Novel Neuroprotective Multicomponent Therapy for Amyotrophic Lateral Sclerosis Designed by Networked Systems

PLoS One. 2016 Jan 25;11(1):e0147626. doi: 10.1371/journal.pone.0147626. eCollection 2016.

Abstract

Amyotrophic Lateral Sclerosis is a fatal, progressive neurodegenerative disease characterized by loss of motor neuron function for which there is no effective treatment. One of the main difficulties in developing new therapies lies on the multiple events that contribute to motor neuron death in amyotrophic lateral sclerosis. Several pathological mechanisms have been identified as underlying events of the disease process, including excitotoxicity, mitochondrial dysfunction, oxidative stress, altered axonal transport, proteasome dysfunction, synaptic deficits, glial cell contribution, and disrupted clearance of misfolded proteins. Our approach in this study was based on a holistic vision of these mechanisms and the use of computational tools to identify polypharmacology for targeting multiple etiopathogenic pathways. By using a repositioning analysis based on systems biology approach (TPMS technology), we identified and validated the neuroprotective potential of two new drug combinations: Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine. In addition, we estimated their molecular mechanisms of action in silico and validated some of these results in a well-established in vitro model of amyotrophic lateral sclerosis based on cultured spinal cord slices. The results verified that Aliretinoin and Pranlukast, and Aliretinoin and Mefloquine promote neuroprotection of motor neurons and reduce microgliosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Animals
  • Chromones / pharmacology
  • Chromones / therapeutic use*
  • Computer Simulation
  • Drug Therapy, Combination
  • Humans
  • Mefloquine / pharmacology
  • Mefloquine / therapeutic use*
  • Models, Theoretical
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Rats
  • Rats, Sprague-Dawley
  • Spinal Cord / drug effects

Substances

  • Chromones
  • Neuroprotective Agents
  • pranlukast
  • Mefloquine

Grant support

MHG was recipient of a postdoctoral fellowship from Fundació La marató-TV3 (#110430). This project has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement No. 306240. PA acknowledges financial support from the Spanish Ministerio de Ciencia e Innovación (BIO2013-48222), the European Commission (Agreement no: 306240) and the European Research Council (Agreements no: 614944). RM and MC are Anaxomics Biotech SL employees and JMM is founder and CEO of Anaxomics. RM and MC have no role in the development of Therapeutic Performance Mapping System (TPMS) proprietary technology; however, JMM contributes in the design of TPMS. The role of Anaxomics’ employees are as follows: RM carried out the ALS characterization used to construct ALS biological network, and performed the analysis of the drug candidates in the context of ALS. JMM designed and carried out the in-silico experiments. MC performed the final selection of drug candidates, designed the in-vitro experimental validation of drugs candidates and wrote the paper.