Mechanistic investigation of methadone, tolfenamic acid, and cilnidipine in traumatic brain injury: a novel multi-target perspective outcome of network pharmacology

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.