The Proinflammatory Cytokine GITRL Contributes to TRAIL-mediated Neurotoxicity in the HCN-2 Human Neuronal Cell Line.

Background: Cytokines belonging to the TNF superfamily play a relevant role in neurodegenerative processes. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), released during neuronal injury, has proven to potently mediate and sustain neurotoxic processes leading to neuronal death. Similarly to TRAIL, the cytokine Glucocorticoid-induced TNF receptor ligand (GITRL) is able to transduce proapoptotic signals.

An LP1 analogue, selective MOR agonist with a peculiar pharmacological profile, used to scrutiny the ligand binding domain.

The hypothesis that central analgesia with reduced side effects is obtainable by occupying an 'allosteric' site in the MOR ligand binding domain requires the development of new ligands with peculiar pharmacological profile to be used as tools. New benzomorphan derivatives, analogues of LP1, a multitarget MOR agonist/DOR antagonist, were designed to examine in depth MOR ligand binding domain. Compound 5, bearing a diphenylic N-substituent on the benzomorphan nucleus, showed an affinity (K=0.

CHF5074 protects SH-SY5Y human neuronal-like cells from amyloidbeta 25-35 and tumor necrosis factor related apoptosis inducing ligand toxicity in vitro.

Alzheimer's disease (AD) is contributed by multiple pathogenic causes. The anomalous protein amyloid-β (Aβ) is regarded as a pivotal factor in AD, and originates from enzymatic cleavage of a precursor protein by the secretase family. 1-(3',4'-Dichloro-2-fluoro[1,1'-biphenyl]-4-yl)-cyclopropanecarboxylic acid (CHF5074) is a non-steroidal antiinflammatory derivative able to inhibit Aβ deposition in the brain of transgenic mouse models of AD.