Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excessive glutamatergic transmission is thought to be responsible for the injury observed in a variety of neurological disorders such as stroke. N-acetylaspartylglutamate (NAAG), a major peptidic component of the brain, has been suggested to serve as a potential storage form of glutamate. N-acetylated-a-linked acidic dipeptidase (NAALADase, EC 3.4.17.21) is responsible for the hydrolysis of NAAG into N-acetylaspartate (NAA) and glutamate. If NAAG is a storage form of glutamate, then inhibition of NAALADase should be neuroprotective in diseases in which excess glutamatergic transmission is detrimental. In addition, NAAG has been demonstrated to be an agonist at group II metabotropic glutamate receptors and functions as a mixed agonist/antagonist at N-methyl-D-aspartate receptors. Therefore, inhibition of NAALADase would also function to increase NAAG levels which, in turn, should provide neuroprotection via the interaction of NAAG with these receptors. Recently, potent and selective inhibitors of the enzyme have been designed and subsequently used to demonstrate that inhibition of NAALADase is neuroprotective in animal models of neurodegeneration. As such, NAALADase inhibition represents a novel method of regulating extracellular glutamate levels and provides a new avenue for the treatment of neurological disorders.
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PMID:Design of NAALADase inhibitors: a novel neuroprotective strategy. 1137 62

Excessive glutamate release is associated with neuronal damage. A new strategy for the treatment of neuronal injury involves inhibition of the neuropeptidase glutamate carboxypeptidase II (GCP II), also known as N-acetylated alpha-linked acidic dipeptidase. GCP II is believed to mediate the hydrolysis of N-acetyl-aspartyl-glutamate (NAAG) to glutamate and N-acetyl-aspartate, and inhibition of NAAG peptidase activity (by GCP II and other peptidases) is neuroprotective. Mice were generated in which the Folh1 gene encoding GCP II was disrupted (Folh1-/- mice). No overt behavioral differences were apparent between Folh1-/- mice and wild-type littermates, with respect to their overall performance in locomotion, coordination, pain threshold, cognition and psychiatric behavioral paradigms. Morphological analysis of peripheral nerves, however, showed significantly smaller axons (reduced myelin sheaths and axon diameters) in sciatic nerves from Folh1-/- mice. Following sciatic nerve crush, Folh1-/- mice suffered less injury and recovered faster than wild-type littermates. In a model of ischemic injury, the Folh1-/- mice exhibited a significant reduction (p < 0.05) in infarct volume compared with their wild-type littermates when subjected to middle cerebral artery occlusion, a model of stroke. These findings support the hypothesis that GCP II inhibitors may represent a novel treatment for peripheral neuropathies as well as stroke.
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PMID:Mice lacking glutamate carboxypeptidase II are protected from peripheral neuropathy and ischemic brain injury. 1619 Aug 66

Membrane-bound glutamate carboxypeptidase II (GCPII) is a zinc metalloenzyme that catalyzes the hydrolysis of the neurotransmitter N-acetyl-L-aspartyl-L-glutamate (NAAG) to N-acetyl-L-aspartate and L-glutamate (which is itself a neurotransmitter). Potent and selective GCPII inhibitors have been shown to decrease brain glutamate and provide neuroprotection in preclinical models of stroke, amyotrophic lateral sclerosis, and neuropathic pain. Here, we report crystal structures of the extracellular part of GCPII in complex with both potent and weak inhibitors and with glutamate, the product of the enzyme's hydrolysis reaction, at 2.0, 2.4, and 2.2 A resolution, respectively. GCPII folds into three domains: protease-like, apical, and C-terminal. All three participate in substrate binding, with two of them directly involved in C-terminal glutamate recognition. One of the carbohydrate moieties of the enzyme is essential for homodimer formation of GCPII. The three-dimensional structures presented here reveal an induced-fit substrate-binding mode of this key enzyme and provide essential information for the design of GCPII inhibitors useful in the treatment of neuronal diseases and prostate cancer.
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PMID:Structure of glutamate carboxypeptidase II, a drug target in neuronal damage and prostate cancer. 1646 55

Glutamate carboxypeptidase II (GCPII) is a transmembrane glycoprotein expressed in various tissues. When expressed in the brain it cleaves the neurotransmitter N-acetylaspartylglutamate (NAAG), yielding free glutamate. In jejunum it hydrolyzes folylpoly-gamma-glutamate, thus facilitating folate absorption. The prostate form of GCPII, known as prostate specific membrane antigen (PSMA), is an established cancer marker. The NAAG-hydrolyzing activity of GCPII has been implicated in a number of pathological conditions in which glutamate is neurotoxic (e.g. amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, epilepsy, schizophrenia, and stroke). Inhibition of GCPII was shown to be neuroprotective in tissue culture and in animal models. GCPII is therefore an interesting putative therapeutic target. However, only very limited and controversial data on the expression and localization of GCPII in human brain are available. Therefore, we set out to analyze the activity and expression of GCPII in various compartments of the human brain using a radiolabeled substrate of the enzyme and the novel monoclonal antibody GCP-04, which recognizes an epitope on the extracellular portion of the enzyme and is more sensitive to GCPII than to the homologous GCPIII. We show that this antibody is more sensitive in immunoblots than the widely used antibody 7E11. By Western blot, we show that there are approximately 50-300 ng of GCPII/mg of total protein in human brain, depending on the specific area. Immunohistochemical analysis revealed that astrocytes specifically express GCPII in all parts of the brain. GCPII is enzymatically active and the level of activity follows the expression pattern. Using pure recombinant GCPII and homologous GCPIII, we conclude that GCPII is responsible for the majority of overall NAAG-hydrolyzing activity in the human brain.
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PMID:Expression of glutamate carboxypeptidase II in human brain. 1715 Mar 6

Human glutamate carboxypeptidase II (GCPII) is a transmembrane metallopeptidase found mainly in the brain, small intestine, and prostate. In the brain, it cleaves N-acetyl-L-aspartyl-glutamate, liberating free glutamate. Inhibition of GCPII has been shown to be neuroprotective in models of stroke and other neurodegenerations. In prostate, it is known as prostate-specific membrane antigen, a cancer marker. Recently, human glutamate carboxypeptidase III (GCPIII), a GCPII homolog with 67% amino acid identity, was cloned. While GCPII is recognized as an important pharmaceutical target, no biochemical study of human GCPIII is available at present. Here, we report the cloning, expression, and characterization of recombinant human GCPIII. We show that GCPIII lacks dipeptidylpeptidase IV-like activity, its activity is dependent on N-glycosylation, and it is effectively inhibited by several known inhibitors of GCPII. In comparison to GCPII, GCPIII has lower N-acetyl-L-aspartyl-glutamate-hydrolyzing activity, different pH and salt concentration dependence, and distinct substrate specificity, indicating that these homologs might play different biological roles. Based on a molecular model, we provide interpretation of the distinct substrate specificity of both enzymes, and examine the amino acid residues responsible for the differences by site-directed mutagenesis. These results may help to design potent and selective inhibitors of both enzymes.
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PMID:Biochemical characterization of human glutamate carboxypeptidase III. 1724 Nov 21

Glutamate carboxypeptidase II (GCPII) is a membrane-bound binuclear zinc metallopeptidase with the highest expression levels found in the nervous and prostatic tissue. Throughout the nervous system, glia-bound GCPII is intimately involved in the neuron-neuron and neuron-glia signaling via the hydrolysis of N-acetylaspartylglutamate (NAAG), the most abundant mammalian peptidic neurotransmitter. The inhibition of the GCPII-controlled NAAG catabolism has been shown to attenuate neurotoxicity associated with enhanced glutamate transmission and GCPII-specific inhibitors demonstrate efficacy in multiple preclinical models including traumatic brain injury, stroke, neuropathic and inflammatory pain, amyotrophic lateral sclerosis, and schizophrenia. The second major area of pharmacological interventions targeting GCPII focuses on prostate carcinoma; GCPII expression levels are highly increased in androgen-independent and metastatic disease. Consequently, the enzyme serves as a potential target for imaging and therapy. This review offers a summary of GCPII structure, physiological functions in healthy tissues, and its association with various pathologies. The review also outlines the development of GCPII-specific small-molecule compounds and their use in preclinical and clinical settings.
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PMID:Glutamate carboxypeptidase II in diagnosis and treatment of neurologic disorders and prostate cancer. 2221 50

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.
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PMID:Glutamate in CNS neurodegeneration and cognition and its regulation by GCPII inhibition. 2230 12

The rationale of this case-control study is to ascertain whether glutamate carboxypeptidase II (GCPII) variants serve as determinants of hyperhomocysteinemia and contribute to the etiology of stroke. Hyperhomocysteinemia was observed in stroke cases compared to controls (14.09 +/- 7.62 micromol/L vs. 8.71 +/- 4.35, P < 0.0001). GCPII sequencing revealed two known variants (R190W and H475Y) and six novel variants (V108A, P160S, Y176H, G206R, G245S and D520E). Among the haplotypes of GCPII, all wild-haplotype H0 showed independent association with stroke risk (OR: 9.89, 95% CI: 4.13-23.68), while H2 representing P160S variant showed reduced risk (OR: 0.17, 95% CI: 0.06-0.50). When compared to subjects with H2 haplotype, H0 haplotype showed elevated homocysteine levels (18.26 +/- 4.31 micromol/L vs. 13.66 +/- 3.72 micromol/L, P = 0.002) and reduced plasma folate levels (7.09 +/- 1.19 ng/ml vs. 8.21 +/- 1.14 ng/ml, P = 0.007). Using GCPII genetic variants, dietary folate and gender as predictor variables and homocysteine as outcome variable, a multiple linear regression model was developed. This model explained 36% variability in plasma homocysteine levels. To conclude, GCPII haplotypes influenced susceptibility to stroke by influencing homocysteine levels.
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PMID:Glutamate carboxypeptidase II (GCPII) genetic variants as determinants of hyperhomocysteinemia: implications in stroke susceptibility. 2325 22

A 65-year-old man with disseminated bone metastases of prostate cancer was referred for Ga-PSMA-HBED-CC-PET/CT (short PSMA-PET/CT) to exclude visceral metastases before treatment of bone metastases with Ra-dichloride. Apart from disseminated bone metastases, PSMA-PET/CT revealed a focal cerebral tracer uptake in the right frontal lobe highly suspicious for cerebral spread. According to patient history, a cerebral infarction occurred 14 days before PSMA imaging in corresponding localization confirmed by MRI scanning. This case demonstrates the possibility of false-positive finding of cerebral metastases in PSMA-PET early after stroke.
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PMID:Subacute Stroke Mimicking Cerebral Metastasis in 68Ga-PSMA-HBED-CC PET/CT. 2735 52

N-Acetylaspartylglutamate (NAAG) is the third most prevalent neurotransmitter in the mammalian nervous system, yet its therapeutic potential is only now being fully recognized. Drugs that inhibit the inactivation of NAAG by glutamate carboxypeptidase II (GCPII) increase its extracellular concentration and its activation of its receptor, mGluR3. These drugs warrant attention, as they are effective in animal models of several clinical disorders including stroke, traumatic brain injury and schizophrenia. In inflammatory and neuropathic pain studies, GCPII inhibitors moderated both the primary and secondary pain responses when given systemically, locally or in brain regions associated with the pain perception pathway. The finding that GCPII inhibition also moderated the motor and cognitive effects of ethanol intoxication led to the discovery of their procognitive efficacy in long-term memory tests in control mice and in short-term memory in a mouse model of Alzheimer's disease. NAAG and GCPII inhibitors respectively reduce cocaine self-administration and the rewarding effects of a synthetic stimulant. Most recently, GCPII inhibition also has been reported to be efficacious in a model of inflammatory bowel disease. GCPII was first discovered as a protein expressed by and released from metastatic prostate cells where it is known as prostate specific membrane antigen (PSMA). GCPII inhibitors with high affinity for this protein have been developed as prostate imaging and radiochemical therapies for prostate cancer. Taken together, these data militate in favor of the development and application of GCPII inhibitors in more advanced preclinical research as a prelude to clinical trials.
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PMID:N-acetylaspartylglutamate (NAAG) and glutamate carboxypeptidase II: An abundant peptide neurotransmitter-enzyme system with multiple clinical applications. 3173 Jul 93


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