Kumar Mohit, Chaudhary Jasmine, Kamboj Sonia, Jain Akash
MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India.
Ch. Devi Lal College of Pharmacy, Bhagwangarh, Jagadhri, Haryana, India.
Inflammopharmacology. 2025 Jul 7. doi: 10.1007/s10787-025-01845-4.
Methadone (MTD) is a synthetic opioid, N-Methyl-D-Aspartate (NMDA) antagonist, Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID), and Cilnidipine (CLD) is a calcium channel blocker widely used for the management of various neurological disorders and their associated complications. Investigating the mechanism of MTD, TA, and CLD drugs with Traumatic Brain Injury (TBI) protein has become easier with the advent of network pharmacology.
The purpose of this study is to use network pharmacology, a contemporary method, to examine the mechanisms of MTD, TA, and CLD in TBI.
A protein-protein interaction (PPI) network was used to determine the primary therapeutic targets of MTD, TA, and CLD against TBI. Several extensive databases (Pubchem, Swiss target prediction database, String and DisGeNET database, ADMET lab2.0, and Swiss ADME database) were consulted to collect MTD, TA, and CLD linked targets and genes relevant to TBI. Drug-Drug interactions (DDIs) of MTD, TA, and CLD were also checked using Drug Bank, Lexicomp Drug Interactions, Dailymed, and Medscape database.
MTD, TA, and CLD were found to have important pathways according to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. MTD inhibits the NOS1, NOS2, NOS3, and MPO, CXCR4 activated gene pathways and stimulates the DRD2, SLC6A3, SLC6A4, SLC18A2, HTR1A, and AKT1 deactivated gene pathways. TA inhibits the GRIN1, MAPK1, and COX-II activated gene pathways. CLD inhibits the MAP2K1, CACNA1C, CACNA1D, PDE4D, CASP3, mTOR, PTGS2, SCN9N, and GSK3B, and stimulates the IGF1R, DRD2, SHH, HTR2A, FASN, CNR1, ABCB1, and PIK3CA deactivated gene pathways. The pharmacokinetic and toxicity profile was checked using ADMET analysis to make sure that it aligned to the optimum values. Drug-drug interactions (DDIs) were assessed to evaluate safety profile, and no interaction were found between MTD, TA and CLD.
This study identified a primary target for MTD such as NOS1, NOS2, NOS3, DRD2, DAT (SLC6A3), MPO, SLC6A4, CXCR4-C-X-C, AKT1, SLC/8A2, HTR1A; for TA: MAPK1, GRIN1 and for CLD: IGF1R, DRD2, SHH, MAP2K1, CACNA1D, HTR2A, PDE4D, CASP3, MTOR, FASN, PTGS2, SCN9N, CNR1, CACNA1C, ABCB1, PIK3CA, GSK3B in the mechanistic regulation of TBI by reducing the activation of several pathways linked to development of TBI.
美沙酮（MTD）是一种合成阿片类药物、N-甲基-D-天冬氨酸（NMDA）拮抗剂，托芬那酸（TA）是一种非甾体抗炎药（NSAID），西尼地平（CLD）是一种钙通道阻滞剂，广泛用于治疗各种神经系统疾病及其相关并发症。随着网络药理学的出现，研究MTD、TA和CLD药物与创伤性脑损伤（TBI）蛋白的作用机制变得更加容易。
本研究旨在使用网络药理学这一现代方法，研究MTD、TA和CLD在TBI中的作用机制。
使用蛋白质-蛋白质相互作用（PPI）网络来确定MTD、TA和CLD针对TBI的主要治疗靶点。查阅了几个广泛的数据库（Pubchem、瑞士靶点预测数据库、String和DisGeNET数据库、ADMET lab2.0和瑞士ADME数据库），以收集与TBI相关的MTD、TA和CLD的相关靶点及基因。还使用药物银行、Lexicomp药物相互作用数据库、Dailymed和Medscape数据库检查了MTD、TA和CLD的药物-药物相互作用（DDIs）。
根据京都基因与基因组百科全书（KEGG）通路，发现MTD、TA和CLD具有重要的通路。MTD抑制一氧化氮合酶1（NOS1）、一氧化氮合酶2（NOS2）、一氧化氮合酶3（NOS3）和髓过氧化物酶（MPO）、CXC趋化因子受体4（CXCR4）激活的基因通路，并刺激多巴胺受体D2（DRD2）、溶质载体家族6成员3（SLC6A3）、溶质载体家族6成员4（SLC6A4）、囊泡单胺转运体2（SLC18A2）、5-羟色胺受体1A（HTR1A）和蛋白激酶B1（AKT1）失活的基因通路。TA抑制谷氨酸离子型受体NMDA1亚基（GRIN1）、丝裂原活化蛋白激酶1（MAPK1）和环氧化酶-2（COX-II）激活的基因通路。CLD抑制丝裂原活化蛋白激酶激酶1（MAP2K1）、L型钙通道α1C亚基（CACNA1C）、L型钙通道α1D亚基（CACNA1D）、磷酸二酯酶4D（PDE4D）、半胱天冬酶3（CASP3）、哺乳动物雷帕霉素靶蛋白（mTOR）、前列腺素内过氧化物合酶2（PTGS2）、电压门控钠通道9型（SCN9N）和糖原合成酶激酶3β（GSK3B），并刺激胰岛素样生长因子1受体（IGF1R）、DRD2、音猬因子（SHH）、5-羟色胺受体2A（HTR2A）、脂肪酸合酶（FASN）、大麻素受体1（CNR1）、ATP结合盒转运体B1（ABCB1）和磷脂酰肌醇-3激酶催化亚基α（PIK3CA）失活的基因通路。使用ADMET分析检查了药代动力学和毒性特征，以确保其符合最佳值。评估了药物-药物相互作用（DDIs）以评估安全性，未发现MTD、TA和CLD之间存在相互作用。
本研究确定了MTD在TBI机制调节中的主要靶点，如NOS1、NOS2、NOS3、DRD2、多巴胺转运体（DAT，SLC6A3）、MPO、SLC6A4、CXCR4-C-X-C、AKT1、SLC/8A2、HTR1A；TA的主要靶点为：MAPK1、GRIN1；CLD的主要靶点为：IGF1R、DRD2、SHH、MAP2K1、CACNA1D、HTR2A、PDE4D、CASP3、MTOR、FASN、PTGS2、SCN9N、CNR1、CACNA1C、ABCB1、PIK3CA、GSK3B，通过减少与TBI发展相关的几条通路的激活来实现。
