Clinical and biological changes under treatment with lithium carbonate and valproic acid in sporadic amyotrophic lateral sclerosis Marie-Catherine Boll a,c , Leo Bayliss a , Steven Vargas-Cañas c , Jorge Burgos d , Sergio Montes b , Guillermo Peñaloza-Solano b , Camilo Rios b , Mireya Alcaraz-Zubeldia b, ⁎ a Clinical Investigation Laboratory, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, México, D.F., México b Department of Neurochemistry, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, México, D.F., México c Nerve and Muscle Clinic, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, México, D.F., México d Department of Neurophysiology, Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, México, D.F., México abstract article info Article history: Received 1 October 2013 Received in revised form 12 February 2014 Accepted 3 March 2014 Available online 11 March 2014 Keywords: Amyotrophic lateral sclerosis Valproic acid Lithium carbonate Superoxide dismutase 1 Glutathione peroxidase ALSFRS-R 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 clin- ical 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 dismut- ase 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 be- cause 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 ad- verse events of the treatment. The results call for large randomized clinical trials with the dual association, but at low doses to avoid adverse events. © 2014 Elsevier B.V. All rights reserved. 1. Introduction Sporadic amyotrophic lateral sclerosis (SALS) is considered to be a multifactorial and fatal neurodegenerative disease. Among the main mechanisms involved in the etiology of ALS, calcium-induced excitotoxicity [5], axon transport impairment [28], neuroinflammation [10], a deficit of neurotrophic factors [32], protein aggregation [18] and oxidative stress [24,29] have been implicated. ALS has also been associated with an overproduction of the superoxide anion and a decreased content of reduced glutathione (GSH; [2,9]). Therapeutic options against ALS are very limited, and riluzole, which possesses an inhibitory effect on glutamate release and a neuroprotec- tive effect against excitotoxic damage, has been confirmed to extend the survival of ALS patients in the early stages of the disease or to extend the time until a tracheostomy is needed [3,20]. Lithium (Li) administration to SOD1 mutant mice G93A has been re- ported to increase life span, accompanied by enhanced autophagy and an increased number of mitochondria and Lamina VII motor neurons [13]. Protection against glutamate excitotoxicity in cultured brain neurons was potentiated by a higher inhibition of GSK-3β when lithium and valproic acid (VPA) were used in combination [21]. Moreover, co- treatment with lithium and valproic acid (Li + VPA) was more effective than lithium or VPA alone by enhancing the immunostaining of phos- phorylated GSK-3β Ser9 in brain and lumbar spinal cord sections from SOD1 G93A mutant mice that showed the same synergistic effect in vivo [12]. Based on the known safety profile of both drugs, we decided to treat ALS patients with lithium carbonate and valproic acid co- treatment. The oxidative response of patients was also recorded to evalu- ate the ability of Li + VPA to improve the oxidative status of ALS patients. 2. Materials and methods 2.1. Participants After a review of 98 files from patients with motor neuron disease attending the Nerve and Muscle Clinic at our Institute during the last 3 years, 67 cases had definite ALS, according to the El Escorial clinical Journal of the Neurological Sciences 340 (2014) 103–108 ⁎ Corresponding author at: Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Ave. Insurgentes Sur # 3877, Col. La Fama, Del. Tlalpan, C.P. 14269, México, D. F., México. Tel.: +52 5556063822x2005; fax: +52 5554240808. E-mail addresses: bollneur@gmail.com (M.-C. Boll), leobayliss@gmail.com (L. Bayliss), stevenvc@hotmail.com (S. Vargas-Cañas), burgosneurofisio@yahoo.com.mx (J. Burgos), sergiomontes@hotmail.com (S. Montes), dammerung.traume@gmail.com (G. Peñaloza-Solano), crios@correo.xoc.uam.mx (C. Rios), miyealcaraz@yahoo.com (M. Alcaraz-Zubeldia). http://dx.doi.org/10.1016/j.jns.2014.03.005 0022-510X/© 2014 Elsevier B.V. All rights reserved. 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