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Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis

Published:March 25, 2014DOI:https://doi.org/10.1016/j.jns.2014.03.005

      Highlights

      • We recorded the functional evolution in patients with definite sporadic ALS.
      • Patients included received dual treatment with lithium carbonate and valproate.
      • Survival in patients under the co-treatment was significantly increased.
      • Antioxidant defenses were improved and correlated with lithium levels.
      • Later adverse effects were the main cause of dropping out from the study.

      Abstract

      The aim of this study was to evaluate the ability of lithium carbonate and valproate cotreatment to modify the survival rate and functional score of patients with definite sporadic amyotrophic lateral sclerosis (ALS). The clinical response of 18 enrolled patients was compared to the evolution of 31 ALS out-patients, carefully paired by age, gender, evolution rate and time of the disease, who never received treatment with lithium and/or valproate. The ALS functional rating scale, revised version (ALSFRS-R), was applied at baseline, 1 month, and every 4 months until the outcome (death or an adverse event). Biochemical markers, such as Cu/Zn superoxide dismutase and glutathione peroxidase activity, and reduced glutathione were assayed in plasma samples obtained at the baseline visit and after 5 and 9 months of treatment. Our results showed that lithium and valproate cotreatment significantly increased survival (p = 0.016), and this treatment also exerted neuroprotection in our patients because all three markers reached levels that were not significantly different from the matched samples of healthy donors. The trial stopped after 21 months, when the sample was reduced to under two-thirds, due to the late adverse events of the treatment. The results call for large randomized clinical trials with the dual association, but at low doses to avoid adverse events.

      Keywords

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      References

        • Aggarwal S.P.
        • Zinman L.
        • Simpson E.
        • McKinley J.
        • Jackson K.E.
        • Pinto H.
        • et al.
        Efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial.
        Lancet Neurol. 2010; 9: 481-488https://doi.org/10.1016/S1474-4422(10)70068-5
        • Babu G.N.
        • Kumar A.
        • Chandra R.
        • Puri S.K.
        • Singh R.L.
        • Kalita J.
        • et al.
        Oxidant-antioxidant imbalance in the erythrocytes of sporadic amyotrophic lateral sclerosis patients correlates with the progression of disease.
        Neurochem Int. 2008; 52: 1284-1289https://doi.org/10.1016/j.neuint.2008.01.009
        • Bensimon G.
        • Lacomblez L.
        • Meininger V.
        Controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group.
        N Engl J Med. 1994; 330: 585-591
        • Boll M.C.
        • Alcaraz-Zubeldia M.
        • Montes S.
        • Murillo-Bonilla L.
        • Ríos C.
        Raised nitrate concentration and low SOD activity in the CSF of sporadic ALS patients.
        Neurochem Res. 2003; 28: 705-709
        • Brockington A.
        • Ning K.
        • Heath P.R.
        • Wood E.
        • Kirby J.
        • Fusi N.
        • et al.
        Unraveling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity.
        Acta Neuropathol. 2013; 125: 95-109https://doi.org/10.1007/s00401-012-1058-5
        • Brooks B.R.
        • Miller R.G.
        • Swash M.
        • Munsat T.L.
        • World Federation of Neurology Research Group on Motor Neuron Diseases
        El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis.
        Amyotroph Lateral Scler Other Motor Neuron Disord. 2000; 1: 293-299
        • Calderó J.
        • Brunet N.
        • Tarabal O.
        • Piedrafita L.
        • Hereu M.
        • Ayala V.
        • et al.
        Lithium prevents excitotoxic cell death of motoneurons in organotypic slice cultures of spinal cord.
        Neuroscience. 2010; 165: 1353-1369https://doi.org/10.1016/j.neuroscience.2009.11.034
        • Cedarbaum J.M.
        • Stambler N.
        • Malta E.
        • Fuller C.
        • Hilt D.
        • Thurmond B.
        • et al.
        The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS study group (Phase III).
        J Neurol Sci. 1999; 169: 13-21
        • Chi L.
        • Ke Y.
        • Luo Ch.
        • Gozal D.
        • Liu R.
        Depletion of reduced glutathione enhances motor neuron degeneration in vitro and in vivo.
        Neuroscience. 2007; 144: 991-1003
        • Corcia P.
        • Tauber C.
        • Vercoullie J.
        • Arlicot N.
        • Prunier C.
        • Praline J.
        • et al.
        Molecular imaging of microglial activation in amyotrophic lateral sclerosis.
        Plos One. 2012; 7: 52941ehttps://doi.org/10.1371/journal.pone.0052941
        • Díaz-Ruiz A.
        • Alcaraz-Zubeldia M.
        • Maldonado V.
        • Salgado-Ceballos H.
        • Mendez-Armenta M.
        • Ríos C.
        Differential time-course of the increase of antioxidant thiol-defenses in the acute phase after spinal cord injury in rats.
        Neurosci Lett. 2009; 452: 56-59https://doi.org/10.1016/j.neulet.2009.01.020
        • Feng H.L.
        • Leng Y.
        • Ma C.H.
        • Zhang J.
        • Ren M.
        • Chuang D.M.
        Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model.
        Neuroscience. 2008; 155: 567-572https://doi.org/10.1016/j.neuroscience.2008.06.040
        • Fornai F.
        • Longone P.
        • Cafaro L.
        • Kastsiuchenka O.
        • Ferrucci M.
        • Manca M.L.
        • et al.
        Lithium delays progression of amyotrophic lateral sclerosis.
        Proc Natl Acad Sci U S A. 2008; 105: 2052-2057https://doi.org/10.1073/pnas.0708022105
        • Galicia-García V.
        • Rojas-López M.
        • Rojas R.
        • Olaiz G.
        • Ríos C.
        Cadmium levels in maternal, cord and newborn blood in Mexico City.
        Toxicol Lett. 1997; 91: 57-61
        • Gordon P.H.
        • Cheng B.
        • Salachas F.
        • Pradat P.F.
        • Bruneteau G.
        • Corcia P.
        • et al.
        Progression in ALS is not linear but is curvilinear.
        J Neurol. 2010; 257: 1713-1717https://doi.org/10.1007/s00415-010-5609-1
        • Hafeman D.G.
        • Sunde R.A.
        • Hoekstra W.G.
        Effect of dietary selenium on erythrocyte and liver glutathione peroxidase in the rat.
        J Nutr. 1974; 104: 580-587
        • Hu M.L.
        Measurement of protein thiol groups and glutathione in plasma.
        Methods Enzymol. 1994; 233: 380-385
        • Kabashi E.
        • Durham H.D.
        Failure of protein quality control in amyotrophic lateral sclerosis.
        Biochim Biophys Acta. 2006; 1762: 1038-1050
        • Kimura F.
        • Fujimura C.
        • Ishida S.
        • Nakajima H.
        • Furutama D.
        • Uehara H.
        • et al.
        Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS.
        Neurology. 2006; 66: 265-267
        • Lacomblez L.
        • Bensimon G.
        • Leigh P.N.
        • Guillet P.
        • Powe L.
        • Durrleman S.
        • et al.
        A confirmatory dose-ranging study of riluzole in ALS. ALS/Riluzole Study Group-II.
        Neurology. 1996; 47: S242-S250
        • Leng Y.
        • Liang M.H.
        • Ren M.
        • Marinova Z.
        • Leeds P.
        • Chuang D.M.
        Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition.
        J Neurosci. 2008; 28: 2576-2588https://doi.org/10.1523/JNEUROSCI.5467-07.2008
        • Lowry O.H.
        • Rosebrough N.J.
        • Farr A.L.
        • Randall R.J.
        Protein measurement with the folin-phenol reagent.
        J Biol Chem. 1951; 193: 265-275
        • Miller R.G.
        • Moore D.H.
        • Forshew D.A.
        • Katz J.S.
        • Barohn R.J.
        • Valan M.D.
        • et al.
        Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis Examining a more efficient trial design.
        Neurology. 2011; 77: 973-979https://doi.org/10.1212/WNL.0b013e31822dc7a5
        • Murata T.
        • Ohtsuka C.
        • Terayama Y.
        Increased mitochondrial oxidative damage in patients with sporadic amyotrophic lateral sclerosis.
        J Neurol Sci. 2008; 267: 66-69
        • Piepers S.
        • Veldink J.H.
        • de Jong S.W.
        • van der Tweel I.
        • van der Pol W.L.
        • Uijtendaal E.V.
        • et al.
        Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis.
        Ann Neurol. 2009; 66: 227-234https://doi.org/10.1002/ana.21620
        • Romieu I.
        • García-Esteban R.
        • Sunyer J.
        • Rios C.
        • Alcaraz-Zubeldia M.
        • Nadif R.
        • et al.
        The effect of supplementation with omega-3 fatty acids on markers of oxidative stress in elderly exposed to PM2.5. Environ.
        Health Perspect. 2008; 116: 1237-1242https://doi.org/10.1289/ehp.10578
        • Rubinsztein D.C.
        • Gestwicki J.E.
        • Murphy L.O.
        • Klionsky D.J.
        Potential therapeutic applications of autophagy.
        Nat Rev Drug Discov. 2007; 6: 304-312
        • Sasaki S.
        • Iwata M.
        Impairment of fast axonal transport in the proximal axons of anterior horn neurons in amyotrophic lateral sclerosis.
        Neurology. 1996; 47: 535-540
        • Siciliano G.
        • D'Avino C.
        • Del Corona A.
        • Barsacchi R.
        • Kusmic C.
        • Rocchi A.
        • et al.
        Impaired oxidative metabolism and lipid peroxidation in exercising muscle from ALS patients.
        Amyotroph Lateral Scler Other Motor Neuron Disord. 2002; 3: 57-62
        • Suwazono Y.
        • Akesson A.
        • Alfven T.
        • Jarup L.
        • Vahter M.
        Creatinine versus specific gravity-adjusted urinary cadmium concentrations.
        Biomarkers. 2005; 10: 117-126
        • Wang I.F.
        • Guo B.S.
        • Liu Y.C.
        • Wu C.C.
        • Yang C.H.
        • Tsai K.J.
        • et al.
        Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43.
        Proc Natl Acad Sci U S A. 2012; 109: 15024-15029https://doi.org/10.1073/pnas.1206362109
        • Krakora D.
        • Mulcrone P.
        • Meyer M.
        • Lewis C.
        • Bernau K.
        • Gowing G.
        • Zimprich C.
        • Aebischer P.
        • Svendsen C.N.
        • Suzuki M.
        Synergistic effects of GDNF and VEGF on lifespan and disease progression in a familial ALS rat model.
        Mol. Ther. 2013; 21: 1602-1610https://doi.org/10.1038/mt.2013.108