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P3‐392: Investigation of the MI 09‐018 series of novel drug leads with potential for treating Alzheimer's disease
Author(s) -
Verdone Melinda L.,
Hanson Seth A.,
Hendrickson Michael L.,
Ockuly Jeffrey C.,
Beck Joseph D.,
Albers Andrea M.,
Farnham James G.,
Abraham Brent D.,
Copp Richard R.,
Twose Trevor M.
Publication year - 2010
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.2010.05.1934
Subject(s) - pharmacology , agonist , muscarinic acetylcholine receptor , cholinergic , acetylcholine , chemistry , medicine , receptor
analysis), and lactate dehydrogenase (LDH) for cell death. Labelling the cells with anti-CD-11b (OX-42) enabled microglia morphology to be visualised under microscopy for qualitative assessment of activation. Results: Findings from these experiments showed that AHPN (5-100 mM) decreased LPSmediated production of NO2 but not cytokines. Western immunoblotting demonstrated a significant attenuation of phosphorylated nuclear factor kappa B (NF-kB) and iNOS by 5 mM AHPN. Microscopy analysis of CD-11b-positive cells indicated that 5 mM AHPN reverted LPS-induced activated morphologies whilst reducing cell number through Cyclin D1 inhibition. However, higher concentrations of AHPN (50-100 mM) induced cell death through increased LDH accumulation and condensation of nuclei (through Hoechst dye staining). Preliminary results also indicated that production of NO2 by Ab1-42 (+ IFN-g) was reduced by AHPN. Conclusions: Taken together, the results show that microglial activation can be attenuated by AHPN, as evidenced by the inhibition of both proliferation and NO2 production through reduced NF-kB activation and iNOS production. In conclusion, these new findings provide a possible antiinflammatory role for synthetic retinoids, which could be a useful therapeutic strategy for neurodegenerative diseases that involve an inflammatory component, such as AD.