Combined lithium and valproate treatment delays disease onset, reduces neurological deficits and prolongs survival in an amyotrophic lateral sclerosis mouse model

Abstract

Lithium and valproic acid (VPA) are two primary drugs used to treat bipolar disorder, and have been shown to have neuroprotective properties in vivo and in vitro. A recent study demonstrated that combined treatment with lithium and VPA elicits synergistic neuroprotective effects against glutamate excitotoxicity in cultured brain neurons, and the synergy involves potentiated inhibition of glycogen synthase kinase-3 (GSK-3) activity through enhanced GSK-3 serine phosphorylation (Leng et al., J Neurosci 28: 2576-2588. We therefore investigated the effects of lithium and VPA cotreatment on the disease symptom onset, survival time and neurological deficits in cooper zinc superoxide dismutase (SOD-1) G93A mutant mice, a commonly used mouse model of amyotrophic lateral sclerosis (ALS). The G93A ALS mice received twice daily intraperitoneal injections with LiCl (60 mg/kg), VPA (300 mg/kg) or lithium plus VPA, starting from the 30 th day after birth and continuing until death. We found that combined treatment with lithium and VPA produced a greater and more consistent effect in delaying the onset of disease symptoms, prolonging the life span and decreasing the neurological deficit scores, compared with the results of monotreatment with lithium or VPA. Moreover, lithium in conjunction with VPA was more effective than lithium or VPA alone in enhancing the immunostaining of phospho-GSK-3β Ser9 in brain and lumbar spinal cord sections. To our knowledge, this is the first demonstration of enhanced neuroprotection by a combinatorial approach using mood stabilizers in a mouse ALS model. Our results suggest that clinical trials using lithium and VPA in combination for ALS patients are a rational strategy.

GSK-3β : une kinase au cœur des maladies neuro-dégénératives ?

“…Dans un modèle murin de SLA, l'activité neuronale de la GSK-3 est augmentée, et l'inhibition de son activité empêche la mort cellulaire. De plus, l'inhibition de la GSK-3 par un traitement combiné de valproate et de lithium retarde l'apparition des symptômes, freine la progression de la maladie et prolonge l'espérance de vie de souris transgéniques modèles de la maladie [37].…”

Protective effect of valproic acid on cultured motor neurons under glutamate excitotoxic conditions. Ultrastructural study

“…Its therapeutic potential has been documented in various cellular and animal models of neurologic, neurodegenerative, and neuropsychiatric disorders [7]. Combined treatment with lithium and VPA delays onset of clinical symptoms, reduces neurological deficits and prolongs survival in the SOD1 mouse model of amyotrophic lateral sclerosis [11]. Co-treatment of cerebellar granular cell cultures with lithium and VPA induced synergistic neuroprotective effects against glutamate excitotoxicity in a time-dependent manner [24].…”

Synergistic Increase of BDNF Release from Rat Primary Cortical Neuron by Combination of Several Medicinal Plant-Derived Compounds

“…In ischemic stroke, it has been suggested that the combined use of a gamma-aminobutyric acid (GABA) agonist and a glutamate antagonist provides synergistic neuroprotective effect (Lyden et al, 2000). Similarly, the combined use of the drugs used in bipolar disorder such as valproic acid and lithium showed neuroprotective effects both in vivo and in vitro (Feng et al, 2008). Likewise, synergistic action of combined treatment of several neurotrophin family members together on spinal cord injury (Novikova et al, 2000) and combination of N-methyl D-aspartate (NMDA) and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor antagonists on acute ischemic injury have been reported .…”