Studies on the in vitro assembly of a beta 1-40: implications for the search for a beta fibril formation inhibitors.

The progressive deposition of the amyloid beta peptide (Abeta) in fibrillar form is a key feature in the development of the pathology in Alzheimer's disease (AD). We have characterized the time course of Abeta fibril formation using a variety of assays and under different experimental conditions. We describe in detail the morphological development of the Abeta polymerization process from pseudo-spherical structures and protofibrils to mature thioflavin-T-positive/Congo red-positive amyloid fibrils.

Effects of the putative P-type calcium channel blocker, R,R-(-)-daurisoline on neurotransmitter release.

The alkaloid and medicinal herb constituent, R,R-(-)-daurisoline, was originally reported to be a N-type Ca2+ channel blocker, but newer evidence indicates that it is a blocker of P-type Ca2+ channels. To clarify its specificity with respect to N- and P-channels, we compared its effects on the electrically induced release of endogenous glutamate, 3H-GABA and 3H-noradrenaline, from brain slices with those of omega-agatoxin IVA and omega-conotoxin GVIA. Like omega-agatoxin IVA (but with about 1000-fold lower potency), and unlike omega-conotoxin GVIA, R.

Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters.

We compared the effects of the antiepileptic drugs carbamazepine, oxcarbazepine, and lamotrigine on the release from rat brain slices of endogenous glutamate, [3H]-GABA, and [3H]-dopamine, elicited by the Na+ channel opener, veratrine, and of the same transmitters as well as [3H]-noradrenaline, [3H]-5-hydroxytryptamine, and [3H]-acetylcholine, elicited by electrical stimulation. The three antiepileptic drugs inhibited veratrine-induced release of endogenous glutamate, [3H]-GABA, and [3H]-dopamine, with IC50 values between 23 and 150 microM, in or near the concentration range in which they interact with Na+ channels, and there was little difference between the compounds. They were five to seven times less potent in inhibiting electrically as compared with veratrine-stimulated release of [3H]-GABA and [3H]-dopamine; similarly, carbamazepine and tetrodotoxin were more potent in inhibiting veratrine-induced as compared with electrically induced release of endogenous glutamate.

GABA and glutamate release affected by GABAB receptor antagonists with similar potency: no evidence for pharmacologically different presynaptic receptors.

1. The effects of a series of nine GABAB receptor antagonists of widely varying potencies on electrically stimulated release from cortical slices of [3H]-GABA in the absence or presence of 10 microM of the GABAB agonist, (-)-baclofen and of endogenous glutamate in the presence of (-)-baclofen were compared. 2.

GABA release in rat cortical slices is unable to cope with demand if the autoreceptor is blocked.

Electrically stimulated release of neurotransmitters in brain slices normally displays frequency dependence because of progressive activation of autoreceptors by endogenously released transmitter, which is abolished by blockade of autoreceptors. In consequence, the maximal increase caused by an autoreceptor antagonist in percent of the corresponding controls should be greater at higher than at lower frequencies. In the case of gamma-aminobutyric acid (GABA), we have previously found a marked deviation from this expectation.