Chronic elevation of extracellular glutamate due to transport blockade is innocuous for spinal motoneurons in vivo

• Published in: Neurochemistry international 2009-03, Vol.54 (3), p.186-191
• Main Authors: Tovar-y-Romo, Luis B., Santa-Cruz, Luz Diana, Zepeda, Angélica, Tapia, Ricardo
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - metabolism; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Aspartic Acid - pharmacology; Biological and medical sciences; Carboxylic Acids - pharmacology; Cell Death - drug effects; Cell Death - physiology; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Drug Administration Schedule; Extracellular Fluid - drug effects; Extracellular Fluid - metabolism; Fundamental and applied biological sciences. Psychology; Gliosis - chemically induced; Gliosis - metabolism; Gliosis - pathology; Glutamate transport; Glutamic Acid - metabolism; Infusion Pumps, Implantable; Male; Medical sciences; Microdialysis; Motoneurons; Motor Neurons - drug effects; Motor Neurons - metabolism; Movement Disorders - metabolism; Movement Disorders - physiopathology; Nerve Degeneration - chemically induced; Nerve Degeneration - metabolism; Nerve Degeneration - physiopathology; Neurology; Pyridines - pharmacology; Rats; Rats, Wistar; Spinal cord; Spinal Cord - drug effects; Spinal Cord - metabolism; Spinal Cord - physiopathology; Up-Regulation - drug effects; Up-Regulation - physiology; Vertebrates: nervous system and sense organs; Vesicular Glutamate Transport Proteins - antagonists & inhibitors; Vesicular Glutamate Transport Proteins - deficiency
• ISSN: 0197-0186; 1872-9754
• DOI: 10.1016/j.neuint.2008.09.015

Glutamate-mediated excitotoxicity has been considered to play an important role in the mechanism of spinal motoneuron death in amyotrophic lateral sclerosis (ALS), and some reports suggest that this excitotoxicity may be due to a decreased glutamate transport and the consequent elevation of its extracellular level. We have previously shown that short lasting increments in extracellular glutamate due to administration of the non-selective glutamate transport blocker l-2,4-trans-pyrrolidine-dicarboxylate (PDC) by microdialysis in the rat spinal cord do not induce motoneuron damage. In the present work we examined the potential involvement of chronic glutamate transport blockade as a causative factor of spinal motoneuron death and paralysis in vivo. Using osmotic minipumps, we infused directly in the spinal cord for up to 10 days PDC and another glutamate transport blocker, dl-threo-β-benzyloxyaspartate (TBOA), and we measured by means of microdialysis and HPLC the extracellular concentration of glutamate and other amino acids. We found that after the infusion of both PDC and TBOA the concentration of endogenous extracellular glutamate was 3–4-fold higher than that of the controls. Nevertheless, in spite of this elevation no motoneuron degeneration or gliosis were observed, assessed by histological examination and choline acetyltransferase and glial fibrillary acidic protein immunocytochemistry. In accord with this lack of toxic effect, no motor deficits, assessed by three motor activity tests, were observed. Because we had previously shown that under identical experimental conditions the infusion of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) induced progressive motoneuron death and paralysis, we conclude that prolonged elevation of extracellular glutamate due to its transport blockade in vivo is innocuous for spinal motoneurons and therefore that these results do not support the hypothesis that glutamate transport deficiency plays a crucial role as a causal factor of spinal motoneuron degeneration in ALS.