BackgroundDiacylglycerol kinase (DGK) is an enzyme that phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). DGKβ is widely distributed in the central nervous system, such as the olfactory bulb, cerebral cortex, striatum, and hippocampus. Recent studies reported that the splice variant at the COOH-terminal of DGKβ was related to bipolar disorder, but its detailed mechanism is still unknown.Methodology/Principal FindingsIn the present study, we performed behavioral tests using DGKβ knockout (KO) mice to investigate the effects of DGKβ deficits on psychomotor behavior. DGKβ KO mice exhibited some behavioral abnormalities, such as hyperactivity, reduced anxiety, and reduced depression. Additionally, hyperactivity and reduced anxiety were attenuated by the administration of the mood stabilizer, lithium, but not haloperidol, diazepam, or imipramine. Moreover, DGKβ KO mice showed impairment in Akt-glycogen synthesis kinase (GSK) 3β signaling and cortical spine formation.Conclusions/SignificanceThese findings suggest that DGKβ KO mice exhibit lithium-sensitive behavioral abnormalities that are, at least in part, due to the impairment of Akt-GSK3β signaling and cortical spine formation.

In terms of mental illnesses, depression has an enormous influence in society. Major symptoms of depression are a "depressed mood" and "loss of interest and joy." Despite recent advances in the knowledge related to brain development and function, the mechanisms underlying the pathogenesis of depression remain unclear.The endoplasmic reticulum is a principal site for protein synthesis, folding, and calcium signaling.1) It is highly sensitive to alterations in calcium homeostasis and perturbations in its environment. A condition that impaired the function of the endoplasmic reticulum, collectively designated "endoplasmic reticulum stress," can lead to an accumulation of unfolded proteins in the endoplasmic reticulum lumen.2) In response to endoplasmic reticulum stress, cells have developed a self-protective signal pathway termed the unfolded protein response (UPR), leading to induction of molecular chaperones such as 78 kDa glucose-regulated protein (GRP78) and 94 kDa glucose-regulated protein (GRP94), translational attenuation, and endoplasmic reticulum associated degradation.3) However, if the damage is excessive, the UPR ultimately activates an apoptotic pathway such as CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) activation. 4)Recently, GRP78 and GRP94 have been found in the temporal cortex of subjects with major depressive disorder who died by suicide.5) Furthermore, in a rodent depression model, endoplasmic reticulum stress-related proteins were increased and these were attenuated by an antidepressant.6) Recently, we have reported that restraint stress increases in the expression of endoplasmic reticulum stress-related genes in the mouse brain.7) These findings indicate that endoplasmic reticulum stress may have some roles in the pathogenesis of depression.Luteolin is a common flavonoid that exists in many types of plants such as Apium graveolens L. var. dulce, 8)Petroselium crispum, 9) and Capsicum annuum L. var.'grossum.' 10) It has various pharmacological activities such as antioxidant, 11) anticancer action, 12) memory-improving, 13) and anxiolytic 14) activities, suggesting that luteolin could penetrate easily into the brain. 15) In this study, we investigated the antidepressant effects of luteolin from the green pepper leaf, as well as its mechanism, using cell death assay induced by endoplasmic reticulum stress in human neuroblastoma (SH-SY5Y) cells and animal models of depression. MATERIALS AND METHODS Purification of LuteolinLuteolin aglycon (luteolin) was provided by Theravalues (Tokyo, Japan). The purity of luteolin was 80%. In the experiments, it was dissolved in phosphate buffered saline contained 1% dimethyl sulfoxide (DMSO) or suspended in the 0.5% carboxymethylcellulose (Wako, Osaka, Japan).Cell Culture SH-SY5Y cells were purchased from the European Collection of Cell Culture (Wiltshire, U.K.) and maintained in Dulbecco's modified Eagle's medium (SigmaAldrich, St. Louis, MO, U.S.A.) containing 10% fetal bovine serum (VALEANT, Costa Mesa, CA, U.S.A.), 100 units/ml of penici...

Intracranial hemorrhage remains a devastating disease. Among antiplatelet drugs, cilostazol, a phosphodiesterase 3 inhibitor, was recently reported to prevent secondary hemorrhagic stroke in patients in a clinical trial. The aim of this study was to evaluate whether pre-treatment with cilostazol could decrease the intracranial hemorrhage volume and examine the protective mechanisms of cilostazol. We evaluated the pre-treatment effects of the antiplatelet drug cilostazol on the collagenase-induced intracranial hemorrhage volume and neurological outcomes in mice. To estimate the mechanism of collagenase injury, we evaluated various vascular components in vitro, including endothelial cells, vascular smooth muscle cells, pericytes, and a blood-brain barrier model. Cilostazol pre-treatment reduced the intracranial hemorrhage volume with sufficient inhibition of platelet aggregation, and motor function was improved by cilostazol treatment. Blood-brain barrier permeability was increased by collagenase-induced intracranial hemorrhage, and cilostazol attenuated blood-brain barrier leakage. Terminal deoxynucleotidyl transferase dUTP nick-end labeling and western blot analysis showed that cilostazol prevented pericyte cell death by inducing cyclic adenosine monophosphate-responsive element-binding protein phosphorylation. Cilostazol also prevented endothelial cell death and protected collagen type 4, laminin, and vascular endothelial- and N-cadherins from collagenase injury. In conclusion, cilostazol reduced collagenase-induced intracranial hemorrhage volume by protecting the blood-brain barrier.

Huperzia serrata has been used as a Chinese folk medicine for many years. It contains huperzine A, which has a protective effect against memory deficits in animal models; however, it is unclear if H. serrata extract exerts any effects in Alzheimer's disease (AD) models. We used H. serrata collected in Japan and determined its huperzine A content using HPLC. We determined its inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. H. serrata extract (30 mg/kg/day) and donepezil (10 mg/kg/day) were orally administrated for 7 days. After repeated administration, we performed the Y-maze and passive avoidance tests. H. serrata extract contained 0.5% huperzine A; H. serrata extract inhibited AChE, but not BuChE. H. serrata extract ameliorated cognitive function in mice. These results indicate that Japanese H. serrata extract ameliorates cognitive function deficits by inhibiting AChE. Therefore, H. serrata extract may be valuable for the prevention or treatment of dementia in AD.

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