Although the involvement of genomic factors in bipolar disorder is clear, its neural basis remains a question. We proposed the mitochondrial dysfunction hypothesis of bipolar disorder in 2000 and have since been testing it. https://www.selleckchem.com/products/picropodophyllin-ppp.html Our results showed that mitochondrial DNA (mtDNA) polymorphisms affected mitochondrial Ca2+ concentration, and mitochondrial Ca2+ uptake and intracellular Ca2+ signaling were altered. Spontaneous repetitive depressive episodes were seen in mice in which mtDNA mutations accumulated in the brain (mutant Polg transgenic mice). We searched for the brain regions with the accumulation of mutant mtDNA in these mice, and found that it was most abundant in the paraventricular nucleus of the thalamus (PVT). Neural circuit manipulation of the PVT caused similar repetitive hypoactive episodes, suggesting that the PVT may be involved in causing bipolar disorder.Galcanezumab, a CGRP monoclonal antibody drug, has been approved by the U.S. Food and Drug Administration (FDA) for the prevention of recurrent cluster headaches. This was done after a randomized, double-blind, placebo-controlled trial found it to be effective and safe. Similarly sphenopalatine ganglion stimulation has been found to be effective and safe in a randomized, controlled trial as an acute treatment for chronic cluster headache. This article reviews the mechanisms of action of these therapies and their clinical trial results, clinical uses, and prospects in Japan.Migraine and cluster headache are common headache disorders that impact patients' quality of life. The pharmacotherapy for acute headache attacks is sometimes ineffective, and the adherence to preventive medications is low due to their side effects and/or lack of efficacy. Recently, several non-invasive neuromodulation devices for primary headache disorders have been launched and attracted the attention of patients and physicians because of their practicality, safety, and the possibility of becoming new treatment options. In this review, we describe external trigeminal nerve stimulation (eTNS), non-invasive vagal nerve stimulation (nVNS), and single-pulse transcranial magnetic stimulation (sTMS) which have been well studied in recent randomized sham-controlled trials and open-label studies. We also describe their mechanisms of action and adverse events.Migraine is a common and debilitating neurological disorder characterized by recurrent headaches of moderate-to-severe intensity. Because of its high prevalence, migraine causes a considerable financial burden on society. There is ample evidence showing that migraine is a complex neurological disorder that involves not only the trigeminovascular and autonomic systems, but also the hypothalamus and cerebral cortex. Calcitonin gene-related peptide (CGRP) was originally discovered as a 37-amino acid neuropeptide derived from a calcitonin gene splicing variant, is enriched in trigeminal ganglion neurons. Much attention has been paid to CGRP since it was found to be released from trigeminal terminals in animal migraine models. Subsequent studies demonstrated that CGRP administration induced migraine-like headaches specifically in migraineurs, thus highlighting its pivotal role CGRP in the development of migraine attacks. Monoclonal antibodies targeting CGRP and its receptor exhibited consistent efficacy for migraine prophylaxis with excellent safety profiles in clinical trials. Furthermore, emerging data support the long-term safety and efficacy of these antibodies. On the other hand, there are several concerns that have newly surfaced in the real-world setting. In this review, the development and perspective of anti-migraine therapeutic strategies using CGRP-related antibodies are discussed.The calcitonin gene-related peptide (CGRP) has been shown to play a major role in the pathophysiology of migraine in recent years. Studies have suggested that blocking CGRP signaling is an effective preventive and therapeutic strategy in patients with migraine. Triptans, considered the mainstay of antimigraine treatment cause vasoconstriction; however, gepants and ditans (two novel classes of therapeutic agents) inhibit CGRP release but do not show a vasoconstrictor effect. Both these drugs are awaiting clinical approval in Japan as antimigraine medications that can be administered to patients with cardiovascular risk factors and to those with triptan-refractory migraine.Migraine is the sixth most common cause of disability worldwide. Historically, three theories regarding the etiology of headache have been suggested vascular, neuronal, and trigeminovascular. However, the mechanism of migraine is still unknown. The advantages of studying the premonitory phase are several as it is the earliest clinical change during a migraine attack, and hence, is likely to disclose brain areas involved right at the beginning. Studying this phase may also allow to reveal the generator of migraine. In human neurophysiology, human functional neuroimaging, and preclinical biochemical studies, the relationship between the premonitory phase and hypothalamus has been suggested. On the other hand, calcitonin gene-related peptide (CGRP) has now been firmly established as a key player in migraine. Trigeminal CGRP and its roles in vasodilation, neurogenic inflammation, and peripheral sensitization are likely to be the most relevant peripheral actions causing the condition. CGRP could also be acting as a neuromodulator of light aversion, central sensitization, and cortical spreading depression (CSD).Carbohydrate recognition by lectins governs critical host-microbe interactions. MpPA14 (Marinomonas primoryensis PA14 domain) lectin is a domain of a 1.5-MDa adhesin responsible for a symbiotic bacterium-diatom interaction in Antarctica. Here, we show that MpPA14 binds various monosaccharides, with l-fucose and N-acetylglucosamine being the strongest ligands (dissociation constant [Kd ], ∼150 μM). High-resolution structures of MpPA14 with 15 different sugars bound elucidated the molecular basis for the lectin's apparent binding promiscuity but underlying selectivity. MpPA14 mediates strong Ca2+-dependent interactions with the 3,4-diols of l-fucopyranose and glucopyranoses, and it binds other sugars via their specific minor isomers. Thus, MpPA14 only binds polysaccharides like branched glucans and fucoidans with these free end groups. Consistent with our findings, adhesion of MpPA14 to diatom cells was selectively blocked by l-fucose, but not by N-acetyl galactosamine. The MpPA14 lectin homolog present in a Vibrio cholerae adhesin was produced and was shown to have the same sugar binding preferences as MpPA14.