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P4‐199: IMPACT OF OXALOACETATE ON BRAIN BIOENERGETIC INFRASTRUCTURES, NEUROGENESIS, AND INFLAMMATION
Author(s) -
Wilkins Heather M.,
Swerdlow Russell H.,
Carl Steven,
Harris Janna,
Lu Jianghua,
Koppel Scott,
E Lezi,
Selfridge Eva,
Hutfles Lewis,
Roy Nairita,
Burns Jeffrey M.,
Brooks William Miles,
Michaelis Mary,
Michaelis Elias
Publication year - 2014
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.2014.05.1716
Subject(s) - tfam , neurogenesis , mitochondrial biogenesis , bioenergetics , nrf1 , biology , citrate synthase , mitochondrial respiratory chain , endocrinology , medicine , mitochondrion , microbiology and biotechnology , biochemistry , enzyme
Background: Reductions in sex steroids and neurosteroid production have been reported in AD brain. Hormonal supplementation has shown benefits in offering neuroprotection and reducing cerebral amyloid load in animal studies. Although requiring further investigation in clinical trials, concerns have been raised with long-term therapeutic application due to potential side-effects. Ligands of the translocator protein (TSPO) can stimulate synthesis of these protective hormones directly in the brain, therefore are promising candidates for the development of a targeted alternative to conventional hormone therapy for use in AD. Classic TSPO ligands have been previously shown to increase neurosteroid levels and reduce cerebralAb i n amousemodel ofAD.However, these ligands have limited clinical usefulness due to low specificity and poor blood-brain barrier penetration. We screened 14 novel TSPO ligands in vitro for safety and efficacy as potential therapeutic agents for AD.Methods: Fourteen novel TSPO ligands based on substituted 2’-phenyl imidazopyridine structure were prepared for evaluation. Structural variations on substituents on the 2’-phenyl ring and the acetamide side chain were made yielding compounds of varying affinity selectivity and biological function. These ligands were screened for toxicity (10 nM-100mM) by MTS and LDH release assay in the M17 human neuroblastoma cell line. Their neurosteroidogenic potency were assessed by measuring pregnenolone levels (the precursor to all other neurosteroids) by ELISA in M17, N2a (human and mouse neuroblastoma, respectively) and C6 (mouse glioma) cell lines. MA-10 Leydig cells were used t o identify ligands specific for inducing steroidogenesis in the brain and not the testes. Results: No toxicity was observed at the steroidogenic dose range (nm) for any of the ligands, although toxicity was observed in 6 out of the 14 ligands at high doses (100 uM). Three novel ligands were selected based on favourable toxicity and neurosteroidogenic potency profiles for assessment of anti-amyloidogenic efficacy. TSPO expression was confirmed by western blot. And finally, Ab and neurosteroid levels were measured by LC-MS/MS.Conclusions:New generation TSPO l igands are promising candidates for the development of a targeted alternative to conventional hormone therapy in AD. Our results represent an innovative model to identify novel TSPO ligands that specifically target neurosteroid production.