Metabolomic and network analysis of pharmacotherapies for sensorineural hearing loss.

HYPOTHESIS Different pharmacotherapies for sensorineural hearing loss (SNHL) are interconnected in metabolic networks with molecular hubs. BACKGROUND Sensorineural hearing loss is the most common sensory deficit worldwide. Dozens of drugs have shown efficacy against SNHL in animal studies and a few in human studies. Analyzing metabolic networks that interconnect these drugs will point to and prioritize development of new pharmacotherapies for human SNHL. METHODS Drugs that have shown efficacy in treating mammalian SNHL were identified through PubMed literature searches. The drugs were analyzed using the metabolomic analysis and the "grow-tool function" in ingenuity pathway analysis (IPA). The top 3 most interconnected molecules and drugs (i.e., the hubs) within the generated networks were considered important targets for the treatment of SNHL. RESULTS A total of 70 drugs were investigated with IPA. The metabolomic analysis revealed 2 statistically significant networks (Networks 1 and 2). A network analysis using the "grow-tool function" generated one statistically significant network (Network 3). Hubs of these networks were as follows: P38 mitogen-activated protein kinases (P38 MAPK), p42/p44 MAP kinase (ERK1/2) and glutathione for Network 1; protein kinase B (Akt), nuclear factor kappa B (NFkB) and ERK for Network 2; and dexamethasone, tretinoin, and cyclosporin A for Network 3. CONCLUSION Metabolomic and network analysis of the existing pharmacotherapies for SNHL has pointed to and prioritized a number of potential novel targets for treatment of SNHL.