The most surprising data for us was the behavior

The most surprising data for us was the behavior of α-synuclein protein; it accumulated in the dopaminergic neurons of the substantia nigra in response to MPTP treatment, and it failed to accumulate during the treatment with KUSs and esculetin (Fig. 9). Related with this, very recently it has been reported that ATP itself has chaperone activities (Patel et al., 2017); ATP may help to prevent misfolding or accumulation of α-synuclein. It has also been reported that α-synuclein acts on mitochondria and stimulates ATP synthesis (Ludtmann et al., 2016). These lines of evidence emphasize a close link between α-synuclein protein levels and ATP levels. It is tempting to speculate that Lewy bodies might be a marker of a prior drop in ATP levels. In addition to the activities shown in this study, esculetin has recently been shown to have cell-protective effects, and to mitigate MPTP-induced Parkinson\'s disease phenotypes in mice (Subramaniam and Ellis, 2013). These effects were proposed to be mediated by the reduction of oxidative stress caused by reactive oxygen species or nitrosylation (Kim et al., 2008; Subramaniam and Ellis, 2013, 2016). These results further support a therapeutic potential of esculetin for the treatment of Parkinson\'s disease. Esculetin has also been shown to possess cell death-inducing activities in several cultured cancerous MLN2238 (Arora et al., 2016; Jeon et al., 2015; Wang et al., 2015), and thus long-term esculetin treatment, if approved, may have the added benefit of reducing cancer occurrence. We have shown that KUSs can protect retinal neurons from death in mouse models of retinitis pigmentosa, glaucoma, and ischemic retinal disease, and we also have repeatedly discussed mechanisms that underlie the profound links between ATP decrease, ER stress, and cell death in these eye diseases (Hasegawa et al., 2016b; Hata et al., 2017; Ikeda et al., 2014; Nakano et al., 2016). In this study, we further showed that KUSs and esculetin can protect dopaminergic neurons from MPTP- or rotenone-induced toxicity in the respective mouse models of Parkinson\'s disease (Figs. 8, 10, Figs. S14, S15, S19). From these results, we propose a model for the pathological features of these disorders, in which ATP decrease or depletion is a common central phenomenon, even though each disease has a unique etiology. An ATP decrease in early stages would diminish the functions of affected cells or organs, and then in later stages it would result in cell death or organ failure, culminating in overt disease phenotypes. Furthermore, this model suggests potential therapeutic strategies commonly applicable to these disorders. Namely, maintenance of ATP levels, by either inhibiting ATP consumption or enhancing ATP production, or both, would slow or stop the disease progression. Functional recovery of the remaining cells might even ameliorate the disease phenotypes.
Funding Sources This research was supported in part by research grants from the Mitsubishi Foundation (28107), the Ministry of Education, Culture, Sports, Science and Technology, Japan (16H05151), and by Solution-Oriented Research for Science and Technology (SORST-H16-3) from the Japan Science and Technology Agency (JST). And this research was supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Platform for Dynamic Approaches to Living Systems) from the Japan Agency for Medical Research and Development (AMED) (16am0101009j0005).
Introduction Although rapid advances in structural neuroimaging studies using voxel-based morphometry (VBM) have enabled systematic assessment of the structural substrates underlying obsessive-compulsive related disorders (Ashburner and Friston, 2000; Lerch et al., 2017), our understanding of these pathological alterations remains shaded by conflicting and inconclusive prior findings. These apparent discrepancies may partially be due to insufficient power, clinical heterogeneity, mixed statistical analytic methods and medication confounds (Abi-Dargham and Horga, 2016; Blackford, 2017; Button et al., 2013; Poldrack et al., 2017; van den Heuvel et al., 2009). Among those confounding factors, pharmacological intervention has thus far received insufficient attention, as yields extremely limited (yet still diverging) evidence regarding the modulatory activity of therapeutics such as selective serotonin reuptake inhibitors (SSRIs) in OCD (Pine and Freedman, 2017; Skapinakis et al., 2016). Early studies selectively analyzed abnormally increased volumes of the thalamus and amygdala in drug-naïve pediatric patients, both of which were normalized by pharmacotherapy (Gilbert et al., 2000; Szeszko et al., 2004). Two whole-brain VBM studies on over a dozen patients found volume reductions in the left putamen (Hoexter et al., 2012) and parietal lobes (Lazaro et al., 2009) that became comparable to controls after medication. To date, the underlying circuit-level therapeutic mechanisms of pharmacotherapy remain essentially unclear while as many as half of patients diagnosed with OCD fail to respond adequately to serotonergic-based drugs (Bloch et al., 2006, 2010; Hirschtritt et al., 2017). Understanding the brain-modulatory effects of medication treatment may help to match the pathological deficits in brain morphology of patients with therapeutic network fingerprints of specific drugs, thereby leading to improved treatment efficacy.