永津 俊治

Abstract The dark pigment neuromelanin (NM) is abundant in cell bodies of dopamine (DA) neurons in the substantia nigra (SN) and norepinephrine (NE) neurons in the locus coeruleus (LC) in the human brain. During the progression of Parkinson’s disease (PD), together with the degeneration of the respective catecholamine (CA) neurons, the NM levels in the SN and LC markedly decrease. However, questions remain among others on how NM is associated with PD and how it is synthesized. The biosynthesis pathway of NM in the human brain has been controversial because the presence of tyrosinase in CA neurons in the SN and LC has been elusive. We propose the following NM synthesis pathway in these CA neurons: (1) Tyrosine is converted by tyrosine hydroxylase (TH) to L-3,4-dihydroxyphenylalanine (L-DOPA), which is converted by aromatic L-amino acid decarboxylase to DA, which in LC neurons is converted by dopamine β-hydroxylase to NE; (2) DA or NE is autoxidized to dopamine quinone (DAQ) or norepinephrine quinone (NEQ); and (3) DAQ or NEQ is converted to eumelanic NM (euNM) and pheomelanic NM (pheoNM) in the absence and presence of cysteine, respectively. This process involves proteins as cysteine source and iron. We also discuss whether the NM amounts per neuromelanin-positive (NM⁺) CA neuron are higher in PD brain, whether NM quantitatively correlates with neurodegeneration, and whether an active lifestyle may reduce NM formation.

Psychotherapies aim to relieve patients from mental distress by guiding them toward healthier attitudes and behaviors. Psychotherapies can differ substantially in concepts and approaches. In this review article, we compare the methods and science of three established psychotherapies: Morita Therapy (MT), which is a 100-year-old method established in Japan; Cognitive Behavioral Therapy (CBT), which-worldwide-has become the major psychotherapy; and Acceptance and Commitment Therapy (ACT), which is a relatively young psychotherapy that shares some characteristics with MT. The neuroscience of psychotherapy as a system is only beginning to be understood, but relatively solid scientific information is available about some of its important aspects such as learning, physical health, and social interactions. On average, psychotherapies work best if combined with pharmacotherapies. This synergy may rely on the drugs helping to "kickstart" the use of neural pathways (behaviors) to which a patient otherwise has poor access. Improved behavior, guided by psychotherapy, can then consolidate these pathways by their continued usage throughout a patient's life.

<title>Abstract</title> Neopterin (NP), biopterin (BP) and monapterin (MP) exist in saliva. The physiological role of salivary NP as well as the pathophysiological role of increased NP in the immune-activated state has been unclear. Saliva is a characteristic specimen different from other body fluids. In this study, we analysed salivary NP and related pterin compounds, BP and MP and revealed some of its feature. High-performance liquid chromatography (HPLC) analysis of saliva and plasma obtained from 26 volunteers revealed that salivary NP existed mostly in its fully oxidized form. The results suggested that salivary NP as well as BP would mostly originate from the oral cavity, perhaps the salivary glands, and that salivary NP levels might not reflect those in the plasma. We also found that a gender difference existed in correlations between concentrations of salivary total concentrations of NP (tNP) and BP (tBP). HPLC analysis of saliva obtained from 5 volunteers revealed that the concentrations of salivary tNP as well as tBP fluctuated in an irregular fashion in various individuals. MP, a diastereomer of NP, might have come from oral cavity NP itself or its precursor. These results indicated that the nature of salivary NP might be different from that of NP in the blood or urine.

5'-Nucleotidase domain-containing protein 2 (NT5DC2) has been revealed by genome-wide association studies (GWAS) as a gene implicated in neuropsychiatric disorders related to the abnormality of dopamine (DA) activity in the brain. Based on its amino acid sequence, NT5DC2 is assumed to be a member of the family of haloacid dehalogenase-type phosphatases; although there is no information about its function and structural conformation. We recently reported that NT5DC2 binds to tyrosine hydroxylase (TH) and that the down-regulation of NT5DC2 tended to increase DA synthesis. In this study, we investigated whether NT5DC2 could regulate the catalytic activity of TH, which converts tyrosine to DOPA, because the phosphorylation level of TH, controlled by protein kinases and phosphatases, is well known to regulate its catalytic activity. The down-regulation of NT5DC2 by siRNA increased mainly DOPA synthesis by TH in PC12D cells, although this down-regulation tended to increase the conversion of DOPA to DA by aromatic L-amino acid decarboxylase. The increased DOPA synthesis should be attributed to the catalytic activity of TH controlled by its phosphorylation, because Western blot analysis revealed that the down-regulation of NT5DC2 tended to increase the level of TH phosphorylated at its Ser residues, but not that of the TH protein. Moreover, the induction of kinase activity by forskolin markedly potentiated the phosphorylation of TH at its Ser40 in PC12D cells having down-regulated NT5DC2. Immunocytochemical analysis of PC12D cells demonstrated that NT5DC2, TH protein, and TH phosphorylated at its Ser40 were predominantly localized in the cytoplasm and that the localization of NT5DC2 and TH proteins partially overlapped. Collectively, our results indicate that NT5DC2 could work to inhibit the DOPA synthesis by decreasing the phosphorylation of TH at its Ser40. We propose that NT5DC2 might decrease this phosphorylation of TH by promoting dephosphorylation or by inhibiting kinase activity.

Objectives: According to our previous work, aripiprazole exerted a protective effect on hydrogen peroxide (H2O2)-treated PC12 cells; haloperidol did not. Because aripiprazole has distinct affinities to a set of neurotransmitter receptor subtypes, this study aimed to clarify which subtype is responsible for rescuing cells from 0.25 mM H2O2 exposure.Methods: A set of compounds, which are more specific to each subset of G-protein coupled receptors, wereexamined for their ability to mimic the pharmacological effects of aripiprazole or haloperidol, including their Ki values.The viability of PC12 cells cultured with test compounds with or without H2O2 was assessed using WST-8 reagent.Results: Results from in vitro studies using PC12 cells showed that agonism at serotonin 5-HT2C-receptors based on the antagonism against 5-HT2B-receptors played a significant role in resistingH2O2-induced cell death. However, the use of a specific 5-HT2B-receptor agonist instead of a 5-HT2B-receptor antagonist completely negated the effect of a specific 5-HT2C-receptor agonist. Furthermore, unlike the dopamine D1-receptor specific antagonist, none of the agonists of dopamine D2-, D3-, and D4-receptors ameliorated the cytopathic effects of H2O2.Conclusion: Antagonism at 5-HT2B-receptors is fundamental for the protection of PC12 cells against the cytopathiceffects caused by 0.25 mM H2O2. However, the role of negatively regulated cyclic adenosine monophosphate in this phenomenon requires further investigation.