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

Abstract

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...

Maternal inflammation leads to impaired glutamate homeostasis and up-regulation of glutamate carboxypeptidase II in activated microglia in the fetal/newborn rabbit brain

“…NAAG has also been shown to prevent NMDA-induced neuronal death (Puttfarcken et al, 1993, Valivullah et al, 1994, Khacho et al, 2015), and induce TGF-β release via activation of Mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K) (Bruno et al, 1998a, D’Onofrio et al, 2001). This may explain the neuroprotective effects of GCPII inhibition and NAAG administration in several adult models of neuroinflammation (Ghadge et al, 2003, Thomas et al, 2003, Rahn et al, 2012) and in hypoxic-ischemia (Slusher et al, 1999, Cai et al, 2002). …”

Chemistry and biochemistry of13C hyperpolarized magnetic resonance using dynamic nuclear polarization

“…181 Typically these are involved in protein regulation and have also been the target of developing chemotherapeutics, 182 treatment of neurodegenerative/inflammatory diseases, 183 and even detection of prostate cancer (PSMA). 184 Typically this is a Zn 2+ -dependent mechanism where the carboxyl carbon of the peptide bond to be cleaved is coordinated by the zinc ion.…”

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

“…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.…”