Brain Research 910 (2001) 182–186 www.elsevier.com / locate / bres Short communication Effects of ENA713 and CHF2819, two anti-Alzheimer’s disease drugs, on rat amino acid levels a, a a a b * Luigia Trabace , Tommaso Cassano , Raffaele Cagiano , Maria Tattoli , Claudio Pietra , a c a Luca Steardo , Keith M. Kendrick , Vincenzo Cuomo a Department of Pharmacology and Human Physiology, Medical School, University of Bari, Policlinico, Piazza Giulio Cesare, 70124 Bari, Italy b Pharmacology Department, Chiesi Farmaceutici S.p. A., Via Palermo 26 / A, 43100 Parma, Italy c Department of Neurobiology, The Babraham Institute, Babraham, Cambridge CB24AT, UK Accepted 15 May 2001 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.  2001 Elsevier Science B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Degenerative disease: Alzheimer’s — neuropharmacology and neurotransmitters Keywords: Anticholinesterase inhibitor; ENA713; CHF2819; Amino acid; Rat hippocampus; Alzheimer’s disease Alzheimer’s disease (AD) is a multifaceted neurode- cortical and hippocampal pyramidal neurons, which are generative brain disorder of elderly humans [16]. Mount- particularly affected by NFTs and neuronal degeneration, ing awareness of the social burden represented by this use glutamate (Glu) or aspartate (Asp) as neurotransmitter disease has generated a large research effort aimed to [13]. Moreover, it has been shown that the distribution of clarify its etiology. In this regard, it has been demonstrated senile plaques in the AD brain correlates with the dis- that AD is characterized by a heterogeneous tribution of glutaminergic synapses [19]. Glu signal trans- etiopathogenesis. The most prominent neuropathological duction at the post-synaptic terminals is initiated by hallmarks of AD are senile plaques, neurofibrillary tangles stimulation of Glu receptors, especially of N-methyl-D- (NFTs), amyloid deposition in neural tissues and vessels, aspartate (NMDA) subtype. In the case of hyperactivity of synaptic loss and subsequent neuronal death [1]. Several Glu neurotransmission [15], including AD, the excessive 21 neurochemical mechanisms may account for cell death and intracellular Ca accumulation leads to an abnormal 21 neurodegeneration in AD, including neuroimmune activation of Ca -dependent enzymes, such as neuronal dysfunction, free radical formation and neurotransmitter nitric oxide synthase (nNOS). This enzyme catalyzes the deficits [1]. In this regard, the cholinergic transmission is formation of nitric oxide (NO) and citrulline (Cit) from clearly implicated in AD [3]. Furthermore, there has been L-arginine (Arg). It has been suggested that taurine (Tau)- considerable interest in excitatory amino acid theories of containing neurons could also be involved in this neurodegenerative disease such as AD [15]. In fact, in AD, pathological process [10]. Taken together, these data suggest a role for amino acids in the clinical manifestation and pathogenesis of AD [15] as an alternative, not necessarily exclusive, to the cholinergic hypothesis. There- *Corresponding author. Tel.: 139-080-5478439; fax: 139-080- fore, on the basis of these findings, it was of interest to 5478444. E-mail address: trabace@farmacol.uniba.it (L. Trabace). investigate the effects of two novel putative anti-AD drugs, 0006-8993 / 01 / $ – see front matter  2001 Elsevier Science B.V. All rights reserved. PII: S0006-8993(01)02653-1