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Chemical Structure| 1415925-18-6 Chemical Structure| 1415925-18-6

Structure of GSK2795039
CAS No.: 1415925-18-6

Chemical Structure| 1415925-18-6

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GSK2795039 is a NADPH oxidase 2 (NOX2) inhibitor with a mean pIC50 of 6 in various cell-free assays. It inhibits reactive oxygen species (ROS) production and NADPH consumption, and reduces apoptosis.

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Singh, Prince Kumar ; Maurya, Shweta ; Saadi, Aseel ; Shekh-Ahmad, Tawfeeq ;

Abstract: Oxidative stress is a pivotal driver of epileptogenesis and seizure-induced neuronal pathology, with NADPH oxidase 2 (NOX2) serving as a major source of reactive oxygen species (ROS) in the brain. Despite its established role in seizure pathophysiology, the therapeutic implications of selective NOX2 inhibition in epilepsy remain insufficiently explored. Here, we evaluate the efficacy of GSK2795039, a potent NOX2 inhibitor, in attenuating epileptiform network activity, oxidative stress, neuroinflammation, and neuronal injury using an in vitro epileptiform model and a pentylenetetrazol (PTZ)-induced seizure rat model. GSK2795039 significantly suppressed epileptiform activity in vitro, reducing synchronous Ca2+ oscillations and ROS accumulation in mixed cortical neuroglial cultures. In PTZ-treated rats, GSK2795039 markedly diminished seizure severity, duration, and cumulative seizure burden, independent of seizure onset latency. Molecular analyses revealed a significant downregulation of NOX2 mRNA in both the hippocampus and cortex, although protein levels remained unaltered. Additionally, GSK2795039 mitigated oxidative DNA damage, selectively preserved hippocampal neuronal integrity, and differentially modulated neuroinflammatory cytokines, including IL-6, IL-1β, and IL-10. These findings underscore NOX2 inhibition as a compelling neuroprotective strategy, highlighting the potential of GSK2795039 to mitigate oxidative and inflammatory cascades in epilepsy. Targeting NOX2 may represent a promising avenue for precision therapeutics in oxidative stress-driven epilepsy.

Keywords: GSK2795039 ; NADPH Oxidase 2 ; Epileptiform activity ; Pentylenetetrazol ; Oxidative stress

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Singh, Prince Kumar ; Maurya, Shweta ; Saadi, Aseel ; Zhang, Taige ; Lieb, Andreas ; Shekh-Ahmad, Tawfeeq

Abstract: NOX2-driven reactive oxygen species mediated oxidative stress and neuroinflammation play a critical role in the pathophysiology of neurological disorders such as epilepsy. However, sex-dependent differences in the regulation of NOX2 associated oxidative stress and neuroinflammation and therapeutic targeting remain largely unexplored. Although various NOX inhibitors have been investigated, many have poor specificity, toxicity, and lack sustained efficacy. There is an urgent need for selective NOX2 inhibitors capable of mitigating oxidative stress and driven neuroinflammation while accounting for their sex-dependent responses. In this study, we investigated the therapeutic potential of GSK2795039, a selective NOX2 inhibitor, in reducing seizure burden, oxidative stress-mediated neuronal damage, and cognitive impairment in a sex-specific manner. GSK2795039 target NOX2 and associated oxidative stress-driven neuroinflammation efficiently in male over female rats following status epilepticus. However, males exhibited a more pronounced therapeutic response, with greater reductions in seizure and interictal spiking frequency, and neuronal loss, as well as improved cognitive outcomes. The comparatively weaker response in females suggests a reliance on alternative antioxidant and neuroprotective pathways. Our findings underscore the importance of considering sex as a biological variable in epilepsy treatment and highlight GSK2795039 as a promising NOX2-targeted therapy with differential efficacy based on sex-dependent redox homeostasis and inflammatory regulation.

Keywords: GSK2795039 ; NADPH Oxidase 2 ; Epileptogenesis ; Kainic Acid ; Oxidative stress

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Product Details of GSK2795039

CAS No. :1415925-18-6
Formula : C23H26N6O2S
M.W : 450.56
SMILES Code : O=S(C1=NN(C)C=C1)(NC2=C3C(N(C(C)C)C=C3C4=CC5=C(C=C4)CCN5C)=NC=C2)=O
MDL No. :MFCD30489720
InChI Key :FMWVTCZKCXPKFW-UHFFFAOYSA-N
Pubchem ID :71090129

Safety of GSK2795039

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Isoform Comparison

Biological Activity

Description
GSK2795039 acts as an inhibitor of NADPH oxidase 2 (NOX2), showing potency with a mean pIC50 of 6 across various cell-free assays. It effectively reduces the production of reactive oxygen species (ROS) and consumption of NADPH[1].

In Vitro:

Cell Line
Concentration Treated Time Description References
Mouse bone-specific endothelial cells 400 mg/dL 4 days To evaluate the effects of high glucose environment on endothelial cell proliferation, viability, and ROS levels, results showed that high glucose environment reduced cell proliferation and viability, and significantly increased ROS levels in ECs. PMC7914348
CTX-TNA2 cells 25 µM after 4 h of OGD Inhibit NOX2 activity and reduce ROS generation PMC10823689
BV2 microglia 25 μM 24 hours NOX2 inhibition significantly reduced ROS levels in microglia exposed to iron and LPS, returning them to control levels PMC6378754
Primary microglia 25 μM 24 hours NOX2 inhibition significantly reduced ROS levels in microglia exposed to iron and LPS, returning them to control levels PMC6378754
VSMCs (spontaneously hypertensive rats) 25 μM 24 hours GSK2795039 inhibited the migration and proliferation of VSMCs in spontaneously hypertensive rats, but its effect was less than that of RND3 overexpression. PMC8661704

In Vivo:

Species
Animal Model
Administration Dosage Frequency Description References
Mice Streptozotocin-induced type 1 diabetic mouse model Drinking water 10 mg/kg Single injection, lasting 24 hours To evaluate the effects of GSK2795039 on bone vessels and bone mass in diabetic mice, results showed that GSK2795039 significantly ameliorated bone vessel impairment and bone mass in diabetic mice. PMC7914348

Protocol

Bio Calculators
Preparing Stock Solutions 1mg 5mg 10mg

1 mM

5 mM

10 mM

2.22mL

0.44mL

0.22mL

11.10mL

2.22mL

1.11mL

22.19mL

4.44mL

2.22mL

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