Discussion
We have used cell culture techniques and whole tissues in combination with 1H-NMR spectroscopy and HPLC analysis and biochemical enzyme assays, to compare the expression of NAA and aspartoacylase in cells derived from the O-2A progenitor lineage and expression of aspartoacylase levels brain regions during development. This study casts new light on the metabolism of NAA at the cellular level and, furthermore, correlates with the expression of aspartoacylase activity with myelination. Previous...
Effects Of Heavy Drinking
10.1 Effects of Abstinence on the Brain Quantitative MRI and MR Spectroscopic Imaging in Chronic Alcohol Abuse (31) Structural brain damage, especially to white matter, is well documented in chronic alcohol abuse, and there is also evidence for brain metabolic abnormalities in this condition. It is unknown, however, to what extent these structural and metabolic changes are still detectable in long-term abstinent alcoholics compared to active chronic drinkers. Therefore we compared 12 recovering...
Axonal Injury Is The Major Determinant Of Permanent Neurologic Disability In Multiple Sclerosis
Even the earliest literature on MS mentioned axonal degeneration. Studies using contemporary technology such as magnetic resonance imaging and confocal microscopy more definitively demonstrated that axonal transection begins at disease onset and that cumulative axonal loss provides the pathologic substrate for the progressive disability that most long-term MS patients experience. Moreover, postmortem studies have shown that several histopathologic abnormalities including axonal loss, can be...
Correlations Between Naa And Fdgpet
The in vivo neuronal contribution to human cerebral metabolic rate of glucose (CMRglc), measured by 18FDG-PET, is unknown. Since NAA is thought to reflect neuron density, evaluating how CMRglc varies as a function of NAA concentration ( NAA ) should reflect the way in which brain glucose metabolism is affected by neuron density and or by NAA content per neuron. The CMRglc-to- NAA relationship could be derived for an individual subject by plotting local CMRglc against local NAA across that...
Schizophrenia
It has been shown by Bita Moghaddam (Moghaddam and Adams 1998, Cartmell et al., 1999, 2000) that stimulation of group II metabotropic glutamate receptors (using mGluR2 3 agonist, LY354740) attenuated the disruptive effects of phencyclidine (PCP) on working memory, stereotypy, locomotion and cortical glutamate release in rats. Phencyclidine (blocker of NMDA receptor) elicits positive and negative schizophrenia-like symptoms in animals (Zukin and Javitt 1989). Schizophrenia is one of the most...
Naa In Normal Aging
Considerable evidence suggests that normal aging is associated with gradual impairment of memory functioning 1 . The medial temporal lobe, especially the hippocampus, plays a central role in declarative memory processing 2 . However, magnetic resonance imaging (MRI) studies have produced controversial results concerning the age-related hippocampal volume loss, which could be due in part to the non-specificity of volume shrinkage as an indicator for neuron loss. In contrast to volume, NAA is...
Naa As A Marker For Neuronal Health
The relatively high concentration of NAA permits its noninvasive detection by magnetic resonance spectroscopy (MRS), which combined with its predominant neuronal localization has enabled use of NAA as a diagnostic marker for neuronal dysfunction loss in a variety of neurological disorders.4,5,7 NAA levels measured by MRS have been reported to be altered in patients suffering from various neurological disorders40-51 (Table 3). These studies have mostly detected decreases in NAA, but in case of...
Gcp Ii Inhibitors Provide Analgesia
GCP II inhibitors were also examined as potential analgesics for neuropathic pain and peripheral neuropathy using a chronic constrictive injury (CCI) model.22 Briefly, one sciatic nerve was exposed by blunt dissection proximal to nerve trifurcation and four ligatures loosely tied. The other side was sham operated. After twelve days, thermal pain threshold (withdrawal latency) was assessed by means of the plantar test.23 The ligated and non-ligated hind limbs of the CCI rats were tested and a...
References
Coyle, J.T., The nagging question of the function of N-acetylaspartylglutamate. Neurobiol. of Dis. 4, 2. Neale, J.H., Bzdega, T., Wroblewska, B., N-Acetylaspartylglutamate The most abundant peptide neurotransmitter in the mammalian central nervous system. J. Neurochem. 75, 443-452, (2000). 3. Moffett, J.R., Namboodiri, M.A.A., Cangro, C.A. and Neale, J.H. Immunohistochemical localization of N-acetylaspartate in rat brain. Neuroreport 2, 131-134, (1991). 4. Anderson, K.J., Monaghan, D.T.,...
Evaluation Of Inhibitors Of Gcp Ii In Acute Spinal Cord Injury In The
Spinal intrathecal injection of the peptide Dynorphin A has been shown to reliably induce ischemia, neuronal injury and persistent flaccid hindlimb paralysis.57-63 Concentrations of the excitatory amino acid neurotransmitters Glu and Asp are significantly increased in lumbar cerebrospinal fluid in the rat, shortly after the onset of dynorphin A-induced hindlimb paralysis.62 In addition, a variety of competitive and noncompetitive inhibitors of the NMDA receptor complex have been shown to...
Therapeutic Studies With Gcp Ii Inhibitors In Rodent Models
Degenerative diseases or injuries to the central nervous system (CNS) are believed to result in elevations of extracellular concentrations of the excitatory amino acid neurotransmitter Glu which, through excessive stimulation of excitatory amino acid receptors, including NMDARs, can evoke a cascade of disruption of intracellular processes inducing cell dysfunction and death.42-44 Although a number of pharmacological agents that selectively antagonize the action of Glu at its receptors have been...
Pathological Changes In Naag And Gcp Ii In Spinal Motoneuron Injury And Disease
In 1984 Koller et al.32 reported reductions in NAAG levels caudal to spinal cord transactions. Given this finding, along with the known association of NAAG with motoneurons21, its co-localization with cholinergic motoneurons33 and the report of marked reduction in choline acetyltransferase activity in the ventral horn of the spinal cord in postmortem studies of patients with amyotrophic lateral sclerosis ALS ,34 it was logical to study levels of NAAG in conditions known to affect motoneurons....
Introduction
This review will focus on W-acetylaspartylglutamate (NAAG) and its catalytic enzyme in motor systems of the spinal cord during injury and disease. NAAG has been studied in the central nervous systems (CNS) of a number of species. It is a dipeptide that fulfills most of the criteria for classification as a neurotransmitter.1,2 Notably, it is localized to neurons,3,4 in synaptic vesicles,5,6 and is released in a calcium-dependent manner upon neuronal depolarization.6,7,8 NAAG has been reported to...
Gcp Ii Inhibitors In The Clinic
Based on the preclinical efficacy of GCP II inhibitors in models of stroke, ALS and peripheral neuropathy, a potent and selective GCP II inhibitor was chosen to be administered to 77 individuals in three Phase I clinical trials. In the first trial, doses of up to 1500 mg were administered to volunteers. Oral bioavailability of the drug, particularly in the fasted state, was very good. Plasma levels were achieved that were above those needed to produce effects in animal models of diabetic...
Canavan Disease
In this section, the elements involved in developing the neuron-vascular control mechanism hypothesis are presented in a logical sequence, with each step evaluated by considering what purpose is served by the particular process or metabolic step involved. Indeed, what follows is more of a description of events than a hypothesis, a description that leads to the conclusions that form the basis of a possible understanding the roles of NAA and NAAG in the brain. 2.1. Neuron requirements for energy...
NAA in Neuronal Energy Metabolism
The first report that NAA might be involved in brain metabolism was by Buniatian and coworkers in 1965.18 The idea that NAA is involved in energy metabolism in the nervous system is based on a number of facts, including that 1) NAA is synthesized by aspartate N-acetyltransferase in neuronal mitochondria19,20, 2) traumatic brain injury causes rapid and partially reversible decreases in NAA concentrations,21-23 3) inhibition of mitochondrial respiration results in the simultaneous decrease of NAA...
Molecular Size Of Native Aspnat
Whether or not the large molecular size of native Asp-NAT was an artifact of the enzyme preparation methods was tested by using different homogenization and solubilization conditions. A buffer that is commonly used in mitochondrial protein purification (Tris-sucrose medium Tris-HCl, 50 mM 1 mM EDTA 0.32 M sucrose 1 mM DTT protease inhibitor cock-tail added according to the quantity of processed tissue pH adjusted to 7.4) was employed to obtain a crude mitochondrial pellet from rat brains....
Adult
Evolution of aspartoacylase activity specific activity, jM min mg protein - mean S.D. n 4 in the optic nerve during postnatal development. A differential distribution of aspartoacylase activity between gray and white matter has been has been demonstrated in previous studies. The study by D'Adamo et al.36 on the occurrence of aspartoacylase activity in the developing rat brain showed an approximately three-fold difference between white and gray matter in the adult cerebral hemispheres,...
NAA as Acetate Carrier for Myelin Lipid Synthesis
One hypothesis on the role of NAA in the nervous system that has mounting experimental support is the acetate hypothesis of myelin lipid synthesis in oligodendrocytes. In the 1960's, D'Adamo and coworkers showed that the acetate moiety of NAA was incorporated into brain lipids during CNS development, indicating that it was likely to be involved in the myelination of axons.12,13 In the early 1990's Burri and colleagues showed that the acetate group from NAA was preferentially incorporated into...
