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HIGH THROUGHPUT SCREEN FOR ANTI‐MANIC DRUG CANDIDATES
Author(s) -
Bazinet Richard Paul,
Rapoport Stanley Isaac,
Weis Margaret Teresa
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a689
Subject(s) - chemistry , ic50 , arachidonic acid , substrate (aquarium) , lithium (medication) , acylation , phospholipase a2 , palmitic acid , enzyme , medicine , fatty acid , pharmacology , biochemistry , in vitro , biology , catalysis , ecology
In the awake rat, anti‐manic drugs selectively decrease brain arachidonic acid (AA) turnover. Lithium and carbamazepine target AA‐selective phospholipase A 2 . Valproate selectively inhibits AACoA formation by brain long chain fatty acyl CoA synthetase (Acsl). Compounds were tested in the valproate‐insensitive (BP1) or valproate‐sensitive (BP2) Acsl fractions of whole rat brain. Triacsin C, a competitive inhibitor of Acsl, inhibited both AA and palmitic acid (PA) utilization. In BP1, there was no substrate selectivity (PA IC50, 489 ± 115 nM; AA IC50, 355 ± 123 nM). In BP2, triacsin C selectively inhibited PA utilization (PA IC50, 207 ± 23.2 nM; AA IC50, 1.89 ± 0.63 μM; p<0.05). Valproate is structurally similar to LEU, ILE and VAL. None of these amino acids inhibited BP1 or BP2 activity, whether the substrate was PA or AA. BP1 was not inhibited by PGE 2 , (up to 50 nM), regardless of substrate. PGE 2 inhibited PA utilization by BP2 (control: 8.51±0.04 pmol/5min/50μl prep; 3 nM PGE 2 : 7.01±0.15 pmol/5min/50μl; p<0.05 vs control, and 6.87 ± 0.4 pmol/5min/50μL 50 nM PGE 2 ; p<0.05 vs control). Even at 50 nM, PGE 2 did not affect AA utilization by BP2. These results suggest that re‐acylation of AA can be favored by inhibiting re‐acylation of other fatty acids, and indicate that prostaglandins may be important in modulating the anabolic metabolism of AA. Supported by NIH/NIA.