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...
Glutamate, first identified in 1866, is the primary excitatory neurotransmitter in the brain. While it is critically important in many highly regulated cortical functions such as learning and memory, glutamate can be much like the magic the Sorcerer's Apprentice used in Goethe's poem: when conjured under unregulated conditions glutamate can get quickly out of control and lead to deleterious consequences. Two broad types of glutamate receptors, the ionotropic and metabotropic, facilitate glutamatergic neurotransmission in the CNS and play key roles in regulating cognitive function. Excessive activation of these receptors leads to excitotoxicity, especially in brain regions that are developmentally and regionally vulnerable to this kind of injury. Dysregulation of glutamate signaling leads to neurodegeneration that plays a role in a number of neuropsychiatric diseases, prompting the development and utilization of novel strategies to balance the beneficial and deleterious potential of this important neurotransmitter. Inhibition of the enzyme glutamate carboxypeptidase II (GCPII) is one method of manipulating glutamate neurotransmission. Positive outcomes (decreased neuronal loss, improved cognition) have been demonstrated in preclinical models of ALS, stroke, and Multiple Sclerosis due to inhibition of GCPII, suggesting this method of glutamate regulation could serve as a therapeutic means for treating neurodegeneration and cognitive impairment.
Preclinical investigations utilizing murine experimental auto-immune encephalomyelitis (EAE), as well as clinical observations in patients with multiple sclerosis (MS), may suggest alteration of endogenous opioid systems in MS. In this study we used the opioid antagonist naltrexone (NTX) to invoke a continuous (High Dose NTX, HDN) or intermittent (Low Dose NTX, LDN) opioid receptor blockade in order to elucidate the role of native opioid peptides in EAE. A mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced EAE was employed in conjunction with daily treatment of LDN (0.1 mg/kg, NTX), HDN (10 mg/kg NTX), or vehicle (saline). No differences in neurological status (incidence, severity, disease index), or neuropathological assessment (activated astrocytes, demyelination, neuronal injury), were noted between MOG-induced mice receiving HDN or vehicle. Over 33% of the MOG-treated animals receiving LDN did not exhibit behavioral signs of disease, and the severity and disease index of the LDN-treated mice were markedly reduced from cohorts injected with vehicle. Although all LDN animals demonstrated neuropathological signs of EAE, LDN-treated mice without behavioral signs of disease had markedly lower levels of activated astrocytes and demyelination than LDN- or vehicle-treated animals with disease. These results imply that endogenous opioids, evoked by treatment with LDN and acting in the rebound period from drug exposure, are inhibitory to the onset and progression of EAE, and suggest that clinical studies of LDN are merited in MS and possibly in other autoimmune disorders.
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