RESUMEN
Studies have shown that neurodegenerative diseases such as AD and PD are related to neuroinflammation. Neuroinflammation is a common inflammatory condition that can lead to a variety of dysfunction in the body. At present, it is no medications specifically approved to prevent or cure neuroinflammation, so even though many drugs can temporarily control the neurological symptoms of neuroinflammation, but no one can reverse the progress of neuroinflammation, let al.one completely cure neuroinflammation. Therefore, it is urgent to develop new drug development for neuroinflammation treatment. In this review, we highlight the therapeutic advancement in the field of neurodegenerative disorders, by focusing on the impact of neuroinflammation treatment has on these conditions, and the effective drugs for the treatment of neuroinflammation and neurodegenerative diseases and their latest research progress are reviewed according to the related signaling pathway, as well as the prospect of their clinical application is also discussed. The purpose of this review is to enable specialists to better understand the mechanisms underlying neuroinflammation and anti-inflammatory drugs, promote the development of therapeutic drugs for neuroinflammation and neurodegenerative diseases, and further provide therapeutic references for clinical neurologists.
RESUMEN
NF-κB contributes to the biosynthesis of various chemokines, cytokines, and enzymes. It plays many crucial roles in the upstream neuroinflammatory pathways. Briefly, the inhibitory IkB subunit is cleaved and phosphorylated by the IKK-α/ß enzyme. It leads to the activation and translocation of the NF-κB (p50/p65) complex into the nucleus. Subsequently, the activated NF-κB interacts with the genomic DNA and contributes to expressing various proinflammatory cytokines. In the present study, we developed a novel NF-κB inhibitor encoded (D5) and investigated the efficacy of our druggable compound through several in silico, in vitro, and in situ analysis. The results demonstrated that D5 not only inhibited the mRNA expression of the IKK-α/ß enzyme (around 86-96% suppression rate for both cell lines at 12 and 24 h time frames) but also by interacting to the active site of the mentioned kinase (dock score -6.14 and binding energy -23.60 kcal/mol) reduced the level of phosphorylated IkB-α in the cytosol around 96-99% and p65 subunit in the nucleus around 73-90% (among all groups in 12 and 24 h time points). Additionally, the results indicated that D5 suppressed the NF-κB target mRNA levels of TNF-α and IL-6 in a total average of around 92%. Overall, The results demonstrated that D5 in a considerably lower concentration than Dis (0.71 µM vs. 52.73 µM) showed significantly higher inhibitory efficacy on NF-κB translocation approx. 200-300%. The results suggested D5 as a potent NF-κB silencer, but further investigations are required to validate our outcomes.
Asunto(s)
Quinasa I-kappa B , FN-kappa B/metabolismo , Enfermedades Neuroinflamatorias , Sistemas de Translocación de Proteínas , Alcaloides/farmacología , Benzodioxoles/farmacología , Línea Celular , Inhibidores Enzimáticos del Citocromo P-450/farmacología , Desarrollo de Medicamentos/métodos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Fosforilación/efectos de los fármacos , Piperidinas/farmacología , Alcamidas Poliinsaturadas/farmacología , Sistemas de Translocación de Proteínas/efectos de los fármacos , Sistemas de Translocación de Proteínas/metabolismo , Transporte de Proteínas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factor de Transcripción ReIA/metabolismoRESUMEN
NF-kB translocation is the key point in the upstream neuroinflammatory pathways. It plays an import role in the pro-inflammatory chemokine, cytokine, and various enzyme expressions, consequently leading to the inflammatory response of the innate immune system. The NF-kB complex consists of structural homolog subunits, including c-Rel, RelB, p52, p65, and p50. Among the p65 subunit has a vital function of NF-kB translocation and DNA binding. NF-kB translocation may occur due to acetylation and phosphorylation LYS 310 and SER311 amino acids in chain A of the p65 subunit in response to IKK-α/ß activity. Therefore, there are two ways to inhibit the NF-kB translocation, either directly blocking the active sites of IKK-α/ß enzymes or protecting the LYS 310 and SER311 of p65 subunit from acetylation and phosphorylation. NF-kB translocation inhibitors can maintain the NF-kB complex in the inactive form inside the cytosol. In this study, we have designed and developed an NF-kB translocation inhibitor, D4. We have performed various in silico, in vitro and in situ studies on the anti-neuroinflammatory function of D4. It showed the ability to inhibit IKK-α/ß in both genome and proteome levels and protect LYS310 of the p65 subunit of NF-kB from the acetylation process. Therefore, we can suggest D4 as the promising anti-neuroinflammatory agent with a function on the upstream process of inflammatory pathways.