Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive
neurodegenerative disease characterized by the loss of motor neurons in the motor cortex, brain stem and spinal cord. Currently, there is no cure for this lethal disease. Although the mechanism underlying neuronal cell death in ALS remains elusive, growing evidence supports a crucial role of endoplasmic reticulum (ER) stress in the pathogenesis of ALS. Recent reports show that
guanabenz, a novel inhibitor of eukaryotic
initiation factor 2α (eIF2α) dephosphorylation, possesses anti-
prion properties, attenuates ER stress and reduces
paralysis and neurodegeneration in mTDP-43 Caenorhabditis elegans and Danio rerio models of ALS. However, the therapeutic potential of
guanabenz for the treatment of ALS has not yet been assessed in a mouse model of ALS. In the present study,
guanabenz was administered to a widely used mouse model of ALS expressing
copper zinc superoxide dismutase-1 (SOD1) with a
glycine to
alanine mutation at position 93 (G93A). The results showed that the administration of
guanabenz significantly extended the lifespan, delayed the onset of disease symptoms, improved motor performance and attenuated motor neuron loss in female SOD1 G93A mice. Moreover, western blotting results revealed that
guanabenz dramatically increased the levels of phosphorylated-eIF2α (P-eIF2α)
protein, without affecting total eIF2α
protein levels. The results also revealed a significant decrease in the levels of the ER chaperone
glucose-regulated
protein 78 (BiP/
Grp78) and markers of another two ER stress pathways, activating
transcription factor 6α (ATF6α) and
inositol-requiring
enzyme 1 (IRE1). In addition,
guanabenz increased the
protein levels of anti-apoptotic
B cell lymphoma/lewkmia-2 (Bcl-2), and down-regulated the
pro-apoptotic protein levels of
C/EBP homologous protein (CHOP),
Bcl-2-associated X protein (BAX) and
cytochrome C in SOD1 G93A mice. Our findings indicate that
guanabenz may represent a novel therapeutic candidate for the treatment of ALS, a lethal human disease with an underlying mechanism involving the attenuation of ER stress and mitochondrial stress via prolonging eIF2α phosphorylation.