Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors

Olszewski, Rafal T.; Wegorzewska, Marta; Monteiro, Ana Carolina; Krolikowski, Kristyn A.; Zhou, Jia; Kozikowski, Alan P.; Long, Katrice D.; Mastropaolo, John; Deutsch, Stephen I.; Neale, Joseph H.

doi:10.1016/j.biopsych.2007.04.016

Cited by 52 publications

(40 citation statements)

References 59 publications

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“…Lack of general sedative effects of 2-MPPA at doses up to 100 mg/kg acutely on locomotor activity, as well as unaltered sensitivity to thermal stimulation on nonligated (i.e., normal) paws in CCI rats after multiple days of treatment suggest a specific effect of GCP II inhibition on decreasing nociceptive input and not decreasing motor outflow. Similar nonsedative effects have been reported for other GCP II inhibitors (Lukawski et al, 2008;Olszewski et al, 2008). The analgesic effects took at least 8 days of daily dosing to become significant even though inhibitory concentrations of the drug were achieved in the nerve rapidly on the first day of dosing and there was no accumulation of drug in plasma or tissue after multiple daily dosing.…”

Section: Discussionsupporting

confidence: 70%

“…2-PMPA was shown to possess therapeutic efficacy in various preclinical models, including ischemia (Slusher et al, 1999), spinal cord injury (Long et al, 2005), neuropathic pain (Jackson et al, 2001;Wozniak et al, 2012), cocaine addiction (Xi et al, 2010a;Xi et al, 2010b), and schizophrenia (Olszewski et al, 2008;Zuo et al, 2012). Thus, GCP-II inhibition may provide broad therapeutic utility in neurologic diseases especially where excess glutamate is presumed pathogenic (Rojas et al, 2011;Ba rinka et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of the Glutamate Carboxypeptidase II Inhibitor 2-MPPA Show Prolonged Alleviation of Neuropathic Pain through an Indirect Mechanism

Vornov

Wozniak

et al. 2013

J Pharmacol Exp Ther

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Glutamate carboxypeptidase II (GCP II) is a therapeutic target in neurologic disorders associated with excessive activation of glutamatergic systems. The potent, orally bioavailable GCP II inhibitor 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA) is effective in preclinical models of diseases where excess glutamate release is implicated, including neuropathic pain, and was the first GCP II inhibitor to be administered to man. The relationships between dosing regimen, pharmacokinetics, and analgesia in a neuropathic pain model were examined in rats to aid development of clinical dosing. The efficacy of oral 2-MPPA in the chronic constrictive injury model was not simply related to plasma concentrations. Even though maximal concentrations were observed within 1 hour of dosing, the analgesic effect took at least 8 days of daily dosing to become significant. The delay was not due to tissue drug accumulation since inhibitory concentrations of the drug were achieved in the nerve within 1 hour of dosing. There was also no accumulation of drug in plasma or tissue after multiple daily dosing. Effects were dependent on reaching a threshold concentration since dividing the daily dose led to a loss of effect. The analgesic effect outlasted plasma exposure and was maintained for days even after daily dosing was halted. The delayed onset, dependence on threshold plasma concentration, and sustained effects after exposure support the hypothesis that an indirect, long-lived mechanism of action exists. Although these longer lasting secondary mechanisms are not yet identified, daily clinical dosing of a GCP II inhibitor seems justified.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of the Glutamate Carboxypeptidase II Inhibitor 2-MPPA Show Prolonged Alleviation of Neuropathic Pain through an Indirect Mechanism

Vornov

Wozniak

et al. 2013

J Pharmacol Exp Ther

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“…NAAG peptidase inhibitors have been shown to reduce positive, negative, and cognitive behaviors elicited by PCP and D-amphetamine in these models (25,26,47,57). 5 The data presented here represent the first demonstration of the neurochemical effects of NAAG peptidase inhibition in brain regions associated with schizophrenia.…”

Section: Discussionmentioning

confidence: 66%

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

Zuo

Bzdega

Olszewski

et al. 2012

Journal of Biological Chemistry

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Background: Inhibitors of the enzyme that inactivates the peptide transmitter N-acetylaspartylglutamate reduce behaviors induced by PCP in animal models of schizophrenia. Results: NAAG peptidase inhibition reduces PCP-induced glutamate release in two brain areas implicated in this disorder. Conclusion: Peptidase-mediated inhibition of glutamate release is consistent with the glutamate model of this disorder. Significance: NAAG peptidase inhibitors warrant further biochemical characterization as potential antipsychotic drugs.

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“…N-acetylaspartylglutamate (NAAG) may be an endogenous ligand for mGlu2/3 receptors in CNS. NAAG has been tested preclinically and shown to inhibit NMDA antagonist-induced behaviors in animals, consistent with an effect on NMDA receptor-mediated neurotransmission (154, 155). …”

Section: Nmda-based Treatmentsmentioning

confidence: 99%

Thinking Glutamatergically: Changing Concepts of Schizophrenia Based Upon Changing Neurochemical Models

Kantrowitz¹,

Javitt²

2010

Clinical Schizophrenia & Related Psychoses

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Clinical concepts of mental illness have always been modulated by underlying theoretical considerations. For the past fifty years, schizophrenia has been considered primarily a disease of dopaminergic neurotransmission. Although this conceptualization has helped greatly in explaining the clinical effects of psychostimulants and guiding the clinical use of both typical and atypical antipsychotics, it has nevertheless shaded how we look at the disorder from both a pathophysiological and therapeutic perspective. For example, most explanatory research in schizophrenia has focused on dopamine-rich regions of the brain, with little investigation of regions of the brain that are relatively dopamine poor. Starting approximately twenty years ago, an alternative formulation of schizophrenia was proposed based upon actions of the “dissociative anesthetic” class of psychotomimetic agents, including phencyclidine (PCP), ketamine and various designer drugs. These compounds induce psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors, suggesting an alternative model for pathogenesis in schizophrenia. As opposed to dopamine, the glutamatergic system is widely distributed throughout the brain and plays a prominent role in sensory processing as well as in subsequent stages of cortical analysis. Glutamatergic theories of schizophrenia, thus, predict that cortical dysfunction will be regionally diffuse but process specific. In addition, NMDA receptors incorporate binding sites for specific endogenous brain compounds, including the amino acids glycine and D-serine and the redox modulator glutathione, and interact closely with dopaminergic, cholinergic and γ-aminobutyric acid (GABA)-ergic systems. Glutamatergic theories, thus, open new potential approaches for treatment of schizophrenia, most of which are only now entering clinical evaluation.

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Phencyclidine and Dizocilpine Induced Behaviors Reduced by N-acetylaspartylglutamate Peptidase Inhibition via Metabotropic Glutamate Receptors

Cited by 52 publications

References 59 publications

Pharmacokinetics and Pharmacodynamics of the Glutamate Carboxypeptidase II Inhibitor 2-MPPA Show Prolonged Alleviation of Neuropathic Pain through an Indirect Mechanism

Pharmacokinetics and Pharmacodynamics of the Glutamate Carboxypeptidase II Inhibitor 2-MPPA Show Prolonged Alleviation of Neuropathic Pain through an Indirect Mechanism

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

Thinking Glutamatergically: Changing Concepts of Schizophrenia Based Upon Changing Neurochemical Models

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