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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 ; Zhang, Taige ; Lieb, Andreas ; Shekh-Ahmad, Tawfeeq

Abstract: Epilepsy, a chronic neurological disorder affecting approximately 1% of the global population, is characterized by recurrent seizures that are often refractory to current antiseizure medications (ASMs). These pharmacotherapies predominantly suppress symptoms without intervening in the underlying pathophysiological cascade, which includes persistent oxidative stress and neuroinflammation, key drivers of epileptogenesis and pharmacoresistance. Among the primary enzymatic sources of reactive oxygen species (ROS), NADPH oxidase 2 (NOX2) has emerged as a central mediator of redox imbalance and neuroimmune activation in the brain. However, the sex-specific roles of NOX2 and its modulation as a therapeutic strategy remain largely unexplored. Here, we investigated the therapeutic efficacy of GSK2795039, a selective and functionally active NOX2 inhibitor, in a kainic acid (KA)-induced status epilepticus (SE) rat model. We examined both acute and chronic outcomes of early NOX2 inhibition on oxidative stress, neuroinflammation, hippocampal neurodegeneration, and cognitive function, incorporating rigorous analysis of sex-dependent responses. Long-term effects on epileptogenesis were assessed using continuous 24/7 video-electrocorticographic (vECoG) monitoring. Our results revealed that early GSK2795039 intervention significantly attenuated SE-induced oxidative damage, pro-inflammatory cytokine expression, and neuronal death, thereby mitigating the development of spontaneous recurrent seizures. Notably, male rats exhibited a more robust therapeutic response, including a marked reduction in seizure burden and improved cognitive performance, whereas females displayed a more modest response, suggesting the presence of compensatory or NOX2-independent antioxidant mechanisms. These findings underscore the pivotal role of NOX2-derived ROS in driving epileptogenesis and highlight the translational potential of NOX2-targeted therapies. Importantly, our study revealed a clear sex divergence in therapeutic outcomes, reinforcing the necessity of integrating sex as a critical biological variable in preclinical and clinical strategies aimed at disease modification in epilepsy.

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

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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 , 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. significantly suppressed epileptiform activity in vitro, reducing synchronous Ca2+ oscillations and accumulation in mixed cortical neuroglial cultures. In PTZ-treated rats, 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|https://www.ambeed.com/protein.html levels remained unaltered. Additionally, mitigated oxidative , 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 to mitigate oxidative and inflammatory cascades in epilepsy. Targeting NOX2 may represent a promising avenue for precision therapeutics in oxidative stress-driven epilepsy.

Keywords: ; 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 , a selective NOX2 inhibitor, in reducing seizure burden, oxidative stress-mediated neuronal damage, and cognitive impairment in a sex-specific manner. 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 and neuroprotective pathways. Our findings underscore the importance of considering sex as a biological variable in epilepsy treatment and highlight as a promising NOX2-targeted therapy with differential efficacy based on sex-dependent redox homeostasis and inflammatory regulation.

Keywords: ; 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].

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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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