Blocking glutamate carboxypeptidase <scp>II</scp> inhibits glutamate excitotoxicity and regulates immune responses in experimental autoimmune encephalomyelitis

Ha, Danbee; Bing, So Jin; Ahn, Ginnae; Kim, Jinhee; Cho, Jin-Hee; Kim, Areum; Herath, Kalahe Hewage Iresha Nadeeka Madushani; Yu, Hak Sun; Jo, Sangmee Ahn; Cho, Ik‐Hyun; Jee, Youngheun

doi:10.1111/febs.13816

Cited by 30 publications

(27 citation statements)

References 40 publications

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“…In EAE, aberrations in the expression of Glu transporters, receptors or metabolizing enzymes were detected which suggested the role of excitotoxicity in this model of MS. Pathological changes like axonal damage, demyelination, and ODC loss were observed which are exhibitive of excitotoxicity. The use of GluR antagonists could suspend these effects and cause disease amelioration [6,27,28,29,30,31]. …”

Section: Excitotoxicity In Multiple Sclerosismentioning

confidence: 99%

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Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis

Rajda

Pukoli

Bende

et al. 2017

IJMS

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). There is increasing evidence that MS is not only characterized by immune mediated inflammatory reactions, but also by neurodegenerative processes. There is cumulating evidence that neurodegenerative processes, for example mitochondrial dysfunction, oxidative stress, and glutamate (Glu) excitotoxicity, seem to play an important role in the pathogenesis of MS. The alteration of mitochondrial homeostasis leads to the formation of excitotoxins and redox disturbances. Mitochondrial dysfunction (energy disposal failure, apoptosis, etc.), redox disturbances (oxidative stress and enhanced reactive oxygen and nitrogen species production), and excitotoxicity (Glu mediated toxicity) may play an important role in the progression of the disease, causing axonal and neuronal damage. This review focuses on the mechanisms of mitochondrial dysfunction (including mitochondrial DNA (mtDNA) defects and mitochondrial structural/functional changes), oxidative stress (including reactive oxygen and nitric species), and excitotoxicity that are involved in MS and also discusses the potential targets and tools for therapeutic approaches in the future.

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Section: Excitotoxicity In Multiple Sclerosismentioning

confidence: 99%

“…Ha et al (2016) [29] examined the impact of an efficient GCPII inhibitor, 2-phosphonomethyl pentanedioic acid (2-PMPA), on EAE mice and detected improvement in disease course and significantly decreased amounts of inflammatory cells infiltrating the CNS. This agent impeded the expression of mGluR1 in CNS and periphery too.…”

Section: Therapeutic Trialsmentioning

confidence: 99%

Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis

Rajda

Pukoli

Bende

et al. 2017

IJMS

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“…1 As a major regulator of extracellular glutamate availability in the brain, 2 GCPII inhibition represents a promising drug target for multiple diseases associated with disrupted glutamate homeostasis including neuropathic pain, 3–7 stroke, 2 diabetic neuropathy, 8–10 schizophrenia, 11 addiction, 12–14 multiple sclerosis, 15–17 and traumatic brain injury. 18,19 Selective inhibitors of GCPII have been shown to attenuate glutamate-mediated excitotoxicity, and ameliorate these disease phenotypes in preclinical models.…”

Section: Introductionmentioning

confidence: 99%

Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester Prodrugs

Nedelcovych¹,

Dash²,

Tenora

et al. 2017

Mol. Pharmaceutics

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2-(Phosphonomethyl)pentanedioic acid (2-PMPA) is a potent and selective inhibitor of glutamate carboxypeptidase-II (GCPII) with efficacy in multiple neurological and psychiatric disease models, but its clinical utility is hampered by low brain penetration due to the inclusion of multiple acidic functionalities. We recently reported an improvement in the brain-to-plasma ratio of 2-PMPA after intranasal (IN) dosing in both rodents and primates. Herein, we describe the synthesis of several 2-PMPA prodrugs with further improved brain delivery of 2-PMPA after IN administration by masking of the γ-carboxylate. When compared to IN 2-PMPA in rats at 1 h post dose, γ-(4-acetoxybenzyl)-2-PMPA (compound 1) resulted in significantly higher 2-PMPA delivery to both plasma (4.1-fold) and brain (11-fold). Subsequent time-dependent evaluation of 1 also showed high brain as well as plasma 2-PMPA exposures with brain-to-plasma ratios of 2.2, 0.48, and 0.26 for olfactory bulb, cortex, and cerebellum, respectively, as well as an improved sciatic nerve to plasma ratio of 0.84. In contrast, IV administration of compound 1 resulted in similar plasma exposure of 2-PMPA versus the IN route (AUCIV: 76 ± 9 h·nmol/mL versus AUCIN: 99 ± 24 h·nmol/mL); but significantly lower nerve and brain tissue exposures with tissue-to-plasma ratios of 0.21, 0.03, 0.04, and 0.04 in nerve, olfactory bulb, cortex, and cerebellum, respectively. In primates, IN administration of 1 more than doubled 2-PMPA concentrations in the cerebrospinal fluid relative to previously reported levels following IN 2-PMPA. The results of these experiments provide a promising strategy for testing GCPII inhibition in neurological and psychiatric disorders.

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“…Studies have shown that increased glutamate levels are responsible for increased production of inflammatory cytokines in activated T cells in autoimmune diseases [41]. 2-PMPA treatment dampened the function of CD4 + T cells (such as T H 1 and T H 17), suppressed mGluR1 expression in both periphery and CNS, and reduced the number of mGluR1-positive CD4 + T cells in experimental autoimmune encephalomyelitis [42]. It has been reported that NAAG receptors can be found in the GI tract, though the roles of NAAG or glutamate in the GI tract are not well characterized [43].…”

Section: Discussionmentioning

confidence: 99%

Local enema treatment to inhibit FOLH1 /GCPII as a novel therapy for inflammatory bowel disease

Date

Rais

Babu

et al. 2017

Journal of Controlled Release

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Here we evaluate the potential for local administration of a small molecule FOLH1/GCPII inhibitor 2-phosphonomethyl pentanedioic acid (2-PMPA) as a novel treatment for inflammatory bowel disease (IBD). We found that FOLH1/GCPII enzyme activity was increased in the colorectal tissues of mice with TNBS-induced colitis, and confirmed that 2-PMPA inhibited FOLH1/GCPII enzyme activity ex vivo. In order to maximize local enema delivery of 2-PMPA, we studied the effect of vehicle tonicity on the absorption of 2-PMPA in the colon. Local administration of 2-PMPA in a hypotonic enema vehicle resulted in increased colorectal tissue absorption at 30 min compared to 2-PMPA administered in an isotonic enema vehicle. Furthermore, local delivery of 2-PMPA in hypotonic enema vehicle resulted in prolonged drug concentrations for at least 24 h with minimal systemic exposure. Finally, daily treatment with the hypotonic 2-PMPA enema ameliorated macroscopic and microscopic symptoms of IBD in the TNBS-induced colitis mouse model, indicating the potential of FOLH1/GCPII inhibitors for the local treatment of IBD.

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Blocking glutamate carboxypeptidase II inhibits glutamate excitotoxicity and regulates immune responses in experimental autoimmune encephalomyelitis

Cited by 30 publications

References 40 publications

Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis

Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis

Enhanced Brain Delivery of 2-(Phosphonomethyl)pentanedioic Acid Following Intranasal Administration of Its γ-Substituted Ester Prodrugs

Local enema treatment to inhibit FOLH1 /GCPII as a novel therapy for inflammatory bowel disease

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