Sodium valproate exerts neuroprotective effects in vivo through CREB-binding protein-dependent mechanisms but does not improve survival in an amyotrophic lateral sclerosis mouse model.
Amyotrophic lateral sclerosis (ALS) is characterized by motoneuron (MN) degeneration, generalized weakness, and muscle atrophy. The premature death of MNs is thought to be a determinant in the onset of this disease. In a transgenic mouse model of ALS expressing the G86R mutant superoxide dismutase 1 (mSOD1), we demonstrated previously that CREB (cAMP response element-binding protein)-binding protein (CBP) and histone acetylation levels were specifically decreased in nuclei of degenerating MNs. We show here that oxidative stress and mSOD1 overexpression can both impinge on CBP levels by transcriptional repression, in an MN-derived cell line. Histone deacetylase inhibitor (HDACi) treatment was able to reset proper acetylation levels and displayed an efficient neuroprotective capacity against oxidative stress in vitro. Interestingly, HDACi also upregulated CBP transcriptional expression in MNs. Moreover, when injected to G86R mice in vivo, the HDACi sodium valproate (VPA) maintained normal acetylation levels in the spinal cord, efficiently restored CBP levels in MNs, and significantly prevented MN death in these animals. However, despite neuroprotection, mean survival of treated animals was not significantly improved (<5%), and they died presenting the classical ALS symptoms. VPA was not able to prevent disruption of neuromuscular junctions, although it slightly delayed the onset of motor decline and retarded muscular atrophy to some extent. Together, these data show that neuroprotection can improve disease onset, but clearly provide evidence that one can uncouple MN survival from whole-animal survival and point to the neuromuscular junction perturbation as a primary event of ALS onset.
Rouaux
Caroline
C
Institut National de la Santé et de la Recherche Médicale, U692, Laboratoire de Signalisations Moléculaires et Neurodégénérescence, Strasbourg F-67085, France.
Panteleeva
Irina
I
René
Frédérique
F
Gonzalez de Aguilar
Jose-Luis
JL
Echaniz-Laguna
Andoni
A
Dupuis
Luc
L
Menger
Yannick
Y
Boutillier
Anne-Laurence
AL
Loeffler
Jean-Philippe
JP
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D000818:Animals; D050882:CREB-Binding Protein / Q000502:physiology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D015996:Survival Rate; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use*
D018696:Neuroprotective Agents; D014635:Valproic Acid; D050882:CREB-Binding Protein; C494363:CREBBP protein, human