The preventive and therapeutic effects of GCPII (NAALADase) inhibition on painful and sensory diabetic neuropathy

  title={The preventive and therapeutic effects of GCPII (NAALADase) inhibition on painful and sensory diabetic neuropathy},
  author={W X Zhang and Yuichi Murakawa and Krystyna M. Wozniak and Barbara S. Slusher and Anders A. F. Sima},
  journal={Journal of the Neurological Sciences},

Glutamate carboxypeptidase activity in human skin biopsies as a pharmacodynamic marker for clinical studies

Monitoring GCP activity in human skin after administration of G CP inhibitors could be readily used as PD marker in the clinical development of GCP inhibitors.

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

It is reported that E2072 attenuates hyperalgesia and nerve conduction velocity deficits in preclinical rodent models of neuropathic pain and oxaliplatin-induced neuropathy, and shows no interference with the antineoplastic efficacy of oxali Platin in mice bearing leukemia.

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

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, and daily clinical dosing of a GCP II inhibitor seems justified.

Glutamate Carboxypeptidase Inhibition Reduces the Severity of Chemotherapy-Induced Peripheral Neurotoxicity in Rat

The neuroprotective effect of an orally available glutamate carboxypeptidase inhibitor on three well-established animal models of chemotherapy (cisplatin, paclitaxel, bortezomib)-induced peripheral neuropathy is reported and support a novel approach for the treatment of chemotherapy-induced peripheral Neuropathy.

Current approaches with the glutamatergic system as targets in the treatment of neuropathic pain

Targeting the glutamatergic system shows a better efficacy and fewer side effects, compared with classical drugs for the treatment of neuropathic pain, and the newer drugs in clinical trials for neuropathicPain are highlighted.

Clavulanic Acid Attenuating Effect on the Diabetic Neuropathic Pain in Rats.

CLAV was found a promising candidate for reliving neuropathic pain in diabetes mellitus, and in all doses of 10, 20 and 40 mg/kg reduced symptoms of allodynia and hyperalgesia, in both prophylactic and therapeutic regimens.

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

I inhibition of GCP II may be beneficial against the peripheral sensory neuropathy caused by pyridoxine, including normalization of hot plate reaction time, foot fault improvements and increased open field distance travelled.

Targeting the Glutamatergic System for the Treatment of HIV-Associated Neurocognitive Disorders

Preliminary experimental evidence is found that approaches to regulate the transporters responsible for modulation of extracellular glutamate such as excitatory amino acidtransporters and the glutamate-cystine antiporter have potential therapeutic utility for the treatment of HAND.

Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer.

This review offers a summary of GCPII structure, physiological functions in healthy tissues, and its association with various pathologies, and outlines the development of G CPII-specific small-molecule compounds and their use in preclinical and clinical settings.



Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury

It is demonstrated that the newly described 2-PMPA (2-(phosphonomethyl)pentanedioic acid) robustly protects against ischemic injury in a neuronal culture model of stroke and in rats after transient middle cerebral artery occlusion, indicating that NAALADase inhibition may have use in neurological disorders in which excessive excitatory amino acid transmission is pathogenic.

C-peptide and diabetic neuropathy

  • A. Sima
  • Biology, Medicine
    Expert opinion on investigational drugs
  • 2003
Evidence to date indicating that replacement of C-peptide in patients with Type 1 diabetes will retard and prevent chronic complication is real and encouraging, and large-scale clinical trials necessary to bring this natural substance into the clinical arena should be encouraged and accelerated.

The central nervous system effects, pharmacokinetics and safety of the NAALADase-inhibitor GPI 5693.

NAALADase inhibition with GPI 5693 was safe and tolerable in healthy subjects and plasma concentrations that were effective in the reversal of hyperalgesia in the chronic constrictive injury animal model of neuropathic pain were obtained.

New insights into the metabolic and molecular basis for diabetic neuropathy

  • A. Sima
  • Medicine, Biology
    Cellular and Molecular Life Sciences CMLS
  • 2003
There is now evidence to suggest that insulin and C-peptide deficiencies are mainly responsible for perturbations of neurotrophic factors and contribute to oxidative stress in diabetic nerve, which may also be true for apoptotic phenomena afflicting both the peripheral and central nervous systems in diabetes.

Molecular alterations underlie nodal and paranodal degeneration in type 1 diabetic neuropathy and are prevented by C-peptide.

The progressive molecular aberrations underlying nodal and paranodal degenerative changes in type 1 diabetic neuropathy are described for the first time and it is demonstrated that they are preventable by insulinomimetic C-peptide.

Effect of 2-(phosphono-methyl)-pentanedioic acid on allodynia and afferent ectopic discharges in a rat model of neuropathic pain.

The data suggest that the antiallodynic effect of 2-PMPA may be mediated, at least in part, by inhibition of ectopic afferent discharges at the site of nerve injury.

Design, synthesis, and biological activity of a potent inhibitor of the neuropeptidase N-acetylated alpha-linked acidic dipeptidase.

Inhibition of NAALADase may show utility as a therapeutic intervention in diseases in which altered levels of glutamate are thought to be involved, and is suggested to act as a storage form of synaptic glutamate.