Abstract:
Sphingomyelin (SM) belongs to a class of lipids termed as sphingolipids. It
is an important component of cell membranes that is present in the myelin sheath
of nerve cell axons in high concentrations. TNF-a is a potent pro-inflammatory cytokine
as well as the master regulator of sphingomyelin signaling pathway, that is
generated in response to various neurological disorders like Alzheimer’s disease,
Parkinson’s disease and Multiple Sclerosis. As second messenger, sphingomyelin and
its downstream sphingolipids are capable of activating various signaling cascades
like PI3K/AKT and MAPK/ERK pathways and control diverse processes coupled
with neuronal viability, survival and death. The current study offers a comprehensive
insilico systems analysis of TNF-a mediated sphingomyelin and related signaling
cascades using model-based quantitative approach. Computational modeling of the
inflammation enabled to study the system dynamics of neuronal cell injury. Network
and sensitivity analysis of the model unveiled the importance of essential reaction
parameters and components during advanced stages of neuroinflammation. Moreover,
the efficacy and potency of FDA-approved drugs at later stages of neuronal
inflammation was also evaluated by studying model’s response towards inhibition
of respective proteins/enzymes. The repurposing of the drugs, namely, Etanercept
and Scyphostatin was found impracticable during inflammatory conditions. However,
Nivocasan effectively reduced neuronal apoptosis via its inhibitory mechanism on the
caspases.
