title: Effects of LF-14, THA and physostigmine in rat hippocampus and cerebral cortex.
abstract: The effects of physostigmine, tetrahydroaminoacridine (THA) and LF-14 [3,3-dimethyl-1(4- amino-3-pyridyl)urea], a 3,4-diaminopyridine derivative, were compared on inhibition of acetyl- cholinesterase (AChE) activity, and release of [(3)H]acetylcholine (ACh) from rat brain cortical and hippocampal slices. All three compounds caused a concentration dependent inhibition of AChE, with an order of potency physostigmine > THA >LF-14. The electrically stimulated release of ACh from hippocampal and cortical slices was decreased by 10(?5)M physostigmine, although the effect was significant only in cortex. THA (5 x 10(5)M) caused a slight, but not significant, decrease in ACh release from both tissues. In contrast, LF-14 (5 x 10(?5) M) caused an approx. 3-fold enhancement of stimulated release. When AChE was inhibited by prior addition of physostigmine, THA caused only a slight enhancement of ACh release, whereas LF-14 greatly increased release. ACh release was also reduced by stimulation of presynaptic muscarinic receptors with oxotremorine. In this case, THA had no effect on ACh release, while LF-14 was able to reverse the inhibition. This study suggests that LF-14 acts to promote ACh release through blocking K(+) channels, and has a less potent AChE inhibitory effect. It is possible that a compound like LF-14 could be useful in treating diseases of cholinergic dysfunction such as Alzheimer's disease, by both promoting the release of ACh and inhibiting its breakdown.
authors.affiliation: Department of Anesthesiology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, NY 10467, U.S.A.
authors.forename: P E
authors.initials: PE
authors.lastname: Potter
authors.forename: S
authors.initials: S
authors.lastname: Nitta
authors.forename: I
authors.initials: I
authors.lastname: Chaudhry
authors.forename: I
authors.initials: I
authors.lastname: Lalezari
authors.forename: P
authors.initials: P
authors.lastname: Goldiner
authors.forename: F F
authors.initials: FF
authors.lastname: Foldes