2-MPPA, a selective glutamate carboxypeptidase II inhibitor, attenuates morphine tolerance but not dependence in C57/Bl mice

Kozela, Ewa; Wróbel, Marta; Kos, Tomasz; Wójcikowski, Jacek; Daniel, W.A.; Wozniak, Krystyna M.; Slusher, Barbara S.; Popik, Piotr

doi:10.1007/s00213-005-0182-5

Cited by 16 publications

(8 citation statements)

References 39 publications

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“…2-MPPA has also been administered to human volunteers and was well tolerated with no reports of adverse CNS effects [18]. In previously published studies 2-MPPA, at similar or greater doses to that tested here, have been shown not to cause any effect when given alone to rats or mice [19], [20], [21], [22].…”

Section: Introductionsupporting

confidence: 52%

Glutamate Carboxypeptidase II Inhibition Behaviorally and Physiologically Improves Pyridoxine-Induced Neuropathy in Rats

Potter

Wozniak

Callizot³

et al. 2014

PLoS ONE

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Pyridoxine is used as a supplement for treating conditions such as vitamin deficiency as well as neurological disorders such as depression, epilepsy and autism. A significant neurologic complication of pyridoxine therapy is peripheral neuropathy thought to be a result of long-term and high dose usage. Although pyridoxine-induced neuropathy is transient and can remit after its withdrawal, the process of complete recovery can be slow. Glutamate carboxypeptidase II (GCP II) inhibition has been shown to improve symptoms of both chemotherapy- and diabetic-induced neuropathy. This study evaluated if GCP II inhibition could behaviorally and physiologically improve pyridoxine-induced neuropathy. In the current study, high doses of pyridoxine (400 mg/kg, twice a day for seven days) were used to induce neuropathy in rats. An orally bioavailable GCP II inhibitor, 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA), was administered daily at a dose of 30 mg/kg starting from the onset of pyridoxine injections. Body weight, motor coordination, heat sensitivity, electromyographical (EMG) parameters and nerve morphological features were monitored. The results show beneficial effects of GCP II inhibition including normalization of hot plate reaction time, foot fault improvements and increased open field distance travelled. H wave frequency, amplitude and latency as well as sensory nerve conduction velocity (SNCV) were also significantly improved by 2-MPPA. Lastly, GCP II inhibition resulted in morphological protection in the spinal cord and sensory fibers in the lumbar region dorsal root ganglia (DRG). In conclusion, inhibition of GCP II may be beneficial against the peripheral sensory neuropathy caused by pyridoxine.

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Section: Introductionsupporting

confidence: 52%

Glutamate Carboxypeptidase II Inhibition Behaviorally and Physiologically Improves Pyridoxine-Induced Neuropathy in Rats

Potter

Wozniak

Callizot³

et al. 2014

PLoS ONE

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“…Reinforcing the conclusion that NAAG mediated these effects via mGluR3, co‐injection of a group II mGluR antagonist, systemically or directly into the nucleus accumbens reversed the effects of the peptide and peptidase inhibitor in these studies. The influence of NAAG on the opiate circuits is somewhat different with peptidase inhibition attenuating tolerance but not dependence in mice (Kozela et al. 2005).…”

Section: Naag Peptidase Inhibition As Drug Abuse Therapymentioning

confidence: 99%

Advances in understanding the peptide neurotransmitter NAAG and appearance of a new member of the NAAG neuropeptide family

Neale

Olszewski

Zuo

et al. 2011

Journal of Neurochemistry

103

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A substantial body of data was reported between 1984 and 2000 demonstrating that the neuropeptide N-acetylaspartylglutamate (NAAG) not only functions as a neurotransmitter but also is the third most prevalent transmitter in the mammalian nervous system behind glutamate and GABA. By 2005, this conclusion was validated further through a series of studies in vivo and in vitro. The primary enzyme responsible for the inactivation of NAAG following its synaptic release had been cloned, characterized and knocked out. Potent inhibitors of this enzyme were developed and their efficacy has been extensively studied in a series of animal models of clinical conditions, including stroke, peripheral neuropathy, traumatic brain injury, inflammatory and neuropathic pain, cocaine addiction, and schizophrenia. Considerable progress also has been made in defining further the mechanism of action of these peptidase inhibitors in elevating synaptic levels of NAAG with the consequent inhibition of transmitter release via the activation of presynaptic mGluR3 by this peptide. Very recent discoveries include identification of two different nervous system enzymes that mediate the synthesis of NAAG from N-acetylaspartate and glutamate and the finding that one of these enzymes also mediates the synthesis of a second member of the NAAG family of neuropeptides, N-acetylaspartylglutamylglutamate (NAAG2).

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“…Many preclinical and clinical studies have been conducted with the purpose of exploring GCPII regulation strategies for pathological CNS disorders. Inhibition of GCPII has demonstrated beneficial and dose-dependent neuroprotective properties in models of inflammatory and neuropathic pain [152][153][154][155][156][157][158][159][160][161][162][163][164][165][166] brain ischemia [167][168][169][170][171] motor neuron disease [172] spinal cord and traumatic brain injury [173][174][175], peripheral neuropathy [156,161,176,177], epilepsy [178] and drug abuse [179][180][181][182][183][184][185]. Inhibition of GCPII in in vitro and in vivo models of injury cause an increase in extracellular NAAG concentration and a decrease in extracellular glutamate concentration [108].…”

Section: Inhibition Of Gcpii Activity As a Novel Strategy To Treat Comentioning

confidence: 99%

Glutamate in CNS Neurodegeneration and Cognition and its Regulation by GCPII Inhibition

Rahn

Slusher²,

Kaplin³

2012

CMC

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Glutamate, first identified in 1866, is the primary excitatory neurotransmitter in the brain. While it is critically important in many highly regulated cortical functions such as learning and memory, glutamate can be much like the magic the Sorcerer's Apprentice used in Goethe's poem: when conjured under unregulated conditions glutamate can get quickly out of control and lead to deleterious consequences. Two broad types of glutamate receptors, the ionotropic and metabotropic, facilitate glutamatergic neurotransmission in the CNS and play key roles in regulating cognitive function. Excessive activation of these receptors leads to excitotoxicity, especially in brain regions that are developmentally and regionally vulnerable to this kind of injury. Dysregulation of glutamate signaling leads to neurodegeneration that plays a role in a number of neuropsychiatric diseases, prompting the development and utilization of novel strategies to balance the beneficial and deleterious potential of this important neurotransmitter. Inhibition of the enzyme glutamate carboxypeptidase II (GCPII) is one method of manipulating glutamate neurotransmission. Positive outcomes (decreased neuronal loss, improved cognition) have been demonstrated in preclinical models of ALS, stroke, and Multiple Sclerosis due to inhibition of GCPII, suggesting this method of glutamate regulation could serve as a therapeutic means for treating neurodegeneration and cognitive impairment.

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2-MPPA, a selective glutamate carboxypeptidase II inhibitor, attenuates morphine tolerance but not dependence in C57/Bl mice

Abstract: The present findings suggest complex effects of GCP II inhibition on morphine dependence and tolerance and imply a role of mGluR II in the actions of 2-MPPA.

Cited by 16 publications

References 39 publications

Glutamate Carboxypeptidase II Inhibition Behaviorally and Physiologically Improves Pyridoxine-Induced Neuropathy in Rats

Glutamate Carboxypeptidase II Inhibition Behaviorally and Physiologically Improves Pyridoxine-Induced Neuropathy in Rats

Advances in understanding the peptide neurotransmitter NAAG and appearance of a new member of the NAAG neuropeptide family

Glutamate in CNS Neurodegeneration and Cognition and its Regulation by GCPII Inhibition

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