MAPK11 inhibitors(mitogen-activated protein kinase 11 inhibitors), p38 MAPK inhibitors(P38 mitogen-activated protein kinase inhibitors), p38α inhibitors(P38 α mitogen-activated protein kinase inhibitors)

Therapeutic Areas-

Active Indication-

Inactive Indication-

Originator Organization

Hong Kong Baptist University

Active Organization

Hong Kong Baptist University

Inactive Organization-

Drug Highest PhaseDiscovery

First Approval Date-

Regulation-

Structure

Molecular FormulaC20H14FN3O

InChIKeyQHKYPYXTTXKZST-UHFFFAOYSA-N

CAS Registry152121-30-7

100 Clinical Results associated with SB-202190

100 Translational Medicine associated with SB-202190

100 Patents (Medical) associated with SB-202190

Literatures (Medical) associated with SB-202190

01 Dec 2024·Biochemical Pharmacology

Sex differences in the metabolic activation of and platelet response to vicagrel in mice: Androgen as a key player

Article

Author: Jia, Yu-Meng ; Sun, Ya-Lan ; Zheng, Zhao-Dong ; Jiang, Li-Ping ; Fu, Min ; Li, Xue-Mei ; Tai, Ting ; Xie, Hong-Guang ; Duan, Fu-Yang ; Ji, Jin-Zi ; Feng, Lei ; Wang, Jin ; Yang, Li ; Ding, Pei-Jie ; Zhu, Ting ; Han, Hao-Ru ; Mi, Qiong-Yu ; Yin, Na

As a biological variable, sex influences the metabolism of and/or response to certain drugs. Vicagrel is being developed as an investigational new drug in China; however, it is unknown whether sex could affect its metabolic activation and platelet responsiveness. This study aimed to determine whether such differences could exist, and to elucidate the mechanisms involved. Orchiectomized (ORX) or ovariectomized (OVX) mouse models were used to investigate the effects of androgens or estrogens on the metabolic activation of and platelet response to vicagrel. Plasma vicagrel active metabolite H4 concentrations, platelet inhibition of vicagrel, and protein levels of intestinal hydrolases Aadac and Ces2 were measured, respectively. Further, p38-MAPK signaling pathway was enriched, whose role was determined using SB202190. Results showed that female mice exhibited significantly elevated systemic exposure of H4 and enhanced platelet responses to vicagrel than males, and that protein expression levels of Aadac and Ces2 differed by sex. OVX mice exhibited less changes than sham mice. ORX mice exhibited increases in protein levels of intestinal hydrolases, systemic exposure of H4, and platelet inhibition of vicagrel, but dihydrotestosterone (DHT) reversed these changes in ORX mice and suppressed these changes in OVX mice. Phosphorylated p38 levels were reduced in female or ORX mice but increased in ORX mice by DHT. SB202190 reversed DHT-induced changes observed in ORX mice. We concluded that sex differences exist in metabolic activation of and platelet response to vicagrel in mice through elevation of p38 phosphorylation by androgens, suggesting sex-based vicagrel dosage adjustments for patient care.

01 Oct 2024·Brain, Behavior, and Immunity

Bacterial peptidoglycan signalling in microglia: Activation by MDP via the NF-κB/MAPK pathway

Article

Author: Sarlus, Heela ; Harris, Robert A ; Diaz Heijtz, Rochellys ; Spielbauer, Julia ; Karlsson, Tobias E ; Glotfelty, Elliot J

Bacterial peptidoglycan (PGN) fragments are commonly studied in the context of bacterial infections. However, PGN fragments recently gained recognition as signalling molecules from the commensal gut microbiota in the healthy host. Here we focus on the minimal bioactive PGN motif muramyl dipeptide (MDP), found in both Gram-positive and Gram-negative commensal bacteria, which signals through the Nod2 receptor. MDP from the gut microbiota translocates to the brain and is associated with changes in neurodevelopment and behaviour, yet there is limited knowledge about the underlying mechanisms. In this study we demonstrate that physiologically relevant doses of MDP induce rapid changes in microglial gene expression and lead to cytokine and chemokine secretion. In immortalised microglial (IMG) cells, C-C Motif Chemokine Ligand 5 (CCL5/RANTES) expression is acutely sensitive to the lowest physiologically prevalent dose (0.1 µg/ml) of MDP. As CCL5 plays an important role in memory formation and synaptic plasticity, microglial CCL5 might be the missing link in elucidating MDP-induced alterations in synaptic gene expression. We observed that a higher physiological dose of MDP elevates the expression of cytokines TNF-α and IL-1β, indicating a transition toward a pro-inflammatory phenotype in IMG cells, which was validated in primary microglial cultures. Furthermore, MDP induces the translocation of NF-κB subunit p65 into the nucleus, which is blocked by MAPK p38 inhibitor SB202190, suggesting that an interplay of both the NF-κB and MAPK pathways is responsible for the MDP-specific microglial phenotype. These findings underscore the significance of different MDP levels in shaping microglial function in the CNS and indicate MDP as a potential mediator for early inflammatory processes in the brain. It also positions microglia as an important target in the gut microbiota-brain-axis pathway through PGN signalling.

01 Oct 2024·Brain Research Bulletin

Inhibition of the P38 MAPK/NLRP3 pathway mitigates cognitive dysfunction and mood alterations in aged mice after abdominal surgery plus sevoflurane

Article

Author: Zhang, Li-Min ; Lv, Jin-Meng ; Li, Bao-Dong ; Wang, Lu-Ying ; Wu, Zi-Qiang ; Lu, Qing-Meng ; Shan, Yong-Lin ; Li, Xiao-Ming ; Gao, Yi-Long ; Zhou, Ting-Ting ; Peng, Heng-Yue

BACKGROUNDCognitive dysfunction, encompassing perioperative psychological distress and cognitive impairment, is a prevalent postoperative complication within the elderly population, and in severe cases, it may lead to dementia. Building upon our prior research that unveiled a connection between postoperative mood fluctuations and cognitive dysfunction with the phosphorylation of P38, this present investigation aims to delve deeper into the involvement of the P38 MAPK/NLRP3 pathway in perioperative neurocognitive disorders (PND) in an abdominal exploratory laparotomy (AEL) aged mice model.METHODSC57BL/6 mice (male, 18-month-old) underwent AEL with 3 % anesthesia. Then, inhibitors targeting P38 MAPK (SB202190, 1 mg/kg) and GSK3β (TWS119, 10 mg/kg) were administered multiple times daily for 7 days post-surgery. The NLRP3-cKO AEL and WT AEL groups only underwent the AEL procedure. Behavioral assessments, including the open field test (OFT), novel object recognition (NOR), force swimming test (FST), and fear conditioning (FC), were initiated on postoperative day 14. Additionally, mice designated for neuroelectrophysiological monitoring had electrodes implanted on day 14 before surgery and underwent novel object recognition while their local field potential (LFP) was concurrently recorded on postoperative day 14. Lastly, after they were euthanasized, pathological analysis and western blot were performed.RESULTSSB202190, TWS119, and astrocyte-conditional knockout NLRP3 all ameliorated the cognitive impairment behaviors induced by AEL in mice and increased mean theta power during novel location exploration. However, it is worth noting that SB202190 may exacerbate postoperative depressive and anxiety-like behaviors in mice, while TWS119 may induce impulsive behaviors.CONCLUSIONSOur study suggests that anesthesia and surgical procedures induce alterations in mood and cognition, which may be intricately linked to the P38 MAPK/NLRP3 pathway.

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