There remain many currently incurable diseases in which cell death is evident in the affected organs. Extensive cell death leads to impaired function of the affected organs, leading to the overt manifestation of the diseases. For example, Parkinson’s disease, the second most common neurodegenerative disorder next to Alzheimer’s disease, is caused by the death of dopaminergic neurons in the substantia nigra. On the other hand, for cells or animals to survive, abundant ATP is necessary, and the depletion of ATP levels is commonly observed in dying cells. With this in mind, we have long searched for compounds that prevent the ATP decrease in affected cells. We have successfully created small chemicals, KUSs (Kyoto University Substances) , which can reduce cellular ATP consumption. Furthermore, we found that esculetin is able to stimulate ATP production. We thus collectively refer to these compounds as "ATP regulators" . We then examined the efficacies of the ATP regulators on cell culture and mouse models of Parkinson’s disease. Both types of ATP regulators showed significant efficacies in preventing the ATP decrease, ER stress, and cell death in dopaminergic neurons. These results raise the possibility that maintenance of ATP levels by the ATP regulators could be a promising therapeutic strategy for Parkinson’s disease.

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Astrocytes, one of the principal glial cells, surround and interact with neurites, synapses and brain vessels, and maintain brain environment. Reactive astrocytes in the pathological brain such as ischemia contribute tissue repair though expression of various membrane proteins and oxidative stress-related molecules. Disease-specific primary changes in astrocytes have been reported in the several neurological disorders such as clasmatodendrosis in acute encephalopathy, Alzheimer type II glia in hepatocerebral syndrome, astrocytic plaque and tuft-shaped astrocyte in tauopathies, and Rosenthal fibers in Alexander disease. Moreover, apoptotic changes in astrocytes are revealed in ischemia-reperfusion injury and neurodegeneration diseases. These primary pathological changes and cell death in astrocytes may cause neuronal dysfunction. Therefore an investigation for astrocytes is important for clarifying the pathology of neurological disorders.

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Structural neuroimaging studies indicate the volume reductions in the prefrontal, tempral, and limbic regions in the brains of patients with schizophrenia. This article reviews the apoptotic mechanisms in the pathogenesis of these changes in the brain and the pharmacological properties of atypical antipsychotic drugs. Apoptotic mechanisms have been proposed as the pathogenesis of neuropil reduction including the decrease in dendritic spines of the pyramidal neurons of the cortex of the brain in schizophrenia, considered to cause the macroscopic volume reductions. Atypical antipsychotic drugs have the properties of being both proapoptotic and antiapoptotic, e. g., agranulocytosis, that is, the serious side effect of clozapine, has been shown to be derived from the apoptosis of the granulocyts, whereas clozapine has neuroprotective effects via the 5-HT_1A agonist, and antioxidative and antiapoptotic actions on neurons. Our recent studies revealed the antioxidative and antiapoptotic actions of olanzapine and clozapine. These neuroprotective effects of atypical antipsychotic drugs may provide invaluable information to develop new therapeutics to ameliorate the histological changes in the brain of schizophrenia patients.

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Studies on brain morphology, gene expression, and animal models of depression suggest that neuronal cell death is associated with the pathophysiology of major depressive disorder (MDD) ; however, MDD is different from neurodegenerative disorders. Nevertheless, some forms of dementia, such as Alzheimer’s disease and dementia with Lewy body, often present with depressive symptoms. This discrepancy may arise because the operational diagnostic criteria (the International Classification of Diseases, tenth revision [ICD-10] and the Diagnostic and Statistical Manual of Mental Disorders, fifth edition [DSM-5] ) rely on depressive symptoms. To solve this problem, it may be useful to design clinical studies to strategically classify depression as a subtype and confirm the results of clinical research with supportive basic research. In this article, we discuss the relationship between depression and neuronal cell death and the future direction of depression research, considering the recent findings and results of our studies.

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Earlier structured MRI studies using manual tracing methods provided evidence of brain abnormalities in depressive disorder and bipolar disorder, and the latest MRI studies for these disorders have used voxel-based morphometry and FreeSurfer software for image analysis of large samples. These findings suggest that patients with depressive disorder and bipolar disorder show small gray matter volumes for the anterior cingulate and insula, both relevant to mood regulation. Familial MRI studies of these disorders have also shown reduced gray matter volumes in these regions. Diffusion tensor imaging studies have demonstrated abnormal white matter integrity for the genu corpus callosum near the anterior cingulate in patients with the two disorders. Future studies are necessary to elucidate the pathophysiologies of depressive and bipolar disorder and to address their diagnostic and treatment biomarkers.

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Functional magnetic resonance imaging (fMRI) allow us to probe the brain function at relatively good spatial and temporal resolution without the use of invasive techniques, and there are a number of promising results about brain mechanisms of psychiatric disorders. Abnormalities in the central executive network including dorsolateral prefrontal cortex and the default mode network are consistent findings in depression. However, there are currently no fMRI biomarkers that are clinically useful for establishing diagnosis or predicting treatment outcome in depression. In this paper, we will summarize main fMRI findings in depression, introduce the current status of biological marker development using machine learning, and discuss about the tasks and perspectives for clinical application.

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Multi-channel near-infrared spectroscopy (NIRS) is a noninvasive examination which is performed in a natural posture with small measurement apparatus. Therefore, brain functions of mental disorders can be more appropriately evaluated under conditions close to real-world. NIRS has been increasingly used to conduct functional activation studies in depression, including researches on developing biomarker (differential diagnosis, prediction of prognosis, and detection of depression severity) and subtype of depression and researches with new paradigm with settings close to everyday life.

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Cognitive psychological models of depression emphasize the significance of the negativity biases or the loss of positive illusions (called depressive realism) in the etiology and maintenance of depressive disorders. This paper reviews researches on the functional brain imaging (fMRI) and positron emission tomography (PET) to understand the neural and molecular mechanisms of cognitive biases in evaluating self and other, and discusses the relationship between the functional networks of cognitive biases related to depression symptoms and the dopamine neurotransmission.

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