is characterized by its ability to modulate protein expression and induce apoptosis. Dehydrocorydaline in vitro studies demonstrate that treatment with concentrations ranging from 0 to 200 μM significantly inhibits the growth of MCF-7 breast cancer cells in a dose-dependent manner, reducing cell viability by approximately 40% after 24 hours at the 200 μM dose. Mechanistically, it increases Bax protein expression while decreasing Bcl-2 expression, and induces the activation of caspase-7 and caspase-8 along with the cleavage of PARP, although it does not affect caspase-9. Furthermore, it has been shown to promote myogenic differentiation via the activation of p38 MAPK.
Regarding Dehydrocorydaline in vivo data, the compound manifests low acute toxicity in mouse models. Following oral administration, the LD50 is approximately 277.5 ± 19.0 mg/kg body weight, while the LD50 for intraperitoneal injection is 21.1 ± 1.4 mg/kg. Additionally, it has demonstrated antinociceptive effects in mouse models of inflammatory pain, involving inflammatory cytokines and opioid receptors. In conclusion, Dehydrocorydaline is a potent isoquinoline alkaloid with significant anti-cancer, anti-malarial, and anti-inflammatory properties.
Keywords
Dehydrocorydaline, 30045-16-0, 13-Methylpalmatine, Bcl-2 Family, Caspase, PARP, p38 MAPK, Parasite, Autophagy, poly ADP ribose polymerase, Inhibitor, inhibitor, inhibit
References
[1] Xu Z, et al. Dehydrocorydaline inhibits breast cancer cells proliferation by inducing apoptosis in MCF-7 cells. Am J Chin Med. 2012;40(1):177-85.
[2] Yin ZY, et al. Antinociceptive effects of dehydrocorydaline in mouse models of inflammatory pain involve the opioid receptor and inflammatory cytokines. Sci Rep. 2016 Jun 7;6:27129.
[3] Yoo M, et al. Dehydrocorydaline promotes myogenic differentiation via p38 MAPK activation. Mol Med Rep. 2016 Oct;14(4):3029-36.
[4] Nonaka M, et al. Screening of a library of traditional Chinese medicines to identify anti-malarial compounds and extracts. Malar J. 2018 Jun 25;17(1):244.
**Background**
Transient Receptor Potential Canonical (TRPC) channels are a subfamily of non-selective cation channels that play critical roles in regulating intracellular calcium homeostasis. Among these, TRPC4 and TRPC5 are closely related channels expressed in various tissues, including the central nervous system and the kidneys, where they modulate signal transduction pathways. Dysregulation of these channels is implicated in various pathological conditions, including inflammatory responses and renal dysfunction. Given their specific roles in mediating calcium entry, the development of selective inhibitors is essential for understanding their physiological functions and exploring potential therapeutic interventions. In this context, we will introduce a potent and selective TRPC4/TRPC5 channel inhibitor – ML204.
**Definition**
ML204 is a potent, selective TRPC4/TRPC5 channel inhibitor with an IC50 value of 0.96 μM for TRPC4β-mediated intracellular calcium rise.
**In Vitro and In Vivo Studies**
According to the ML204 description, this compound exhibits high selectivity, being at least 19-fold more selective against TRPC6 and showing no appreciable effect on other TRP channels or voltage-gated sodium, potassium, or calcium channels. In terms of ML204 in vitro activity, the compound inhibits TRPC4β-mediated intracellular Ca2+ rise in HEK293 cells with an IC50 of 0.96 μM. It effectively blocks TRPC4β activity induced by Gi/o stimulation (via μ-opioid, 5HT 1A serotonin, and M2 muscarinic receptors) or Gq/11 stimulation (via endogenous M3-like muscarinic receptors). Additionally, QPatch clamp assays in HEK293 cells demonstrated an IC50 of 2.6 μM for the inhibition of DAMGO-induced current. ML204 also blocks LPS-induced TRPC5 channel activity.
Regarding ML204 In Vivo studies, the compound was administered to nonfasted male C57BL/6 mice (2-3 months old) at a dosage of 1 mg/kg via subcutaneous injection twice a day for 5 days prior to LPS injection. The results indicated that ML204 caused mortality associated with exacerbated hypothermia and decreased peritoneal leukocyte numbers and cytokines in LPS-injected mice. For researchers seeking detailed ML204 technical information, these findings highlight the compound’s significant impact on the systemic inflammatory response. In conclusion, ML204 is a potent and selective inhibitor of TRPC4 and TRPC5 channels suitable for pharmacological research.
Keywords
ML204, 5465-86-1, ML 204, ML-204, TRP Channel, Transient receptor potential channels, ion, channels, membrane, biophysics, transport, receptor, regulation, transient, potential, canonical, TRP, Inhibitor, inhibitor, inhibit
References
[1] Miller M, et al. Identification of ML204, a novel potent antagonist that selectively modulates native TRPC4/C5 ion channels. J Biol Chem. 2011 Sep 23;286(38):33436-46.
[2] Miller MR, et al. Novel Chemical Inhibitor of TRPC4 Channels. Probe Reports from the NIH Molecular Libraries Program [Internet].
[3] Thomas Schaldecker, et al. Inhibition of the TRPC5 ion channel protects the kidney filter. J Clin Invest. 2013 Dec 2; 123(12): 5298–5309.
[4] Domingos M S Pereira, et al. Transient Receptor Potential Canonical Channels 4 and 5 Mediate Escherichia coli-Derived Thioredoxin Effects in Lipopolysaccharide-Injected Mice. Oxid Med Cell Longev. 2018 Jun 10;2018:4904696.
**Background**
Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system, playing a critical role in synaptic plasticity, learning, and memory. It exerts its effects by binding to various ionotropic and metabotropic glutamate receptors, including NMDA, AMPA, and mGlu receptors. Dysregulation of glutamatergic signaling is closely linked to various neurological conditions, where excessive glutamate can lead to excitotoxicity and neuronal death, while insufficient signaling may impair cognitive functions. Understanding the precise interaction between this amino acid and its receptors is essential for developing therapies for neurodegenerative diseases. In this context, we will introduce an excitatory amino acid neurotransmitter – L-Glutamic acid.
**Definition**
L-Glutamic acid is an agonist for all subtypes of glutamate receptors, including metabotropic and ionotropic receptors. According to the L-Glutamic acid technical information, it exhibits potent agonist activity with EC50 values ranging from 0.06 μM at human mGluR3 to 1.8 μM at rat NR1/NR2A receptors.
**In Vitro and In Vivo Studies**
The L-Glutamic acid biological activity has been extensively characterized across various models. In vitro, L-Glutamic acid (120, 500, 750, 1000 mg/dL) has been shown to reduce the harmful effects of lithium on the embryonic development of Xenopus laevis. Furthermore, in human neuroblastoma cell lines including SH-SY5Y, IMR-32, and SK-N-BE(2), L-Glutamic acid (2, 5, 10, 20 mM; 24-48 h) induces neuroexcitotoxicity, resulting in a dose-dependent reduction in cell viability.
L-Glutamic acid in vivo studies have demonstrated its dual role in toxicity and protection. In a Crv4 mice model, a single subcutaneous injection of L-Glutamic acid (3 g/kg) promoted the excitotoxic degeneration of retinal ganglion cells, reducing the number of Brn-3a+ RGCs by over 70%, an effect that was diminished in the absence of the mGlu1 receptor. Conversely, in a chlorpyrifos (CPF)-induced rat model, intraperitoneal administration of L-Glutamic acid (750 mg/kg) inhibited oxidative stress by increasing GSH levels and the activity of GSH-related enzymes. In conclusion, L-Glutamic acid is a versatile excitatory neurotransmitter and agonist used widely in the study of neurological diseases and excitotoxicity.
Keywords
L-Glutamic acid, 56-86-0, Endogenous Metabolite, iGluR, Ferroptosis, Apoptosis, Ionotropic glutamate receptors, NMDA, Agonist, SH-SY5Y, IMR-32, SK-N-BE(2), Neurotoxicity, Crv4 mice, Inhibitor
References
[1] Liberatore F, et al. Permissive role for mGlu1 metabotropic glutamate receptors in excitotoxic retinal degeneration. Neuroscience. 2017 Nov 5;363:142-149.
[2] Giorguieff MF, et al. Presynaptic effect of L-glutamic acid on the release of dopamine in rat striatal slices. Neurosci Lett. 1977 Oct;6(1):73-7.
[3] Boga Pekmezekmek A, et al. L-Glutamic acid monosodium salt reduces the harmful effect of lithium on the development of Xenopus laevis embryos. Environ Sci Pollut Res Int. 2020 Nov;27(33):42124-42132.
[4] Croce N, et al. Hydrochloric acid alters the effect of L-glutamic acid on cell viability in human neuroblastoma cell cultures. J Neurosci Methods. 2013 Jul 15;217(1-2):26-30.
[5] Salyha N, et al. Protective role of l-glutamic acid and l-cysteine in mitigation the chlorpyrifos-induced oxidative stress in rats. Environ Toxicol Pharmacol. 2018 Dec;64:155-163.