Well, I'll make my own decision based on the DD I know.
Nice to see that these folks and the MAYO Clinic agree:
Among other innovative pharmacological strategies designed toimprove mitochondrial function are antioxidant therapies that mitigatelocal ROS production in mitochondria compared to the reduction ofglobal levels of ROS. These compounds include coenzyme Q10, idebe-none, creatine, MitoQ, MitoVitE, MitoTEMPOL, latrepirdine, methyle-neblue, triterpenoids, a series of Szeto-Schiller (SS) peptides, curcumin,Ginkgo biloba, and omega-3 polyunsaturated fatty acids (Murphy andHartley, 2018). These mitochondria-targeted compounds have beenextensively evaluated in multiple laboratories using variousin vivoandin vitromodels of AD. Multiple benefits of these compounds includeimproved bioenergetics, reduced oxidative stress, improved mitochon-drial dynamics and trafficking. For example, a peptide, 6'-di-methyltyrosine-Lys-Phe-NH2(SS31) binds to cardiolipin, a lipid that islocalized specifically to the mitochondrial membranes, and promotesthe efficiency of mitochondrial OXPHOS machinery. SS31 has beenshown efficacious in protecting against Aß-induced oxidative stress,synaptic loss, mitochondrial dysfunction, and abnormal calciumhomeostasisin vitroandin vivo(Reddy et al., 2012; Reddy et al., 2017).Some of these compounds have demonstrated promising results inclinical trials (Kumar and Singh, 2015; Feniouk and Skulachev, 2016).However, in many cases the precise mechanism of pharmacologicalintervention remains uncertain. For example, application of quinazoli-none, a mitochondria division inhibitor 1 (Mdivi-1), originally de-scribed as a selective inhibitor of mitochondrialfission protein DRP1,induced neuroprotection in in vitro and in vivo models of AD, Parkin-son's disease (PD), traumatic brain injury and other diseases via en-hancing mitochondrial fusion, increasing mitochondrial biogenesis andlevels of synaptic proteins (Manczak et al., 2018; Bido et al., 2017;Wuet al., 2016;Smith and Gallo, 2017). More recently, Mdivi-1 was shownto act as a reversible mitochondrial complex I inhibitor that reducesROS production suggesting that positive changes in mitochondrialfunction and reducedfission may not be related to the proposed directeffect of Mdivi-1 on DRP1 GTPase activity (Bordt et al., 2017). Never-theless, recent extensive studies conducted in neuronal N2a cells sup-port the notion that Mdivi-1 is a DRP1 inhibitor that reduces mi-tochondrial fragmentation (Manczak et al., 2019). Furthermore,application of Mdivi-1 appears to significantly improve energy pro-duction under conditions where complexes, I, II and IV of the ETC areimpaired (Manczak et al., 2019). It remains to be determined whetherMdivi-1 acts via multiple mechanisms including partial inhibition ofcomplex I. Since Mdivi-1 has been considered for clinical trials, addi-tional investigations into its molecular targets might be necessary toensure safety and efficacy of the application in humans (Smith andGallo, 2017). Similarly, implementation of antioxidant therapies hasmet with mixed success. While common antioxidants, such as vitaminsE and C, did not produce consistent results in clinical trials, novel ap-proaches include the design of molecules that could specifically targetmitochondria to reduce ROS generated by a dysfunctional organelles (Murphy, 2016). Oral administration of MitoQ, a ubiquinone linked to alipophilic triphenylphosphonium cation, produced encouraging resultsreducing oxidative stress in multiple animal models advancing MitoQinto clinical trials (Rossman et al., 2018). However, future work is re-quired to unequivocally demonstrate the feasibility of mitochondria-targeted antioxidants as a therapeutic strategy for AD. An additionalapproach recently developed by Anavex was shown beneficial in clin-ical phase 2a trial for AD where ANAVEX 2-73, a sigma 1 receptoragonist, improved cognitive performance and functional measure inpatients. A chaperone protein, sigma 1 is activated in response to acuteand chronic cellular stressors and modulates multiple mechanisms in-volved in neurodegeneration such as glutamate and calcium activity,reactionto oxidative stress, and mitochondrial function (Lahmy et al.,2013). Most recent data suggest that application of ANAVEX 2-73 maymediate beneficial effect also via activation of autophagy (Christ et al.,2019). Similarly, activation of mitophagy has been shown as an es-sential mechanism of neuroprotection in multiple animal models of ADgranting further development of mitophagy activators for clinical ap-plication (Fang et al., 2019).
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