Posted - 11/28/2007 : 07:47:49
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Title: Preliminary results on tolerability of lithium salts in amyotrophic lateral sclerosis patients
Location: San Diego Convention Center: Halls B-H
Presentation Start/End Time: Tuesday, Nov 06, 2007, 8:00 AM - 9:00 AM
Authors: A. CARAMELLI1, C. CARLESI1, C. URBANO2, *G. U. CORSINI1;
1Dept. Neurosci, Univ. pisa, Pisa, Italy; 2Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
Previous data from our Department indicated that lithium is able to reverse the neurological damage induced by vinca alkaloids in rodents and humans as well (J.N.T. 1999, 106, 569). Afterward the neuroprotective effects of lithium have been largely demonstrated in in vitro and in vivo models by several Authors. Recently, in an animal model of amyotrophic lateral sclerosis (ALS), Gwag et al. reported substantial increase in motoneuron survival, improvement of motor skill and reduction of lethality by the lithium salt administration (Mol. Pharmacol. 71:965-975, 2007). On this basis, a spontaneous open study on the effectiveness of lithium carbonate in ALS patients has been undertaken. Until now four patients with the diagnosis of ALS according to EL Escorial revised criteria have been treated with lithium carbonate (Carbolithium CR tablets) at increasing dose regimen with constant lithium plasma level monitoring. The patients were at different stages of the disease, from mild to moderate, and lithium was added to the previous therapy consisting mainly in riluzole (1 tablet twice a day) after accurate evaluations for exclusion criteria. Lithium plasma levels were always under 0.5 mEq/l in all patients because of the several lithium-related side effects. Polyuria, polydipsia and drowsiness were early present in all patients. Slurred speech, tremor and diarrea were observed in one patient. All the side effects were dose-related and ceased when lithium therapy was temporarily discontinued.
This preliminary observation which cannot suggest up to now any neuroprotective effect of lithium on the degenerative progression, indicates nevertheless the low tolerability of ALS patients to lithium therapy. This may be due to the disease itself or to drug interactions with current therapy.
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Edited by - Dan on 11/28/2007 08:30:17
Posted - 11/28/2007 : 07:55:27
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Title: Neuroprotection by lithium following kainate-mediated excitotoxicity of transgenic-Cu/Zn SOD1 motor neurons
Location: San Diego Convention Center: Halls B-H
Presentation Start/End Time: Monday, Nov 05, 2007, 4:00 PM - 5:00 PM
Authors: P. LONGONE1, A. SPALLONI1, P. LENZI2, *F. E. FORNAI2;
1Mol. Neurobiology Unit, Santa Lucia Fndn., Rome, Italy; 2Dept Human Morphology & Applied Biol, Univ. Pisa, Pisa 55100, Italy
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a loss of motor neurons in the spinal cord, brain stem and cerebral cortex. Familial ALS contributes to 5-10% of ALS cases. There is evidence that mutations in the Cu/Zn superoxide dismutase (SOD1) gene are implicated in 20% of familial ALS and transgenic mice overexpressing the human SOD1 mutation (G93A) show an ALS-like phenotype consisting of progressive weakness and muscle atrophy preceding motor impairment. To date, mechanisms by which ALS triggers neuronal injury include excitotoxicity, mitochondrial dysfunction, oxidative damage, protein misfolding and aggregation, neurofilament disorganization and inflammatory changes. In fact, a unifying hypothesis accounting for the selective motor neuron degeneration is still lacking.
In addition to the well-documented mood-stabilizing effects of lithium in manic-depressive illness patients, recent in vitro and in vivo studies in rodents and humans have increasingly implicated that lithium can be used in the treatment of acute brain injuries (e.g., ischemia) and chronic neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, tauopathies, and Huntington's disease).
Here we show that lithium is protective in primary culture of G93A motor neurons against excitotoxicity. A pretreatment with lithium (20 min) completely prevents the G93A motor neurons death induced by Kainate (100 uM, 15 min). The molecular mechanisms beneath lithium protection and the possible therapeutic role of lithium in ALS will be discussed
renzo
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Title: Preliminary results on tolerability of lithium salts in amyotrophic lateral sclerosis patients
Location: San Diego Convention Center: Halls B-H
Presentation Start/End Time: Tuesday, Nov 06, 2007, 8:00 AM - 9:00 AM
Authors: A. CARAMELLI1, C. CARLESI1, C. URBANO2, *G. U. CORSINI1;
1Dept. Neurosci, Univ. pisa, Pisa, Italy; 2Azienda Ospedaliera Universitaria Pisana, Pisa, Italy
Previous data from our Department indicated that lithium is able to reverse the neurological damage induced by vinca alkaloids in rodents and humans as well (J.N.T. 1999, 106, 569). Afterward the neuroprotective effects of lithium have been largely demonstrated in in vitro and in vivo models by several Authors. Recently, in an animal model of amyotrophic lateral sclerosis (ALS), Gwag et al. reported substantial increase in motoneuron survival, improvement of motor skill and reduction of lethality by the lithium salt administration (Mol. Pharmacol. 71:965-975, 2007). On this basis, a spontaneous open study on the effectiveness of lithium carbonate in ALS patients has been undertaken. Until now four patients with the diagnosis of ALS according to EL Escorial revised criteria have been treated with lithium carbonate (Carbolithium CR tablets) at increasing dose regimen with constant lithium plasma level monitoring. The patients were at different stages of the disease, from mild to moderate, and lithium was added to the previous therapy consisting mainly in riluzole (1 tablet twice a day) after accurate evaluations for exclusion criteria. Lithium plasma levels were always under 0.5 mEq/l in all patients because of the several lithium-related side effects. Polyuria, polydipsia and drowsiness were early present in all patients. Slurred speech, tremor and diarrea were observed in one patient. All the side effects were dose-related and ceased when lithium therapy was temporarily discontinued.
This preliminary observation which cannot suggest up to now any neuroprotective effect of lithium on the degenerative progression, indicates nevertheless the low tolerability of ALS patients to lithium therapy. This may be due to the disease itself or to drug interactions with current therapy.
--------------------------------------------------------------------------------
Edited by - Dan on 11/28/2007 08:30:17
Posted - 11/28/2007 : 07:55:27
--------------------------------------------------------------------------------
Title: Neuroprotection by lithium following kainate-mediated excitotoxicity of transgenic-Cu/Zn SOD1 motor neurons
Location: San Diego Convention Center: Halls B-H
Presentation Start/End Time: Monday, Nov 05, 2007, 4:00 PM - 5:00 PM
Authors: P. LONGONE1, A. SPALLONI1, P. LENZI2, *F. E. FORNAI2;
1Mol. Neurobiology Unit, Santa Lucia Fndn., Rome, Italy; 2Dept Human Morphology & Applied Biol, Univ. Pisa, Pisa 55100, Italy
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by a loss of motor neurons in the spinal cord, brain stem and cerebral cortex. Familial ALS contributes to 5-10% of ALS cases. There is evidence that mutations in the Cu/Zn superoxide dismutase (SOD1) gene are implicated in 20% of familial ALS and transgenic mice overexpressing the human SOD1 mutation (G93A) show an ALS-like phenotype consisting of progressive weakness and muscle atrophy preceding motor impairment. To date, mechanisms by which ALS triggers neuronal injury include excitotoxicity, mitochondrial dysfunction, oxidative damage, protein misfolding and aggregation, neurofilament disorganization and inflammatory changes. In fact, a unifying hypothesis accounting for the selective motor neuron degeneration is still lacking.
In addition to the well-documented mood-stabilizing effects of lithium in manic-depressive illness patients, recent in vitro and in vivo studies in rodents and humans have increasingly implicated that lithium can be used in the treatment of acute brain injuries (e.g., ischemia) and chronic neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, tauopathies, and Huntington's disease).
Here we show that lithium is protective in primary culture of G93A motor neurons against excitotoxicity. A pretreatment with lithium (20 min) completely prevents the G93A motor neurons death induced by Kainate (100 uM, 15 min). The molecular mechanisms beneath lithium protection and the possible therapeutic role of lithium in ALS will be discussed
renzo
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