The EDRF discovered in 1986 by Furchgott was later identified as NO by Ignarro. NO was a widely noted gas with diverse functions, having arginine (L-Arg) as a substrate for the NO synthase (NOS). L-Arg and L-citrulline (L-Cit) have long been associated with the urea cycle. L-Cit was produced with NO by the reaction of L-Arg and oxygen. It was shown that administration of L-Arg in animals and humans caused vasodilation and anti-arteriosclerosis effects. Despite the arginine paradox ratio of intracellular arginine concentration to the Km value of NOS gaining widespread attention, advanced arteriosclerosis is known to reduce vascular reactivity towards L-Arg. In recent years, the anti-arteriosclerosis and anti-cell aging effects of the reactive substance citrulline (L-Cit) have been studied. L-Cit and L-Arg combination therapy are starting to be considered in various clinical applications as well.

Nitric oxide (NO), formed from NO synthases (NOSs), plays a pathogenetic role in pulmonary hypertension (PH). However, the role of NO/NOSs in bone marrow (BM) cells in PH remains to be clarified. We addressed this point in clinical and basic studies. We demonstrated that, in 36 consecutive patients with idiopathic pulmonary fibrosis, pulmonary artery systolic pressure is inversely correlated with NOx levels in the bronchoalveolar lavage fluid, suggesting reduced pulmonary NO production in group III PH. We then revealed that transplantation of BM cells from mice lacking all NOSs aggravates hypoxia-induced PH in wild-type (WT) mice, and transplantation of BM cells from the WT mice ameliorates hypoxia-induced PH in the NOSs^−/− mice, indicating a protective role of myelocytic NOSs in the pathogenesis of PH. Immune and inflammatory mechanisms appeared to be involved in the aggravation of hypoxia-induced PH caused by transplantation of BM cells from the NOSs^−/− mice. Our findings provide novel insights into the cellular and molecular basis of group III PH.

Recently, hydrogen sulfide (H₂S) has been recognized as the third gasotransmitter besides nitric oxide and carbon monoxide, and it has been reported that H₂S exhibits various physiological functions such as neuromodulation and vasorelaxation. In the lower urinary tract (bladder and prostate), it is reported that donors of H₂S induce contraction of the rat detrusor and relaxation of the pig bladder neck. These reports suggest a possibility that H₂S may have site-specific effects on the bladder. However, the detailed functions of H₂S in each part of the bladder are still unclear. In addition, there is no report showing physiological roles of H₂S in the prostate. In this article, we will review the distribution of enzymes related to H₂S biosynthesis and physiological roles of H₂S in the lower urinary tract based on reports from our and other groups. We will also introduce a possibility that H₂S can be a new therapeutic target against lower urinary tract symptoms (LUTS) based on our data from spontaneously hypertensive rats (SHRs), which develop hypertension-mediated LUTS.

Because visual information accounts for 80–90% of sensory information that we get from our circumstance, loss of vision seriously diminishes our quality of life. According to a recent epidemiological study, glaucoma is the first, and retinitis pigmentosa (RP) is the second leading causes of acquired blindness in Japan. Degeneration of the retinal ganglion cells (RGC) and photoreceptor cells causes glaucoma and RP, respectively. Intraocular pressure-lowering therapy is an only effective treatment for glaucoma, and the agents that protect RGC directly against glaucomatous injury have not been available yet. In addition, there is no effective treatment for RP at present. microRNAs are a class of small, endogenous, non-coding RNAs comprised of approximately 20 nucleotides. It has been clarified that microRNAs reduces the stability of the target mRNAs and/or repress the translation of the target genes. A single microRNA can affect the transcription of multiple mRNAs, and almost 30% of human genes are thought to be regulated by microRNAs. Therefore, it has been considered that the expression changes of microRNAs are possible to cause various diseases, such as cancer and neurodegenerative diseases. Recently, the expression changes in microRNAs have been reported in the retina of experimental model animals for glaucoma and RP. The expressional changes of microRNAs are suggested to be related with development and progression of glaucoma and RP. Here, we will discuss about the relationship between the expressional changes of microRNAs and neuronal cell death in glaucoma and RP.

Glaucoma, progressive optic neuropathy, is the first cause of blindness in Japan. Blindness in this disease is induced by damages or degeneration of retinal ganglion cells (RGCs), retinal neurons transmit visual information to brain. An elevated intraocular pressure (IOP) is widely recognized as one of the most important risk factors and that IOP directly damages RGCs by mechanical stress, however, accumulating evidences have shown that a majority of Japanese patients for primary open angle glaucoma shows normal level of IOP. Thus, new target for glaucoma pathology is emerged. In this issue, we introduce potential roles of glial cells for pathogenesis of glaucoma. In the CNS, reactive gliosis has been recognized in a variety of neurodegenerative diseases. Such glial activation is also found in retinae of human glaucoma patients and animal models. Importantly, glial activation precedes RGS degeneration, indicating the possibility that reactive glial cells actively contribute to pathogenesis of glaucoma. In this issue, we will focus on macroglial cells such as Muller cells and astrocytes, and discuss their roles in glaucoma.

Retinitis pigmentosa (RP) is a group of hereditary diseases that involve loss of photoreceptors. There has been no established treatment for RP, and it is now the 2^nd leading cause of blindness in Japan. Previous clinical researches using human fetal retina transplantation suggested some functional recovery in vision, but it did not become a standard therapy because of ethical concerns for using fetus tissues. Invention of induced pluripotent stem cells (iPSC) in 2006 and the establishment of retinal organoids induction protocol from ES/iPS cells have paved a way of cell therapy for RP without ethical concerns. Our team has shown that mouse iPSC derived retinas can survive and mature after subretinal transplantation to the end-stage retinal degeneration model mice. Further, human ESC derived retinas survived and matured in retinal degeneration monkey models. Recently, we have established a qualitative and quantitative evaluation tool for photoreceptor synapses, QUANTOS, and showed that photoreceptors in mouse iPSC derived retina can form photoreceptor synapses in a time dependent manner after transplantation. We are now moving toward 1^st in human clinical trial using iPSC derived retina for RP.

Animals can make appropriate decisions based on sensory information about the environment. Vision is one of the most critical ability for survival in dynamic situations in nature, particularly for mammalian species, such as primates, carnivores, and rodents. Although there is a huge computational cost involved in processing visual information, the brain can perform this task very rapidly using well-organized parallel and hierarchical neural circuits, enabling animals to rapidly sense the environment and, in turn, perform adaptive actions. Physiological, psychophysical, and clinical studies over hundreds of years have delineated the neural circuit mechanisms of the visual system. Artificial intelligence and robotics have also started making progress in this area. However, due to technical limitations, there are still many open questions that elude explanation in understanding the neural mechanism of visuomotor integration. Herein, we initially describe the anatomical structures of occipital cortices related to vision and then provide an overview of the physiological and clinical studies of the dorsal visual pathway related to spatial perception and prediction in non-human primate species. Finally, we introduce recent approaches in which rodents have been used as model species to elucidate the neural circuit mechanism of visually-guided behavior. Uncovering neural implementation of the association between visual-spatial perception and visuomotor function could provide key insights into the engineering of highly active robots and could also contribute to the development of novel therapeutic strategies addressing visual impairment and psychiatric/neurological disorders.

Nalmefene (Selincro^®), an opioid receptor modulator, is approved in Japan, the European Union, and other countries for reducing alcohol consumption in patients with alcohol dependence. This article reviews the efficacy and safety of as-needed use of nalmefene in the treatment of alcohol dependence, as well as summarizing its pharmacological properties. Ethanol increases the release of endogenous opioids, such as β-endorphin, a μ-opioid receptor agonist; and dynorphin, a κ-opioid receptor agonist. Preclinical data suggest that nalmefene acts as an antagonist at the μ-opioid receptor and a partial agonist at the κ-opioid receptor, and reduces ethanol self-administration in ethanol-dependent and ethanol-non-dependent rats. Nalmefene counters alcohol-induced dysregulation of the β-endorphin/μ-opioid receptor and the dynorphin/κ-opioid receptor systems. In a multicenter, randomized, double-blind, phase 3 study of as-needed use of nalmefene combined with psychosocial support in alcohol-dependent Japanese patients with at least high drinking risk level, compared with placebo, nalmefene 10 mg and 20 mg significantly reduced the number of heavy drinking days and total alcohol consumption at week 12. In the 24-week treatment period, treatment-emergent adverse events occurred in ≥5% of patients in either the nalmefene 10 mg or 20 mg group and at least twice as often as in the placebo group were nausea, dizziness, somnolence, vomiting, insomnia, decreased appetite, constipation, malaise, and palpitations. Most adverse events were mild or moderate in severity. In conclusion, as-needed use of nalmefene provides a new concept for the treatment of alcohol dependence: namely, “reduction of alcohol intake”.