Effects of NAAG peptidase inhibitor 2-PMPA in model chronic pain – relation to brain concentration

Nagel, Jens; Belozertseva, Irina; Greco, Sergio; Kashkin, Vladimir A.; Malyshkin, A.; Jirgensons, Aigars; Shekunova, E.V.; Eilbacher, Bernd; Bespalov, Anton; Danysz, Wojciech

doi:10.1016/j.neuropharm.2006.07.018

Cited by 44 publications

(39 citation statements)

References 55 publications

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“…Therefore, early detection and treatment of cognitive impairment in MS would have a tremendous impact on quality of life. Based on our initial finding of a positive relationship between hippocampal NAAG/Cr concentration and cognitive function in MS patients, we tested a compound previously demonstrated to increase brain NAAG levels, 2-PMPA (17,26), in an animal model of MS and measured cognitive performance. Data from the present experiment reveal that up-regulation of CNS NAAG concentration through inhibition of GCPII improves cognitive function in EAE mice.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

Rahn

Watkins

Alt³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi of MS patients, compared the findings to performance on a neurocognitive test battery, and found that N-acetylaspartylglutamate (NAAG) concentration correlated with cognitive functioning. Specifically, MS patients with cognitive impairment had low hippocampal NAAG levels, whereas those with normal cognition demonstrated higher levels. We then evaluated glutamate carboxypeptidase II (GCPII) inhibitors, known to increase brain NAAG levels, on cognition in the experimental autoimmune encephalomyelitis (EAE) model of MS. Whereas GCPII inhibitor administration did not affect physical disabilities, it increased brain NAAG levels and dramatically improved learning and memory test performance compared with vehicle-treated EAE mice. These data suggest that NAAG is a unique biomarker for cognitive function in MS and that inhibition of GCPII might be a unique therapeutic strategy for recovery of cognitive function.G lutamate carboxypeptidase II (GCPII), previously called Nacetylated-α-linked acidic dipeptidase (NAALADase), is a membrane-bound enzyme expressed on the surface of astrocytes that catalyzes the cleavage of N-acetylaspartylglutamate (NAAG) into N-acetylaspartate (NAA) and glutamate ( Fig. 1) (1, 2). NAAG, the most abundant neuropeptide in the mammalian brain, is a selective agonist for metabotropic glutamate receptor 3 (mGluR3) (1, 2). mGluR3s are expressed on the surface of presynaptic neurons and astrocytes in the CNS. Activation of mGluR3s by NAAG reduces cAMP and cGMP levels, inhibits glutamate release, and stimulates a release of transforming growth factor beta (1, 2). A recent study reported impaired performance on spatial reference and working memory tasks in mGluR2/3 knockout mice (3), suggesting a role for group II mGluRs in cognitive function.Cognitive impairment is a frequent comorbidity of many neurological diseases, including multiple sclerosis (MS). MS affects over 2 million individuals worldwide, and ∼40-65% of all MS patients experience cognitive impairment (4). The most commonly and severely affected facets of cognition in MS patients are anterograde episodic memory, working memory, and processing speed (5-7), and these impairments strongly contribute to the high frequency of unemployment in MS patient populations (8). Global brain atrophy, candidate genetic risk factors, accelerated inflammatory processes (7), and dysregulated signaling pathways (9) have been implicated as contributing factors, but an incomplete understanding of the molecular mechanisms behind cognitive impairment in MS has prevented the development and Food and Drug Administration (FDA) approval of drug therapies.The most widely used animal model of MS, experimental autoimmune encephalomyelitis (EAE), is a valuable tool for developing treatments for MS. Three FDA-approved disease-modifying agents were deve...

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Section: Discussionmentioning

confidence: 99%

“…In the present study, we found that right hippocampal NAAG/creatine (Cr) concentrations positively correlate to cognitive function in MS patients. Based on these data, we used a potent and selective small molecule inhibitor of GCPII (17) to increase brain NAAG levels in an animal model of MS with cognitive impairment (12).…”

mentioning

confidence: 99%

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

Rahn

Watkins

Alt³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…For example, spinal delivery of the GCPII inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) (Jackson et al, 2001) was found to attenuate nociception in the hot plate and formalin pain test (Yamamoto et al, 2001). Intraperitoneal 2-PMPA was found to attenuate allodynia and accompanying increased ectopic discharges after partial sciatic nerve ligation in a model of neuropathic pain (Chen et al, 2002), as well as reduced mechanical allodynia in rats receiving carrageenan (Yamamoto et al, 2001) or unilateral sciatic nerve ligation (Nagel et al, 2006). 2-PMPA markedly inhibits noxious evoked dorsal horn activity in normal and inflamed rats (Carpenter et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

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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“…Chen et al [66] has studied its role in attenuating dynamic allodynia in partial sciatic nerve ligation model (PSNL) of neuropathic pain. Results from various other studies on 2-PMPA include reduced mechanical allodynia induced by paw carrageenan injection in the rats [85] and reduced dynamic allodynia in rats with unilateral sciatic nerve ligation [86]. In a model of excitotoxic spinal cord injury, 2-PMPA inhibited dynorphin A-induced elevations in cerebrospinal fluid glutamate levels and improved histological score [87].…”

Section: N-acetylated-a-linked Acidic Dipeptidase (Naaladase) Inhibitorsmentioning

confidence: 95%

“…Some of them are found to be therapeutically active, but are associated with side effects like psychomimetic symptoms, cognitive impairment, dizziness and sedation [7,48]. Newer approaches have been identified to overcome these side effects, which include, inhibiting other binding sites of NMDA receptor like the NR2B, glycine B site [49][50][51][52][53][54][55][56][57][58][59][60][61][62], targeting other receptors like AMPA [63][64][65][66][67], kainate [68][69][70][71][72] and mGluR1 -5 [73][74][75][76][77][78][79][80][81][82], enhancing the activity of glutamate transporters that sequester the extracellular glutamate [23,24,83] and inhibiting glutamate release by designing various enzyme inhibitors [84][85][86][87][88][89][90][91...…”

Section: Glutamatergic System As a Target For Neuropathic Painmentioning

confidence: 99%

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

Yogeeswari

Semwal²,

Mishra³

et al. 2009

Expert Opinion on Therapeutic Targets

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Glutamate is the most widely distributed and a major excitatory neurotransmitter in the CNS. It has been found to play a critical role in various physiological functions in which increased glutamate or its subsequent stimulation is thought to have a role in pathophysiological mechanism of various CNS diseases like epilepsy, stroke, depression and pain. Early attempts to develop glutamatergic antagonists failed in clinical studies due to nonselective or competitive antagonism and have a lot of safety issues like loss of cognitive functions, psychomimetic effect and sedation. Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. At present, there are very few effective therapies for neuropathic pain. The current approach includes targeting specific or alternate binding sites of glutamate receptors, resulting in reduced CNS liabilities. Targeting the glutamatergic system shows a better efficacy and fewer side effects, compared with classical drugs for the treatment of neuropathic pain. This review discusses the various targets on glutamatergic system, which includes the receptors, transporters and enzymes, for the treatment of neuropathic pain and their advantages over classical glutamatergic antagonists. The review also highlights the newer drugs in clinical trials for neuropathic pain.

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Effects of NAAG peptidase inhibitor 2-PMPA in model chronic pain – relation to brain concentration

Cited by 44 publications

References 55 publications

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

Inhibition of Glutamate Carboxypeptidase II (GCPII) activity as a treatment for cognitive impairment in multiple sclerosis

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

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

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