Altered in-vitro and in-vivo expression of glial glutamate transporter-1 following exposure to cerebrospinal fluid of amyotrophic lateral sclerosis patients

The Neuroprotection Exerted by Memantine, Minocycline and Lithium, against Neurotoxicity of CSF from Patients with Amyotrophic Lateral Sclerosis, Is Antagonized by Riluzole

“…This observation corroborates recent [29] and earlier findings [21,22,23,24,25,26,27] on the neurotoxicity elicited by ALS/CSF on neuronal cultures as well as after its in vivo intracerebroventricular or intrathecal administration [39,40,41]. …”

Oxidative and excitotoxic insults exert differential effects on spinal motoneurons and astrocytic glutamate transporters: Implications for the role of astrogliosis in amyotrophic lateral sclerosis

“…Both the oxidative and excitotoxic treatments mediated changes in astrocytic phenotype, which were much more prominent following oxidative insult, typical of reactive astrocytes (Pekny and Nilsson, 2005), and likely to improve handling of extracellular Glu (Escartin et al, 2006). The early maintenance of Glu uptake after SIN-1 treatment was not due to either altered overall or cell surface expression of EAAT1/2, indicating astrocytes possess mechanisms to preserve net EAAT activity, and which here was accomplished by a kinetic compensation (increased K m despite decreased V max ) normalizing transport for 2 h. Given the changes in astrocytic phenotype and EAAT distribution, and evidence that GFAP modulates EAAT function and is co-localized with EAAT2 (Hughes et al, 2004;Shobha et al, 2007;Zhou and Sutherland, 2004), the early increase in GFAP may be involved in the initial maintenance of Glu transport in the face of oxidative stressors. In the context of GFAP-EAAT2 interactions, this relationship may be relevant to the progression of ALS (Boillee et al, 2006) as the increase in GFAP immunoreactivity continued for 8 h and may represent a homeostatic response, which was unable to prevent the major loss of EAAT2.…”

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

“…Evidence supporting the MNLS model includes: (1) the concentration of serum lactic acid is higher in persons with ALS (2.77 Ϯ 0.79 mmol/L) and chronic denervated non-ALS patients (2.79 Ϯ 1.29 mmol/L) compared with controls (1.48 Ϯ 0.49 mmol/L) (Siciliano et al, 2001); (2) lactic acid can induce death in neurons (Nedergaard et al, 1991); (3) increased lactate concentrations have been reported in other neurodegenerative conditions such as Huntington disease (Bowling and Beal, 1995) as well as in models of severe and mild brain injury (Ramonet et al, 2004); (4) neuroprotective drugs like nizofenone that block lactate accumulation are used to treat other neurodegenerative diseases ; (5) lactate metabolism in ALS is associated with glutamate excitotoxicity related to neuronal degeneration (Shobha et al, 2007); (6) mitochondrial oxidative phosphorylation is dysfunctional in SOD1 G93A transgenic mice (Jung et al, 2002;Mattiazzi et al, 2002;Vijayvergiya et al, 2005); (7) the malate-aspartate shuttle is inhibited in hSOD1 G93A expressing cells (Mali and Zisapels, 2008) and this may explain the elevated levels of lactate and the damage to neurons (Mali and Zisapels, 2008); (8) hSOD1 G93A -expressing cells showed increased concentrations of cytoplasmic malate dehydrogenase messenger ribonucleic acid (mRNA), malate, and lactate compared with noninduced or wild-type-hSOD1-expressing cells (Mali and Zisapels, 2008); (9) the mitochondrial NADH/NADϩ ratio is elevated in hSOD1 G93A -expressing cells indicating an increased conversion of oxaloacetate to malate in the mitochondria by NADH-dependent mitochondrial malate dehydrogenase MDH (Mali and Zisapels, 2008); (10) impairments in the malate-aspartate shuttle which controls the brain mitochondrial NADH/NAD ϩ balance is known to drive anaerobic metabolism (particularly damaging to neurons) as well as vulnerability to impairments of glycolytic pathways (Mali and Zisapels, 2008); (11) impaired oxidative metabolism and accumulation of lactate was reported in exercising ALS patients (Siciliano et al, 2001);and (12) functional motor unit failure precedes neuromuscular degeneration in motoneuron disease (Balice- Gordon et al, 2000;Fischer et al, 2004).…”

“…The exposure of SALS-serum to rat motoneurons increases their LDH activity and depletes the glutamate transporter GLT-1 and the cells subsequently die presumably due to increased levels of glutamate triggering glutamate-mediated toxicity (Shobha et al, 2007;Vijayalakshmi et al, 2009). Interestingly, this observation ties glutamate toxicity to lactate levels.…”