Priceless. Considering it took many centuries to get from the wheel to the jet engine I guess we are not doing too badly w/CNS cellular Homeostasis by comparison. The learning process is not for the weak. Expecting that news from RSD AVXL processes this week starts a chain reaction which escalates quickly. There is nothing that suggests this particular string has to go on for another century. So many have passed due to lack of knowledge. It's time. we are due.
In general, deficits in Sig-1R expression or activity are linked to neurodegeneration and the activation of Sig-1R is associated with neuroprotection in different in vitro and in vivo models, employing different types of pharmacological Sig-1R activators with different pharmacological profiles [15,23]. The pharmacological activation of Sig-1R leads to pluripotent modulatory downstream effects, and incorrect function of Sig-1R is strongly suggested to be also involved in the pathogenesis of neurodegeneration [24]. This is the basis of an effort to design novel and highly specific pharmacological Sig-1R activators for the therapy of neurodegenerative disease, including AD [25]. In this context a novel Sig-1R agonist, tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73), was developed. Pharmacologically, ANAVEX2-73 shows a dual activity on Sig-1 as well as on muscarinic receptors, acting with described affinities in the low micromolar range [26,27]. Previously, pre-clinical studies in animal models demonstrated robust disease-modifying activities of ANAVEX2-73. Regarding AD, ANAVEX2-73 has undergone testing in Phase 2a trial of patients demonstrating a favorable safety profile and a concentration-dependent improvement against exploratory endpoints [28,29,30]. A variety of neuromodulatory and neuroprotective effects are also already known for ANAVEX2-73, including mitochondrial protection in mouse models of AD, regulation of ERK activation and promotion of survival of astrocytes, as well as protection against oxidative stress [31,32,33]. First evidence for a possible link of Sig-1R, autophagy, and neurodegeneration has been recently shown in the context of ALS. It was discovered that ALS-linked mutant Sig1-R causes an accumulation of autophagic material and actually reduced autophagy [34], and that mice with genetically-altered Sig-1R show defective autophagy [35]. Moreover, it was demonstrated that cocaine-mediated autophagy in astrocytes involves Sig-1R [36]. In addition, it was found that a small-molecule Sig-1R modulator induces autophagic degradation of programmed-death ligand 1 (PD-L1) in cancer cells [37]. These findings prompted us to study the potential of ANAVEX2-73 to have an effect on autophagy in human HeLa and HEK293 cells (in vitro) as well as in C. elegans (in vivo), employing standard measures to analyze autophagic activity [38,39,40,41]. Moreover, the effects of ANAVEX2-73 on protein aggregation and, subsequently, the impact of protein aggregates on movement behavior in C. elegans were studied. Excitingly, ANAVEX2-73 is a potent inducer of autophagic flux in vitro and in vivo and ameliorates protein aggregate formation and paralysis in C. elegans.
