Effects of LF-14, THA and physostigmine in rat hippocampus and cerebral cortex

P. E. Potter, S. Nitta, I. Chaudhry, I. Lalezari, P. Goldiner, F. F. Foldes

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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 [3H]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 10-5M physostigmine, although the effect was significant only in cortex. THA (5 × 105M) caused a slight, but not significant, decrease in ACh release from both tissues. In contrast, LF-14 (5 × 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.

Original languageEnglish
Pages (from-to)433-438
Number of pages6
JournalNeurochemistry International
Issue number4
StatePublished - 1989
Externally publishedYes


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