Effects of ENA713 and CHF2819, two anti-Alzheimer’s disease drugs, on rat amino acid levels

doi:10.1016/S0006-8993(01)02653-1

Brain Research

Volume 910, Issues 1–2, 10 August 2001, Pages 182-186

https://doi.org/10.1016/S0006-8993(01)02653-1 Get rights and content

Abstract

The effects of oral ENA713 and CHF2819 (0.5, 1.5 and 4.5 mg/kg), two novel acetylcholinesterase inhibitors, on extracellular concentrations of amino acids in rat hippocampus, were evaluated using in vivo microdialysis. ENA713, at 4.5 mg/kg, but not CHF2819, significantly decreased glutamate, taurine, arginine and citrulline levels, without affecting aspartate concentrations. These results suggest that the modulation of amino acidergic transmission could represent an additional mechanism of action in Alzheimer’s disease for some acetylcholinesterase inhibitors.

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Furthermore, mice with the neuronal glutamate transporter EAAC1 (excitatory amino acid carrier) knocked out show early signs of neurodegeneration combined with decreased spatial learning abilities and cognitive impairment (Aoyama et al., 2006), and over expression of the transporter causes rescue of neurons (Kiryu-Seo et al., 2006). Interestingly, localisation of neurofibrillary tangles and senile plaques, two of the hallmarks in Alzheimer's disease, has been found to parallel the distribution of glutamatergic synapses (Rogers and Morrison, 1985; Trabace et al., 2001). The cognitive functions described above rely on the hippocampus.
Interaction with the environment has a key role in refining the neuronal circuitry required for normal brain function throughout life. Profound effects of enriched environment have been shown on neuronal structure and chemistry in experimental animals. Epidemiological studies imply that this is true also in man, thus cognitive stimulation has a protective effect on neurodegeneration, e.g., in Alzheimer's disease. Glutamatergic pathways are imperative for cognitive functions, such as memory, learning and long-term potentiation, and relies on the AMPA and NMDA glutamate receptors and the hippocampus, with its specific subregions, is an important anatomical substrate in this. The glutamate signalling is also dependent on a fine-tuned transport system, in the hippocampus primarily achieved by the glutamate transporter EAAC1. In this study we show how environmental enrichment modulates these parts of the glutamatergic system using quantitative in situ hybridisation. This work demonstrates for the first time that environmental enrichment modulates the mRNA expression of EAAC1 which is significantly and region specifically decreased in the hippocampus. We also provide evidence for regional and hemisphere-specific upregulation of NMDA mRNA in the hippocampus after environmental enrichment. The current work also shows that AMPA mRNA of the hippocampus is not per se changed by environmental enrichment in adult animals. Taken together, our results extend the knowledge of the glutamatergic system of specific regions of the hippocampus and its modulation by environmental enrichment and could contribute to the development of strategies aimed at limiting pathological changes associated with glutamatergic dysfunctions.

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Short communicationEffects of ENA713 and CHF2819, two anti-Alzheimer’s disease drugs, on rat amino acid levels

Abstract

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Neuroscience

Trends Neurosci.

Jpn. J. Pharmacol. Suppl.

Brain Res. Rev.

Brain Res. Rev.

Brain Res.

Therapeutic strategies in Alzheimer’s disease

Ann. Psychiatry

CSF excitatory amino acids and severity of illness in Alzheimer’s disease

Neurology

Short communication
Effects of ENA713 and CHF2819, two anti-Alzheimer’s disease drugs, on rat amino acid levels