Guanabenz delays the onset of disease symptoms, extends lifespan, improves motor performance and attenuates motor neuron loss in the SOD1 G93A mouse model of amyotrophic lateral sclerosis

• Published in: Neuroscience Vol. 277; pp. 132 - 138
• Main Authors: Jiang, H.-Q., Ren, M., Jiang, H.-Z., Wang, J., Zhang, J., Yin, X., Wang, S.-Y., Qi, Y., Wang, X.-D., Feng, H.-L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 26.09.2014
• Subjects: Age of Onset; ALS; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - pathology; Amyotrophic Lateral Sclerosis - physiopathology; Animals; Caenorhabditis elegans; Cell Death - drug effects; Cell Death - physiology; Danio rerio; Disease Models, Animal; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - physiology; ER stress; Female; guanabenz; Guanabenz - pharmacology; Mice, Transgenic; Mitochondria - drug effects; Mitochondria - pathology; Mitochondria - physiology; Motor Activity - drug effects; Motor Activity - physiology; Motor Neurons - drug effects; Motor Neurons - pathology; Motor Neurons - physiology; Nerve Degeneration - drug therapy; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; neurodegeneration; Neurology; Neuroprotective Agents - pharmacology; P-eIF2α; Random Allocation; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Survival Analysis; Bcl-2; G93A; BiP/Grp78; ALS; neurodegeneration; ER stress; P-eIF2α; PERK; ER; SOD1; eIF2α; NeuN; UPR; IRE1; BAX; CHOP; ATF6; WT; guanabenz; ATF4; phosphorylated-eIF2α; B cell lymphoma/lewkmia-2; amyotrophic lateral sclerosis; inositol-requiring enzyme 1; neuronal nuclei; eukaryotic initiation factor-2α; C/EBP homologous protein; glucose-regulated protein 78; unfolded protein response; Bcl-2-associated X protein; double-stranded RNA-activated protein kinase-like ER kinase; glycine to alanine at position 93; copper zinc superoxide dismutase-1; wild-type; activating transcription factor 6; endoplasmic reticulum; activating transcription factor 4
• ISSN: 0306-4522; 1873-7544; 1873-7544
• DOI: 10.1016/j.neuroscience.2014.03.047

•Guanabenz extended the lifespan of SOD1 G93A mice.•Guanabenz delayed the disease onset of SOD1 G93A mice.•Guanabenz improved motor performance in SOD1 G93A mice.•Guanabenz attenuated motor neuron loss in SOD1 G93A mice.•Guanabenz attenuated ER stress and mitochondrial stress. 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.