Neural circuitry formation depends on the molecular control of axonal projection during development. By screening with fluorophore-assisted light inactivation in the developing mouse brain, we identified cartilage acidic protein–1B as a key molecule for lateral olfactory tract (LOT) formation and named it LOT usher substance (LOTUS). We further identified Nogo receptor–1 (NgR1) as a LOTUS-binding protein. NgR1 is a receptor of myelin-derived axon growth inhibitors, such as Nogo, which prevent neural regeneration in the adult. LOTUS suppressed Nogo-NgR1 binding and Nogo-induced growth cone collapse. A defasciculated LOT was present in lotus-deficient mice but not in mice lacking both lotus- and ngr1. These findings suggest that endogenous antagonism of NgR1 by LOTUS is crucial for normal LOT formation.

Oxidative stress and neuroinflammation cause many neurological disorders. Recently, it has been reported that molecular hydrogen (H2) functions as an antioxidant and anti-inflammatory agent. The routes of H2 administration in animal model and human clinical studies are roughly classified into three types, inhalation of H2 gas, drinking H2-dissolved water, and injection of H2-dissolved saline. This review discusses some of the remarkable progress that has been made in the research of H2 use for neurological disorders, such as cerebrovascular diseases, neurodegenerative disorders, and neonatal brain disorders. Although most neurological disorders are currently incurable, these studies suggest the clinical potential of H2 administration for their prevention, treatment, and mitigation. Several of the potential effectors of H2 will also be discussed, including cell signaling molecules and hormones that are responsible for preventing oxidative stress and inflammation. Nevertheless, further investigation will be required to determine the direct target molecule of H2.

In phacoemulsification, ultrasound induces hydroxyl radical (·OH) formation, damaging corneal endothelium. Whether H2 can prevent such oxidative damage in phacoemulsification was examined by in vitro and in vivo studies. H2 was dissolved in a commercial irrigating solution. The effects of H2 against ·OH generation were first confirmed in vitro by electron-spin resonance (ESR) and hydroxyphenyl fluorescein (HPF). ESR showed a significantly decreased signal magnitude, and fluorescence intensity by oxidized HPF was significantly less in the H2-dissolved solution. The effects of H2 in phacoemulsification were evaluated in rabbits, comparing H2-dissolved and control solutions. Five hours after the procedure, the whole cornea was excised and subjected to image analysis for corneal edema, real-time semiquantitative PCR (qPCR) for heme oxygenase (HO)-1, catalase (CAT), superoxide dismutase 1 (SOD1), and SOD2 mRNA, and immunohistochemistry. Corneal edema was significantly less and the increases in anti-oxidative HO-1, CAT and SOD2 mRNA expressions were significantly suppressed in the H2 group. In addition, corneal endothelial cell expressions of two oxidative stress markers, 4-HNE and 8-OHdG, were significantly lower in the H2 group. In conclusion, H2 dissolved in the ocular irrigating solution protected corneal endothelial cells from phacoemulsification-induced oxidative stress and damage.

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Collapsin response mediator protein 1 (CRMP1) and CRMP2 have been known as mediators of extracellular guidance cues such as semaphorin 3A and contribute to cytoskeletal reorganization in the axonal pathfinding process. To date, how CRMP1 and CRMP2 focally regulate axonal pathfinding in the growth cone has not been elucidated. To delineate the local functions of these CRMPs, we carried out microscale-chromophore-assisted light inactivation (micro-CALI), which enables investigation of localized molecular functions with highly spatial and temporal resolutions. Inactivation of either CRMP1 or CRMP2 in the neurite shaft led to arrested neurite outgrowth. Micro-CALI of CRMP2 in the central domain of the growth cones consistently arrested neurite outgrowth, whereas micro-CALI of CRMP1 in the same region caused significant lamellipodial retraction, followed by retardation of neurite outgrowth. Focal inactivation of CRMP1 in its half region of the growth cone resulted in the growth cone turning away from the irradiated site. Conversely, focal inactivation of CRMP2 resulted in the growth cone turning toward the irradiated site. These findings suggest different functions for CRMP1 and CRMP2 in growth cone behavior and neurite outgrowth.

Despite significant advances in antibiotic therapy and intensive care, sepsis remains the most common cause of death in intensive care units. We previously reported that molecular hydrogen (H2) acts as a therapeutic and preventive antioxidant. Here, we show that preadministration of H2-dissolved water (HW) suppresses lipopolysaccharide (LPS)-induced endotoxin shock in mice. Drinking HW for 3 days before LPS injection prolonged survival in a mouse model of sepsis. The H2 concentration immediately increased in the liver but not in the kidney after drinking HW. The protective effects of the preadministration of HW on LPS-induced liver injury were examined. Twenty-four hours after LPS injection, preadministration of HW reduced the increase in both apoptosis and oxidative stress. Moreover, preadministration of HW enhanced LPS-induced expression of heme oxyganase-1 and reduced endothelin-1 expression. These results indicate the therapeutic potential of HW in preventing acute injury of the liver with attenuation of an increase in oxidative stress. HW is likely to trigger adaptive responses against oxidative stress.

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