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

doi:10.1016/j.neuroscience.2008.06.040

Neuroscience

Volume 155, Issue 3, 26 August 2008, Pages 567-572

https://doi.org/10.1016/j.neuroscience.2008.06.040 Get rights and content

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 Y, Liang MH, Ren M, Marinova Z, Leeds P, Chuang DM (2008) Synergistic neuroprotective effects of lithium and valproic acid or other histone deacetylase inhibitors in neurons: roles of glycogen synthase kinase-3 inhibition. 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 (SOD1) G93A mutant mice, a commonly used mouse model of amyotrophic lateral sclerosis (ALS). The G93A ALS mice received twice daily i.p. 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 lifespan 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.

Section snippets

Animals and drug treatments

Transgenic mice carrying high copy numbers of the transgene with the G93A human SOD1 mutation were obtained from the Jackson Laboratory (Bar Harbor, ME, USA). Male SOD1-G93A mice were crossed with B6SJLF1/J hybrid females as previously described (Gurney et al., 1994). All transgenic mice were genotyped by PCR amplification of DNA extracted from the tails to identify the SOD1 mutation. Mice were randomly divided into vehicle, LiCl, VPA, LiCl plus VPA groups, and were matched for littermates.

Results

To assess whether combined treatment with lithium and VPA is superior to treatment with lithium or VPA alone, mutant SOD1-1 G93A ALS mice were twice daily i.p. injected with lithium (60 mg/kg or 1.41 mEq/kg), VPA (300 mg/kg or 1.80 mEq/kg) or lithium (60 mg/kg) plus VPA (300 mg/kg), starting from 30 days after birth and continuing till death. The onset of neurological symptoms was considered as the appearance of a subtle deficit as determined by any single behavioral test, namely, rotarod

Discussion

The present study compared the effects of combined treatment with two mood stabilizers, lithium and VPA, with those of monotreatment with either drug in the SOD1 G93A mouse model of ALS. We showed that combination of lithium and VPA was more consistent than lithium or VPA alone in delaying the onset of motor dysfunction, prolonging survival-time and reducing neurological deficits. Although lithium and VPA have been tested previously in SOD1 transgenic ALS mice, this is the first combinatorial

Acknowledgments

This research was supported by the grant from Natural Science Foundation of China (No. 30470584). The authors wish to thank Nanjing University Animal Model Research Center in China for assistance in the genotyping and breeding of the ALS transgenic mice. We also thank Peter Leeds of the Molecular Neurobiology Section, NIMH, NIH, USA for editorial work.

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

Abstract

Section snippets

Animals and drug treatments

Results

Discussion

Acknowledgments

J Biol Chem

J Biol Chem

Lancet Neurol

Neurosci Biobehav Rev

Biol Psychiatry

VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model

Nature

Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination

Stroke

The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials

Ann N Y Acad Sci

Motor performance in rats exposed to severe forebrain ischemia: effect of fasting and 1,3-butanediol

Stroke

Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury

Science

Microarray analysis of the cellular pathways involved in the adaptation to and progression of motor neuron injury in the SOD1 G93A mouse model of familial ALS

J Neurosci

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