Effect of 2-(Phosphono-methyl)-pentanedioic Acid on Allodynia and Afferent Ectopic Discharges in a Rat Model of Neuropathic Pain

Abstract

Increased glutamate availability in the spinal cord and primary afferent nerves plays an important role in acute and chronic pain. Afferent ectopic discharges from the site of nerve injury constitute a source of abnormal sensory input to the spinal dorsal horn. The ectopic afferent activity is largely responsible for the development of hypersensitivity of dorsal horn neurons and neuropathic pain. Inhibition of glutamate carboxypeptidase II (GCP II) reduces glutamate release generated from N-acetylaspartyl-glutamate in nerve tissues and may have an analgesic effect on neuropathic pain. In the present study, we determined the effect of a GCP II inhibitor, 2-(phosphono-methyl)-pentanedioic acid (2-PMPA), on allodynia and ectopic afferent discharges in an animal model of neuropathic pain. Neuropathic pain was induced by partial ligation of the left sciatic nerve in

PMPA for Nephroprotection in PSMA-Targeted Radionuclide Therapy of Prostate Cancer

“…This finding indicates an approximately 10-fold safety factor in comparison to our recommended starting dose for the evaluation of PMPA-based kidney protection during PSMA-targeted radionuclide therapy in humans. In animal studies even much higher doses of PMPA have also been found tolerable (32). Preliminary data also suggest that selective PSMA inhibitors such as 2-MPPA (2-(3-mercaptopropyl) pentanedioic acid) or 2-PMPA may have inherent potential against prostate cancer and may simultaneously attenuate docetaxel-induced neuropathy (33).…”

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

“…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).…”

“…Glutamate has also been widely implicated in pain perception, so consequently there has been interest in the development of potent orally available GCPII inhibitors as therapeutics for chronic pain states . The initial characterization of early GCPII inhibitors showed alleviation of allodynia and thermal hyperalgesia in neuropathic pain models (Chen et al, 2002;Majer et al, 2003) and attenuation of thermal hyperalgesia, nerve conduction velocity (NCV) deficits, and neuropathological changes in models of diabetic neuropathy (Zhang et al, 2002(Zhang et al, , 2006. These early inhibitors, however, were not orally available and/or did not readily penetrate into nervous tissues, thus requiring large doses or local/intrathecal administration for efficacy.…”

Amino acids at the N‐ and C‐termini of human glutamate carboxypeptidase II are required for enzymatic activity and proper folding

“…Similarly to the transferrin receptor, GCPII probably exists as a homodimer under physiological conditions and the dimerization seems to be essential for its hydrolytic activity [15]. The protein is proposed to consist of six domains: the N-terminal cytoplasmic tail (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18], the helical transmembrane region (amino acids , and four extracellular domains spanning amino acids 44-150 (domain C), 151-274 (domain D), 275-586 (domain E), and 587-750 (domain F). While the domain spanning amino acids 275-586 is believed to be the catalytic domain, the importance/ function of the three remaining extracellular domains is unknown [16].…”

“…The GCPII form expressed in the brain, termed N-acetylated-a-linked acidic dipeptidase, plays an important role in neurotransmission, as it cleaves N-acetyl-Laspartyl-L-glutamate (NAAG), the most abundant peptidic transmitter within the human central nervous system [4], and terminates its activity [5]. Inhibition of the brain form of GCPII has been shown to be neuroprotective in animal models of stroke, neuropathic pain, or amyotrophic lateral sclerosis [6][7][8]. The physiological role of GCPII in the prostate is unknown [9].…”