A-804598 effectively crosses into the central nervous system and acts as a competitive inhibitor, selectively targeting P2X7 receptors. It demonstrates IC50 values of 9 nM for mice, 10 nM for rats, and 11 nM for humans, showcasing its efficacy across these species' P2X7 receptors[1]. Treating cells with A-804598 at concentrations ranging from 0.1 to 10 μM for one hour markedly reduces cell death caused by BzATP in a dose-dependent fashion. The most substantial protective effect against the cytotoxicity triggered by BzATP is observed at a concentration of 3 μM A-804598[2].
A-804598 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Primary microglia from SOD1-G93A mice
10 μM
15 minutes
To investigate the effect of P2X7 activation on the expression of the autophagic marker LC3B-II in SOD1-G93A microglia. Results show that P2X7 activation significantly increases LC3B-II expression, and this effect is inhibited by the P2X7 antagonist A-804598.
Front Cell Neurosci. 2017 Aug 21;11:249.
Microglia
10 µM
30 minutes
To investigate the effects of A-804598 on microglial morphology and cytokine secretion. Results showed that A-804598 reduced the proportion of round/ameboid microglia and increased complex morphologies, while also decreasing pro-inflammatory cytokine levels (e.g., IL-1β, IL-6, and TNFα) and increasing anti-inflammatory cytokine IL-4 secretion.
Front Pharmacol. 2023 Apr 10;14:1148190.
Neuronal and non-neuronal cells in trigeminal ganglion cultures
100 nM
15 min
To investigate the effect of A-804598 on BzATP-induced membrane pore permeability. Results showed that A-804598 significantly reduced the BzATP-evoked fluorescence signal and the number of responding cells in R192Q KI cultures.
Purinergic Signal. 2017 Dec;13(4):511-520.
J774 macrophages
10 μM
15 minutes
To assess the effect of A-804598 on ATP-induced ethidium+ uptake, results showed A-804598 near-completely abrogated ATP-induced ethidium+ uptake
Purinergic Signal. 2017 Dec;13(4):405-415.
Retinal ganglion cells
30 μM
10 minutes
To investigate the effect of P2X7 receptor antagonist A804598 on BzATP-induced suppression of RGC ON-fEPSP, results showed that A804598 significantly attenuated the inhibitory effect of BzATP.
Purinergic Signal. 2016 Dec;12(4):611-625.
A-804598 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6J mice
Chronic intragastric ethanol infusion and high-fat diet (Hybrid) model
Intragastric administration
5 mg/kg
3 times a week for 3 weeks
A804598 reversed the changes in microglia and astrocytes, reduced/abolished increases in mRNA levels of inflammatory markers including IL-1β, iNOS, CXCR2, and components of inflammatory signaling pathways such as TLR2, CASP1, NF-kB1, and CREB1, as well as protein levels of pro-IL-1β and Nf-kB1. The P2X7R antagonist did not affect the increase in mRNA levels of fractalkine (CX3CL1) and its receptor CX3CR1, an interaction that plays a neuroprotective role in neuron-glia communication. P2X7R antagonism also resulted in reduction of inflammatory markers but did not alter liver steatosis.
J Neuroimmune Pharmacol. 2019 Jun;14(2):263-277
SOD1-G93A transgenic mice
ALS mouse model
Intraperitoneal injection
30 mg/kg
Five times a week until end stage of disease
To evaluate the effect of the P2X7 antagonist A-804598 on the expression of the autophagic marker SQSTM1/p62 in the lumbar spinal cord of SOD1-G93A mice. Results show that A-804598 treatment significantly decreases SQSTM1/p62 expression but has no significant effect on disease progression and survival.
Front Cell Neurosci. 2017 Aug 21;11:249.
Sprague-Dawley rats
High-fat diet induced anxiety and anhedonia model
Intraperitoneal injection
5 mg/kg
Twice daily for 25 days
To investigate the reversal effect of P2X7 receptor antagonist A804598 on high-fat diet-induced anxiety behaviors. Results showed that A804598 significantly reduced anxiety behaviors in high-fat diet rats in the open field test and elevated plus maze.
Neuropsychopharmacology. 2016 Jun;41(7):1874-87
Sprague-Dawley rats
Traumatic brain injury model
Intraperitoneal injection
10 mg/kg
Once daily for 5 consecutive days
A804598 reduced the number of MV-like particles released by microglial cells after traumatic brain injury, reduced neuronal apoptosis, increased neuronal survival, and improved neurobehavioral outcomes
Purinergic Signal. 2017 Dec;13(4):529-544
BALB/c mice
IMQ-induced psoriasis-like inflammation model
Intraperitoneal injection
50 mg/kg
Injected every second day (days 0 and 2)
To evaluate the effect of A-804598 on IMQ-induced psoriasis-like inflammation, results showed A-804598 had no significant effect on ear swelling and skin pathology
Purinergic Signal. 2017 Dec;13(4):405-415.
Mice
Ex vivo retinal whole mount preparation
Perfusion
30 μM
Single administration, lasting 10 minutes
To investigate the effect of P2X7 receptor antagonist A804598 on BzATP-induced suppression of RGC ON-fEPSP, results showed that A804598 significantly attenuated the inhibitory effect of BzATP.
Purinergic Signal. 2016 Dec;12(4):611-625.
A-804598 动物研究
Animal study
Administering A-804598 through intraperitoneal injections at a dosage of 30 mg/kg five times weekly results in a reduction of LC3B-II and SQSTM1/p62 levels in the lumbar spinal cord during the terminal phase of the disease[3].
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