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, Daiying; Bzdega, Tomasz; Olszewski, Rafal T.; Moffett, John R.; Neale, Joseph H.

doi:10.1074/jbc.m112.363226

Cited by 45 publications

(38 citation statements)

References 60 publications

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“…These data suggest that GCPII inhibition increases NAAG, which in turn mediates its effects predominantly, if not exclusively, via mGluR3 to the resultant alleviation of pain. However, it remains possible that NAAG attenuates the excitability of postsynaptic neurons by interfering with the binding of released glutamate at the N-methyl-D-aspartate receptor as suggested previously (Carpenter et al, 2003), although this effect may be indirect (Zuo et al, 2012) and remains controversial (Losi et al, 2004). It should also be noted that the analgesic effects of NAAG (mediated directly or via GCPII inhibition) may be at least partially caused by interactions with other transmitters in the ascending and descending pathways .…”

Section: Discussionmentioning

confidence: 94%

The Orally Active Glutamate Carboxypeptidase II Inhibitor E2072 Exhibits Sustained Nerve Exposure and Attenuates Peripheral Neuropathy

Wozniak

Wu²,

Vornov

et al. 2012

J Pharmacol Exp Ther

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Peripheral neuropathy from nerve trauma is a significant problem in the human population and often constitutes a doselimiting toxicity in patients receiving chemotherapy. (3-2-Mercaptoethyl)biphenyl-2,3-dicarboxylic acid (E2072) is a potent (K i ϭ 10 nM), selective, and orally available inhibitor of glutamate carboxypeptidase II (GCPII). Here, we report that E2072 attenuates hyperalgesia and nerve conduction velocity deficits in preclinical rodent models of neuropathic pain and oxaliplatininduced neuropathy. In the chronic constrictive injury model, orally administered E2072 reversed pre-existing thermal hyperalgesia in rats in a dose-dependent fashion with a minimally effective dose of 0.1 mg/kg/day. It is noteworthy that multiple days of dosing of E2072 were required before analgesia was realized even though GCPII inhibitory exposures were achieved on the first day of dosing. In addition, analgesia was found to persist for up to 7 days after cessation of dosing, consistent with E2072's pharmacokinetic profile and sustained exposure. Furthermore, in a chronic oxaliplatin-induced neuropathy model (6 mg/kg i.p. oxaliplatin twice weekly for 4 weeks), female BALB/c mice receiving daily oral E2072 at 1.0 and 0.1 mg/kg displayed no deficits in either caudal or digital velocity compared with significant deficits observed in mice treated with oxaliplatin alone (12 Ϯ 3 and 9 Ϯ 2%, respectively). Similar findings were seen with oxaliplatin-induced digital and caudal amplitude deficits. It is noteworthy that E2072 showed no interference with the antineoplastic efficacy of oxaliplatin in mice bearing leukemia (L1210), even at doses 100 times its neuroprotective/analgesic dose, indicating a selective effect on neuropathy. These data support the therapeutic utility of GCPII inhibitors in neuropathy and neuropathic pain.

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Section: Discussionmentioning

confidence: 94%

The Orally Active Glutamate Carboxypeptidase II Inhibitor E2072 Exhibits Sustained Nerve Exposure and Attenuates Peripheral Neuropathy

Wozniak

Wu²,

Vornov

et al. 2012

J Pharmacol Exp Ther

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“…We did not find major differences in the spontaneous behavior of wild type and Abcc5 Ϫ/Ϫ mice using an automated home cage monitoring system that monitors various aspects of behavior (26), however. Zuo et al (71) previously showed that pharmacological inhibition of GCP2 results in increased NAAG levels and reduced phencyclidine-induced locomotor activity in an animal model for schizophrenia. Such a difference was not found between our wild type and Abcc5 Ϫ/Ϫ mice, however (data not shown).…”

Section: Discussionmentioning

confidence: 99%

ATP-binding Cassette Subfamily C Member 5 (ABCC5) Functions as an Efflux Transporter of Glutamate Conjugates and Analogs

Jansen

Mahakena

Haas

et al. 2015

Journal of Biological Chemistry

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“…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%

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

Cited by 45 publications

References 60 publications

The Orally Active Glutamate Carboxypeptidase II Inhibitor E2072 Exhibits Sustained Nerve Exposure and Attenuates Peripheral Neuropathy

The Orally Active Glutamate Carboxypeptidase II Inhibitor E2072 Exhibits Sustained Nerve Exposure and Attenuates Peripheral Neuropathy

ATP-binding Cassette Subfamily C Member 5 (ABCC5) Functions as an Efflux Transporter of Glutamate Conjugates and Analogs

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

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