Franz-Josef van der Staay

Effects of nicotinamide on central cholinergic transmission and on spatial learning in rats

High-dose nicotinamide (1000 mg/kg) leads to a minor increase of plasma choline but to a major increase of the choline concentrations in the intra- and extracellular spaces of the brain. In the hippocampus, the nicotinamide-induced increase in choline was associated with an increase in the release of acetylcholine under stimulated conditions. In young rats, nicotinamide in doses between 10 and 1000 mg/kg did not influence spatial learning, as tested in the Morris water maze. In old rats, low doses of nicotinamide were ineffective whereas the high dose of 1000 mg/kg even impaired spatial learning. The combined administration of choline and nicotinamide had a synergistic effect on brain choline levels but had similar effects as nicotinamide given alone in the behavioral experiments. Additional tests for spontaneous behaviour and locomotion revealed procholinergic and sedative effects of the compound. We conclude that the ineffectiveness of the putative cognition enhancer nicotinamide in the learning task may be due to the observed sedative effect. Therefore, the development of nonsedative nicotinamide derivatives is recommended.

Receptor interaction profile and CNS general pharmacology of metrifonate and its transformation product dichlorvos in rodents

In this study we assessed the possible effects of the putative Alzheimer therapeutic, metrifonate (39, 120, 390 μmol/kg), and its active transformation product, dichlorvos (4.5, 13.6, 45 μmol/kg), on the mammalian central nervous system (CNS). We did this by (1) investigating the receptor interaction profile of the two compounds in a range of in‐vitro radioligand binding assays, and (2) by studying the acute compound effects in rats and mice using a battery of behavioral tests after a single oral administration. Metrifonate and dichlorvos failed to displace various radioligands from their respective receptor binding sites on cell membranes at a concentration of 10 μM. In particular, there was no high‐affinity interaction with muscarinic or nicotinic acetylcholine receptor binding in‐vitro. In the modified Irwin test (rat) both compounds induced transient cholinergic symptoms after oral administration of a single dose of 390 μmol/kg metrifonate and 13.6–45 μmol/kg dichlorvos. The observed symptoms, such as salivation, tremor, and diarrhea, lasted for up to 75 min. In the open field test (rat) metrifonate increased the number of rearings at all doses, whereas dichlorvos had no effect on the parameters tested. Both compounds dose‐dependently reduced the pentylenetetrazole threshold dose in mice. In this test, only the highest dose of metrifonate, but all doses of dichlorvos, caused a significant reduction of the convulsion threshold dose. Metrifonate and dichlorvos did not influence traction ability in mice. Metrifonate and dichlorvos did not influence hexobarbital‐induced anesthesia in mice. Metrifonate induced hypothermia in rats only at the dose of 390 μmol/kg. Dichlorvos did not affect body temperature. No analgesic potential was observed in the hot‐plate test in mice. Furthermore, metrifonate and dichlorvos neither influenced motor coordination nor exhibited any cataleptic potential when administered to rats. Taken together, at cognition‐enhancing doses, metrifonate (39–120 μmol/kg) is safe and well tolerated. The adverse symptoms observed at higher doses, together with the apparent lack of high‐affinity interaction with neurotransmitter receptors in brain tissue and the similar profile of the active transformation product, dichlorvos, support the assumption that these compounds mediate a highly selective activation of the cholinergic system.

Preclinical Pharmacology of Metrifonate: A Promise for Alzheimer Therapy

Among the multiple transmitter deficits which have been described in Alzheimer’s Disease (AD), the degeneration of brain cholinergic cell bodies is the most sensitive, specific and severe, as indicated by the good correlation between the cholinergic pathology and dementia. Therefore, current drug development strategies in AD therapy focus on the enhancement of cholinergic neurotransmission. The most advanced class of compounds in this respect are cholinesterase (ChE) inhibitors which aim to restore the concentration of acetylcholine (ACh) in the synaptic cleft.

Effects of acute and repeated administration of a cholinesterase inhibitor on timing behaviour

It has been hypothesised that a leftward shift in the response distribution obtained in the peak interval (PI) procedure is a characteristic of cognitive enhancement in which mental processes are speeded. Metrifonate, a cholinesterase inhibitor with reported cognitive enhancing properties in many animal models of learning and memory, was tested in the PI procedure. Acute administration of 3 and 60 mg/kg but not 1 and 30 mg/kg in fully trained rats shifted the response distribution to the right, whereas subchronic administration of 10, 30 or 50 mg/kg during task acquisition had no effect on timing behaviour. On the basis of the present data, it can be concluded that the effects of a cognition enhancer in the PI procedure cannot be predicted from the scalar expectancy theory (SET). Furthermore, SET does not appear to be an appropriate tool for analysing the acquisition of timing behaviour.