Title:Design, Synthesis, and Anti-Neuroinflammatory Activity of Amide- Containing Dithiolethiones
Volume: 17
Issue: 10
Author(s): Karrington Craig, Paula Avila and Dennis A. Brown*
Affiliation:
- Manchester University College of Pharmacy and Health Sciences, 10627 Diebold Rd, Fort Wayne, IN 46845,United States
Keywords:
Neuroinflammation, dithiolethiones, multiple sclerosis, glutathione, CNS, neurodegeneration.
Abstract:
Background: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central
nervous system characterized by demyelination of neurons and neurodegeneration. Current MS therapies
ameliorate inflammatory damage but are unable to address the degenerative aspects of the disease.
Objective: In this report, we evaluate the ability of amide-based dithiolethiones (DTTs) to suppress
neuroinflammation in microglia and increase anti-oxidant capacity in neuron-like cells.
Methods: A series of amide-containing DTTs were designed, synthesized, and assayed for the ability
to suppress pro-neuroinflammatory cytokines IL-12p40 and IL-23p19 induced by LPS in the BV2
microglial cell line. Lead analog 2c was identified and further characterized.
Results: Structure-activity data revealed tolerance towards a variety of amides. Morpholine analog 2c
dose-dependently reduced various other inflammatory cytokines and mediators, including TNF, IL-6,
IL-1β, NOS2, and COX2. Additionally, 2c elevated cellular levels of glutathione in SH-SH5Y neuronal
cell line. Furthermore, mechanistic studies showed that 2c increased the expression of antiinflammatory
Nrf2 and HMOX proteins.
Conclusion: The combination of anti-neuroinflammatory and anti-oxidant activities of amide-based
DTTs suggests that they are promising agents for the treatment of both demyelination and neurodegeneration
in MS.
