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P3‐447: Preclinical development of new tetrahydrofurannes derivatives as neuroprotectants targeting the sigma‐1 chaperone protein in Alzheimer's disease
Author(s) -
Maurice Tangui,
Villard Vanessa,
Meunier Johann,
Lahmy Valentine,
Keller Emeline,
Vamvakides Alexandre
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1891
Subject(s) - neuroprotection , sigma 1 receptor , chemistry , unfolded protein response , oxidative stress , pharmacology , microbiology and biotechnology , endoplasmic reticulum , neurodegeneration , muscarinic acetylcholine receptor , biochemistry , biology , receptor , medicine , agonist , 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.