High mobility group box-1 (HMGB1), a representative damage-associated molecular patterns (DAMPs), has been reported to be involved in many inflammatory diseases. To validate HMGB1 as a target molecule of inflammatory diseases and to examine the effects of inhibition of HMGB1 on the diseases, we raised anti-HMGB1 monoclonal antibody (mAb) neutralizing extracellular HMGB1 and characterized it. We report the effects of anti-HMGB1 mAb on brain infarction, brain hemorrhage, brain trauma, epilepsy and neuropathic pain using animal models. In these wide range of disease conditions, we found a common event; the injury-induced translocation of HMGB1 from nuclei to extracellular space, especially in neurons. Released HMGB1 disrupt the integrity of blood-brain barrier (BBB) and increased the permeability of BBB, associated with inflammatory responses including the induction of pro-inflammatory cytokines. The intravenous injection of anti-HMGB1 mAb inhibited translocation of HMGB1, BBB disruption, expression of inflammatory molecules and improved neurological symptoms of different kinds of disease models. These results as a whole indicated that HMGB1 may be a very sensitive factor which is mobilized readily by different injurious insults to the brain and that HMGB1 release may be present most upstream of cascade of events triggering BBB disruption and brain inflammation. Thus, HMGB1 may be an excellent target for the treatment of above-mentioned diseases. Anti-HMGB1 mAb provide a novel and potential therapy for these severe disease conditions.

Inflammation is an essential step for the pathology of ischemic stroke, and is also an important therapeutic target for developing novel therapeutic methods which have a wide therapeutic time window. Since there is no pathogen in the brain, the inflammation will be triggered by some endogenous molecules which are called as danger associated molecular patterns (DAMPs). So far two important DAMPs, high mobility group box 1 (HMGB1) and peroxiredoxin (PRX), have been recently identified in the ischemic brain. HMGB1 exaggerates the disruption of blood brain barrier; on the other hand, PRX activates mononuclear phagocytes and induces the inflammatory cytokine production through the activation of Toll-like receptor 2 (TLR2) and TLR4. Various inflammatory molecules produced from infiltrating immune cells have been known to exacerbate the neurological deficits of ischemic stroke patients. Recently, it has been paid attention that the inflammation after tissue injury also induces tissue repair, while its mechanisms remain to be clarified. Novel therapeutic methods will be established by clarifying detailed molecular mechanisms underlying the induction of neural repair after cerebral post-ischemic inflammation.

Prothymosin alpha (ProTα) has been identified as an anti-necrotic factor from the conditioned medium of primary cultured of rat cortical neurons under the serum-free starving condition. ProTα is released in a non-vesicular manner from neurons or astrocytes by the help of cargo protein S100A13. Thus released ProTα is found to have robustness roles in the brain under the condition of neuronal necrosis or apoptosis. ProTα inhibits necrosis by plasma membrane-translocation of glucose transporters endocytosed by ischemia/starving stress, through an activation of unidentified G protein-coupled receptor and protein kinase Cβ. In the cerebral or retinal ischemia model, systemic injection of ProTα protects brain or retina from ischemic damages by converting necrosis to apoptosis, which is in turn blocked by neurotrophic factors. In the retinal ischemia model, ProTα prevents the damages by another mechanism through toll-like receptor 4 (TLR4) and downstream TRIF signaling. The direct interaction between ProTα and TLR4/MD2 is also evidenced by the study of molecular dynamics and protein-protein interaction. All these findings indicate that ProTα could be called a cytoprotective member of damage-associated molecular patterns (DAMPs) or alarmins. ProTα and its modified peptide fragment, NEVDQE (P6Q) show the vasculoprotective actions by itself in a model of cerebral ischemia as well as neuroprotective actions. The concomitant administration of these peptides abolishes the cerebral hemorrhage induced tissue plasminogen activator (tPA), which is treated late after cerebral ischemia models. Thus, ProTα and P6Q seem to have promising therapeutic potencies to directly protect neurons and inhibit the hemorrhage by late treatment with tPA against stroke.

G-protein-coupled receptor 40 (GPR40)/free fatty acid receptor (FFAR) 1 is activated by long-chain fatty acids such as docosahexaenoic acid (DHA). Its receptor is expressed predominantly in the central nervous system (CNS) and in β-cells in the pancreatic Islets. We have already demonstrated that the intracerebroventricular administration of DHA or GW9508, a GPR40/FFAR1 agonist, suppresses formalin-induced pain behavior. It also attenuates complete Freund’s adjuvant-induced mechanical allodynia and thermal hyperalgesia, suggesting that these effects occur by increasing β-endorphin release from propiomelanocortin neurons. Furthermore, we found that the brain GPR40/FFAR1 signaling may involve in the regulation of the descending pain control system, whereas the deletion of GPR40/FFAR1 might exacerbate mechanical allodynia in postoperative pain. Therefore, it is possible that the brain n-3 fatty acid-GPR40/FFAR1 signaling may play a key role in the modulation of the endogenous pain control system and emotional function. Here, we discuss the role of brain n-3 fatty acids-GPR40/FFAR1 signaling in a pain, and we review the current status and future prospects of the brain GPR40/FFAR1.

The functions of n-3 fatty acids are known to be diverse, and they play roles in cardiovascular and neuronal systems and in lipid metabolism. Docosahexaenoic acid (DHA), which is the most abundant n-3 fatty acid in the brain, is essential for the maintenance of brain functions throughout the human lifespan. Epidemiological studies have demonstrated that reduced n-3 fatty acid intake is closely associated with the onset of mental and neurological diseases such as brain developmental disorders, depression, and Alzheimer’s disease. DHA is primarily involved in neurogenesis, synapse formation, neuronal differentiation, neurite outgrowth, maintenance of membrane fluidity, anti-inflammatory action, and antioxidant action. Its mechanism of action include: 1) the effects on ion channels and membrane bound receptors/enzymes achieved by changing membrane fluidity, as a cell membrane constituent, and 2) free DHA molecules, derived from the cell membrane that directly or metabolically, by conversion to protectin D1 and other molecules, indirectly regulates the gene expression and the activity of intracellular proteins. Although future studies are required, the supplementation of n-3 fatty acids such as DHA may suppress the deterioration of brain functions, delay the onset and progression of various mental/neurological diseases, and further improve the outcome of the neuronal diseases.

Circadian clock system has been widely maintained in many spices from prokaryote to mammals. “Circadian” means “approximately day” in Latin, thus circadian rhythm means about 24 hour rhythms. The earth revolves once every 24 hours, and our circadian system has been developed for adjusting to this 24 hour cycles, to get sun light information for getting their foods or for alive in birds or mammals. We have two different circadian systems so-called main oscillator located in the suprachiasmatic nucleus (SCN) of the hypothalamus, and local oscillator located in the various peripheral organ tissues such as liver, kidney and skeletal muscle. The SCN is directly entrained by light-dark information through retinal-hypothalamic tract, and then organizes local clock in peripheral tissues via many pathways including neural and hormonal functions. On the other hand, peripheral local clocks are entrained by feeding, exercise and stress stimuli through several cell signaling. Foods (protein, carbohydrate, and lipid) are important regulator of circadian clocks in peripheral tissues. Thus, controlling the timing of food consumption and food composition, a concept known as chrononutrition, is one area of active research to aid recovery from many physiological dysfunctions. In this review, we focus on molecular mechanisms of entrainment and the relationships between circadian clock systems and n-3 polyunsaturated fatty acid. We concentrate on experimental data obtained from cells or animals and humans and discuss how these findings translate into clinical research, and we highlight the latest developments in chrononutritional studies.