oa Editorial [Hot Topic: Regulation of Glutamate Synthesis Via Inhibition of Glutamate Carboxypeptidase II (GCPII): An Effective Method to Treat Central and Peripheral Nervous System Disorders (Guest Editors: Guido Cavaletti and Barbara Slusher)]

Glutamate is a highly abundant excitatory neurotransmitter in the central nervous system residing in vesicles within chemical synapses. Once a nerve impulse triggers the release of glutamate from the pre-synaptic cell, it binds to and activates both ionotropic (ion channel- forming) and metabotropic (G protein-activating) glutamate receptors on the opposing post-synaptic cell. Subsequently glutamate transporters, localized in neuronal and glial membranes, rapidly and efficiently remove glutamate from the extracellular space thus inactivating the signaling. Glutamate excitatory neurotransmisison is involved in most aspects of normal brain function including cognition, memory and learning. However in several neurological and psychiatric diseases excess glutamate accumulates outside the cells resulting in hyperactivation of post synaptic glutamate receptors and causing massive calcium influx, damage to mitochondria and activation of proapoptotic genes. For this reason pharmacological blockade of this so-called “excitotoxic” effect via antagonism of post synaptic glutamate receptors has been of significant therapeutic interest. Unfortunately, although post synaptic receptor blockers have shown significant promise in preclinical animal models, they have been fraught with untoward side effects in the clinic thus limiting their therapeutic utility [1, 2]. Given this limitation, alternative strategies have been sought targeting processes upstream of the excitotoxic insult, i.e. blocking glutamate release from presynaptic terminals. This approach rationalizes that diminishing the amount of glutamate in the synaptic cleft will attenuate several diverse downstream pathologic processes simultaneously. Lamotrigine and riluzole are two examples of such strategy. Both drugs are presynaptic sodium channel blockers which limit glutamate release and are used in clinical practice to alleviate symptoms of epilepsy and amyotrophic lateral sclerosis, respectively [3, 4]. Recent data from multiple laboratories has identified an alternative approach to attenuate excess glutamate transmission. This approach is based upon inhibiting the hydrolysis of N-Acetyl-aspartyl-glutamate (NAAG), the most abundant mammalian peptidic neurotransmitter. NAAG is hydrolyzed to N-acetyl-aspartyl and glutamate by Glutamate Carboxypeptidase II (GCPII), a glially localized membrane-bound binuclear zinc metallopeptidase [5]. Inhibiting GCPII has been shown to dampen excessive glutamate transmission by both decreasing extracellular NAAG-derived glutamate as well as increasing NAAG. Increased NAAG results in activation of presynaptic mGluR3 [6] and the release of the neuroprotective trophic factor TGFβ [7]. Many families of structurally distinct small molecule inhibitors of GCPII have been synthesized and shown to attenuate neurotoxicity in several animal models of disease whereby enhanced glutamate transmission is presumed pathogenic. These models include inflammatory and neuropathic pain, brain ischemia, motoneuron disease, spinal cord and traumatic brain injury, peripheral neuropathy, epilepsy, and drug abuse (for review see [8-10]). This new approach to modulate glutamate levels via GCPII inhibition is therapeutically exciting, since it does not appear to affect basal glutamate function but rather selectively inhibits excessive glutamate neurotransmission [11]. From a therapeutic standpoint, this is ideal. If this holds true in the clinic, GCPII inhibition could limit excess glutamate release and provide neuroprotection without the untoward side effects observed with potent glutamate receptor antagonists. Data from the first clinical evaluation of a small molecule GCPII inhibitor supports this possibility [12]. The current knowledge of the role of glutamate under normal and pathologic conditions as well as the utility and development of inhibitors of GCPII able to target glutamate synthetic machinery will be reviewed in the following chapters. REFERENCES [1] Low, S. J.; Roland, C. L., Review of NMDA antagonist-induced neurotoxicity and implications for clinical development. Int J Clin Pharmacol Ther 2004, 42 (1), 1-14. [2] Javitt, D. C.; Schoepp, D.; Kalivas, P. W.; Volkow, N. D.; Zarate, C.; Merchant, K.; Bear, M. F.; Umbricht, D.; Hajos, M.; Potter, W. Z.; Lee, C. M., Translating glutamate: from pathophysiology to treatment. Sci Transl Med 3 (102), 102mr2. [3] Gordon, P. H., Amyotrophic lateral sclerosis: pathophysiology, diagnosis and management. CNS Drugs 25 (1), 1-15. [4] Syed, T. U.; Sajatovic, M., Extended-release lamotrigine in the treatment of patients with epilepsy. 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