Drug target identification at the crossroad of neuronal apoptosis and survival

Abstract

Introduction: Inappropriate activation of apoptosis may contribute to neurodegeneration, a multifaceted process that results in various chronic disorders, including Alzheimer's and Parkinson's diseases. Several in vitro and in vivo studies demonstrated that neuronal apoptosis is a multi-pathway cell-death program that requires RNA synthesis. Thus, transcriptionally activated genes whose products induce cell death can be triggered by different stimuli and antagonized by neurotrophic factors. Systems biology is now unveiling the series of intracellular signaling pathways and key drug targets at the intersection of neuronal apoptosis and survival. Areas covered: This review introduces a genomic approach that can be used to elucidate the systems biology of neuronal apoptosis and survival, and to rationally select drug targets, no longer oriented to emulate the action of growth factors at the membrane receptor level, but rather to modulate their downstream signals. Expert opinion: The advent of genomics is offering an unprecedented opportunity to explore how the delicate balance between apoptosis and survival-inducing signals triggers a transcriptional program. Characterization of this program can be useful to identify potential pharmacological targets for existing drugs. Such knowledge might pave the way towards an innovative pharmacology. ARTICLE HISTORY

SARM1 acts downstream of neuroinflammatory and necroptotic signaling to induce axon degeneration

“…Early efforts to identify a common mechanism focused on neuronal apoptosis in hopes of blocking neuronal cell death. While tremendous strides were made in delineating the molecular mechanisms of apoptosis in neurons, targeting this pathway has not generated new treatments for neurodegeneration (Mattson, 2000;Maino et al, 2017). There are multiple reasons for this failure.…”

The trophic effect of nerve growth factor in primary cultures of rat hippocampal neurons is associated to an anti‐inflammatory and immunosuppressive transcriptional program

“…A deeper understanding of the mechanisms underlying the trophic effects of Ngf may lead to the identification of new potential drug candidates (Supplementary data, Table S3) useful for therapeutic strategies (Tendi et al, ), including those able to target selective steps in the complement and neuro‐inflammation cascades. This innovative pharmacology may be based on systems biology and focused on downstream targets or networks, rather than membrane receptors interference, as it was done until today (Maino et al, ).…”

Resveratrol: Multi-Targets Mechanism on Neurodegenerative Diseases Based on Network Pharmacology

“…Apoptosis is a process of programmed cell death, which is vital for normal neural development (Ghavami et al, 2014). Under pathologic conditions, apoptosis also coresponsible for the loss of neurons associated with NDs (Maino et al, 2017). The proteins of Bcl-2 family, caspases and Apaf1 are main molecular components of the apoptosis program (Burek et al, 2006).…”