Preclinical development of new tetrahydrofurannes derivatives as neuroprotectants targeting the sigma-1 chaperone protein in Alzheimer's disease

method. The convert phase microscope was used to analyse the number of the neurons with neurites (NNN) as well as the average length of the neurites (ALN). Enzyme-linked immunoadsordent assay (ELISA) was carried out to analyze neuronal As42 production. For revealing the actions of Nogo-66 receptor and its downstream signaling molecules, ROCK and PKC, several tool drugs were used: Nogo-P4, a Nogo-66 receptor agonist; NEP1-40, a Nogo-66 receptor antagonist; Y-27632, a ROCK inhibitor; and G€ O6976, a PKC inhibitor. Finally, we preliminarily screened some effective compounds from traditional Chinese medicine to bind to above targets. Results:Nogo-66 receptor agonist, Nogo-P4, could reduce NNN and ALN, as well as significantly increased As42 production, while Nogo-66 receptor antagonist, NEP1-40, could promote neuronal neurite regeneration, but not reduce As42 production. PKC inhibitor, G€ O6976, could also promote neurite regeneration, but increased As42 production. ROCK inhibitor, Y27632, not only promoted neurite regeneration, but also reduced As42 production. One effective compound binding to Nogo-66 receptor, SQ, was found, which it could antagonize a part action of Nogo-P4, but not reduce As42 production. Conclusions: Nogo-66 receptor activated by Nogo-P4 inhibits neurite regeneration, and promotes As42 production, while Nogo-66 receptor blocked by NEP1-40 promotes neurite regeneration, but does not inhibit As42 production. PKC inhibited by G€ O6976 can promote neurite regeneration, but also promote As42 production. ROCK inhibited by Y-27632 not only inhibits As42 production but also promotes neurite regeneration, is an ideal drug target for AD treatment. The research suggests that the ROCK, instead of the Nogo-66 receptor, has the dual role both inhibitingAs production and promoting neurite regeneration, which is probably more effective for AD treatment.