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

New Zebrafish Models of Neurodegeneration

“…Three agents (salubrinal, guanabenz and phenazine) were found to rescue paralysis, neurodegeneration and oxidative stress, albeit through different parts of the ER stress pathway (Figure 1 D) [26]. These results show that the ER unfolded protein response is an important target for therapeutic development, and this has recently been borne out by guanabenz treatment in G93A mtSOD1 transgenic mice, which results in a delay in onset, elongation of the early disease phase, and lengthened survival [27,28]. This zebrafish research has therefore contributed directly to the identification of guanabenz, an approved drug for hypertension, as a priority drug to pursue for the treatment of ALS.…”

Therapeutic progress in amyotrophic lateral sclerosis-beginning to learning

“…It has been found to be neuroprotective in both zebrafish and roundworm using a TDP-43 ALS model [150]. More recently, it has been investigated in two separate preclinical trials using the SOD1 G93A mice [151,152]. The results from these studies suggest that guanabenz reduces ER stress by activating the UPR pathway through upregulation of pelF2a which in turn reduces the amount of mutant SOD1.…”

TDP-43 Toxicity Proceeds via Calcium Dysregulation and Necrosis in AgingCaenorhabditis elegansMotor Neurons

“…Further insights into the induction of the ER stress response and neurodegeneration come from a recent report using a C. elegans model of SOD1 neuronal toxicity (Thompson et al, 2014). Linking the model organism studies to mammals are the ER stress-protective compounds salubrinal (Saxena et al, 2009) and guanabenz (Jiang et al, 2014), both of which show neuroprotective activity in mouse SOD-1 models. Thus, work from C. elegans models may be predictive for mechanisms of motor neuron degeneration in mammalian systems.…”

“…Importantly, the fact that nei- The role of endogenous TDP-1/TDP-43 in neurodegeneration Our group (Vaccaro et al, 2012b), plus another research team (Zhang et al, 2012), previously reported that endogenous TDP-1 (C. elegans ortholog of TDP-43) is required for toxicity caused by the transgenic expression of mutant TDP-43 in the C. elegans nervous system. Additionally, we also showed that TDP-1/ TDP-43 is required for the toxicity of mutant polyglutamine proteins in C. elegans and mammalian cell culture models of Huntington's disease (Tauffenberger et al, 2013).…”