Choline pivaloyl ester enhances brain expression of both nerve growth factor and high-affinity receptor TrkA, and reverses memory and cognitive deficits, in rats with excitotoxic lesion of nucleus basalis magnocellularis.

The aim of present work was the evaluation of the effects on brain levels of nerve growth factor (NGF) and of its high-affinity tyrosine kinase A receptor (TrkA), induced in rats unilaterally lesioned at nucleus basalis magnocellularis (NBM), by treatment with choline pivaloyl ester (CPE). CPE was daily administered (60 micromol/Kg ip) during 3 weeks to rats selectively lesioned by AMPA infusion into right NBM; the intact left NBM serving as control. NGF levels were determined in cerebral cortex and hippocampus by Elisa assay. TrkA receptor expression was evaluated in right NBM by Western blotting analysis. CPE treatment significantly increased NGF levels in both hippocampus and neocortex in right NBM, compared with intact left counter-part and controls. Western blotting showed an evident enhancement in TrkA receptor expression in lesioned right NBM in comparison with intact left counter-part and controls. CPE treatment was also able to restore, in bilaterally NBM-lesioned rats, the disrupted cortical EEG and HVS activities as well as to reverse deficits in learning and memory in spatial navigation and probe trials, and cognitive capacities in object recognition task.

Electroencephalographic effects induced by choline pivaloyl esters in scopolamine-treated or nucleus basalis magnocellularis lesioned rats.

The electroencephalographic (EEG) effects of two choline pivaloyl esters, [2-(2,2-dimethylpropionyloxy)ethyl]trimethylammonium iodide (1) and [2-(2,2-dimethylpropionyloxy)ethyl]trimethylammonium 2,2-dimethylpropionate (2), were evaluated in scopolamine-treated or nucleus basalis magnocellularis (NBM) lesioned rats. In scopolamine-treated animals, Compounds 1 and 2 prevented or reduced EEG effects, such as increased amplitude of total spectra and high-voltage spindle (HVS) activity as well. Furthermore, choline esters showed a noticeable effectiveness in reversing the EEG changes produced in rats by AMPA-induced lesion of NBM. Indeed, Compounds 1 and 2 were able to induce EEG desynchronisation, a significant decrease in the total EEG power (0.25-16 Hz) and in the lower frequency delta and theta bands (0.25-3 and 3-6 Hz, respectively). The EEG effects produced by Compounds 1 and 2 were well comparable with that evoked by Tacrine, used as a reference compound. The results of the present work allow us to put forward the hypothesis that the EEG effects observed are most likely mediated through the stimulation of the cholinergic neurotransmission ensuing from enhanced cerebral levels of acetylcholine (ACh) consequent upon acetylcholinesterase (AChE) inhibition by choline pivaloyl esters.

Choline pivaloyl esters improve in rats cognitive and memory performances impaired by scopolamine treatment or lesions of the nucleus basalis of Meynert.

The effects of two choline pivaloyl esters, [2-(2,2-dimethylpropionyloxy)ethyl]trimethylammonium iodide (1) and [2-(2,2-dimethylpropionyloxy)ethyl]trimethylammonium 2,2-dimethylpropionate (2), on learning and memory impairments induced in rats by scopolamine or lesions of nucleus basalis magnocellularis (NBM) have been evaluated by object recognition and Morris water maze tests in comparison with Tacrine (THA). Both 1 and 2 restored discrimination in object recognition test for assessing working-episodic memory and improved spatial memory in scopolamine or NBM-lesioned rats as well. The positive effects produced by 1 and 2 on cognitive and memory deficits were well comparable with those evoked by THA, used as reference compound.

Synthesis and biological evaluation of GABA derivatives able to cross the blood-brain barrier in rats.

Two new GABA derivatives, 1 and 2, were synthesized and tested for their capacity to display CNS activity, which was assessed by determining the effects on the duration of pentobarbital-induced hypnosis in rats. Compound 1, peripherally injected, significantly prolonged the hypnosis time, a typical GABA-mimetic effect, while both intracerebroventricular and intravenous administration of compound 2 surprisingly shortened the hypnotic effect in an atropine-sensitive way. The study was extended also to compounds 1a, 1b and 2a, putative oxidative/hydrolytic metabolites of 1 and 2.