Glutamate, excitotoxicity and amyotrophic lateral sclerosis

Shaw, Pamela J.; Ince, Paul G.

doi:10.1007/bf03160574

Cited by 275 publications

(161 citation statements)

References 120 publications

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“…Also, for drug screening, large scale expression of neuroreceptor ligand binding domains offers attractive perspectives: pathological alterations of ligand-gated neuroreceptor ion channels are implicated in diseases or pathological conditions such as endogenous depression (␥-aminobutyric acid A receptors and 5-hydroxytryptamine 3 receptors) (47), stroke and amyotrophic lateral sclerosis (excitotoxicity and glutamate receptors) (48), schizophrenia (nAChR and ␥-aminobutyric acid A receptors) (49 and 50), myasthenia gravis, morbus Alzheimer, morbus Parkinson, and Chagas's disease (nAChR) (51,52).…”

Section: Discussionmentioning

confidence: 99%

Expression and Renaturation of the N-terminal Extracellular Domain of Torpedo Nicotinic Acetylcholine Receptor α-Subunit

Schrattenholz¹,

Pfeiffer²,

Pejovic³

et al. 1998

Journal of Biological Chemistry

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The N-terminal extracellular region (amino acids 1-209) of the ␣-subunit of the nicotinic acetylcholine receptor (nAChR) from Torpedo marmorata electric tissue was expressed as inclusion bodies in Escherichia coli using the pET 3a vector. Employing a novel protocol of unfolding and refolding, in the absence of detergent, a water-soluble globular protein of 25 kDa was obtained displaying approximately 15% ␣-helical and 45% ␤-structure. The fragment bound ␣- So far, most of our knowledge on the three-dimensional structure of neuroreceptors is based on a combination of electronmicroscopical, biochemical and immunological data obtained for the nicotinic acetylcholine receptor (nAChR) 1 from the electric ray Torpedo (1, 2). These studies have elucidated the overall dimensions of the receptor protein (3), its position with respect to the surrounding lipid bilayer, the locations of functional domains and amino acid residues belonging to the integral ion channel (4, 5), its gating structures (6, 7), and the binding sites for several classes of ligands (1, 2, 7-12). However, a high resolution three-dimensional structure of the nAChR or any other neuroreceptor is still missing. If available, it could provide a molecular correlate for the recognition function of the receptor and thereby also for rational drug design.Prompted by the fact that all attempts to crystallize the detergent-solubilized whole nAChR protein have been unsuccessful for the past more than 20 years, we have begun to overexpress selected domains of the receptor in bacterial expression systems. If successfully renatured, the domains that are not transmembranous should be water-soluble and thus should provide a better material for protein crystallization than the detergent-solubilized whole receptor protein. Moreover, if small enough in size, such fragments should be suited for multidimensional NMR analysis (13). As presented here for the N-terminal extracellular region of the nAChR ␣-subunit, we attempted and achieved expression as a water-soluble globular protein that displays ligand binding properties comparable to or better than those of the SDS gel-isolated ␣-subunit. To achieve appropriate renaturation, we developed a protocol for the complete unfolding (by means of chaotropic agents and disulfide-reducing agents) and refolding (by means of an oxido shuffling system and L-arginine as structure-stabilizing agent) of the expressed polypeptide (14). The experimental conditions were such that self-organization of the unfolded protein was favored at the expense of (unwanted) aggregation and denaturation. In this way, we are able to prepare large quantities of the functional ligand binding domain from inclusion bodies of transformed Escherichia coli bacteria. Our results confirm that the N-terminal extracellular domain indeed harbors major elements of the ligand recognition function of the nAChR, as has long been suggested on the basis of affinity labeling and immunological studies (for recent reviews, see Refs. 1,2,8,9,15,and 16). EXPERIMENTAL PROCEDURE...

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Section: Discussionmentioning

confidence: 99%

Expression and Renaturation of the N-terminal Extracellular Domain of Torpedo Nicotinic Acetylcholine Receptor α-Subunit

Schrattenholz¹,

Pfeiffer²,

Pejovic³

et al. 1998

Journal of Biological Chemistry

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“…Such excitotoxic effects can be pronounced during acute events such as ischemic stroke and trauma, or milder but prolonged in chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis 76,[80][81][82] . As will be discussed in the second article of this series, glutamatergic dysfunction is also involved in the symptomatology of disorders such schizophrenia, anxiety, and depression 50,74 .…”

Section: Excitotoxicitymentioning

confidence: 99%

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Rousseaux

2008

J Toxicol Pathol

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Seventy years ago it was discovered that glutamate is abundant in the brain and that it plays a central role in brain metabolism. However, it took the scientific community a long time to realize that glutamate also acts as a neurotransmitter. Glutamate is an amino acid and brain tissue contains as much as 5 -15 mM glutamate per kg depending on the region, which is more than of any other amino acid. The main motivation for the ongoing research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning. In this review, the basic biology of the excitatory amino acids glutamate, glutamate receptors, GABA, and glycine will first be explored. In the second part of this review, the known pathophysiology and pathology will be described. (J Toxicol Pathol 2008; 21: 25-51)

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“…Nevertheless, other mechanisms including glutamatemediated excitotoxicity, acidotoxicity, and inflammation are thought to participate in the process of neuronal injury 13 . The role of glutamate excitotoxicity has been demonstrated in focal ischaemic model 14 and several neurodegenerative diseases [15][16][17] . However, further detailed study about glutamate excitotoxicity involvement in chronic cerebral hypoperfusion has yet to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Ceftriaxone improves spatial learning and memory in chronic cerebral hypoperfused rats

Koomhin¹,

Tilokskulchai²,

Tapechum

2012

ScienceAsia

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Cerebral hypoperfusion is associated with cognitive decline in ageing, mild cognitive impairment, vascular type dementia, and Alzheimer's disease. The mechanisms leading to such neurological impairments are still uncertain. Although several mechanisms have been proposed as contributing factors leading to neuronal injury, glutamate excitotoxicity seems to be the relevant one. Recently, it was found that β-lactam antibiotics such as ceftriaxone show a neuroprotective effect by upregulation of glutamate transporter and reduction of glutamate excitotoxicity. To study the contribution of glutamate excitotoxicity and the effects of ceftriaxone on spatial learning and memory in chronic cerebral hypoperfusion, we conducted experiments in rats subjected to permanent bilateral common carotid artery occlusion. Ceftriaxone (200 mg/kg) was injected daily in rats for 5 days after the onset of the arterial ligation. A Morris water maze was used to assess learning and memory two months after arterial ligation. Hippocampal histology and glutamate transporter 1 (GLT-1) expression were also studied. Results showed that ceftriaxone improved learning and memory performance. Consistently, the histological study showed an increase hippocampal CA1 and CA3 neuronal numbers in the ceftriaxone-treated group compared with the vehicle-treated group. Although not statistically significant, the GLT-1 protein level in the hippocampus was 86% higher than the sham group. We conclude that ceftriaxone treatment can attenuate neuronal injury and improve spatial learning and memory after chronic cerebral hypoperfusion and that glutamate excitotoxicity may play an important role in the pathophysiology of chronic cerebral hypoperfusion.

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Glutamate, excitotoxicity and amyotrophic lateral sclerosis

Cited by 275 publications

References 120 publications

Expression and Renaturation of the N-terminal Extracellular Domain of Torpedo Nicotinic Acetylcholine Receptor α-Subunit

Expression and Renaturation of the N-terminal Extracellular Domain of Torpedo Nicotinic Acetylcholine Receptor α-Subunit

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Ceftriaxone improves spatial learning and memory in chronic cerebral hypoperfused rats

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