The potential role of melatonin on sleep deprivation-induced cognitive impairments: implication of FMRP on cognitive function.

While prolonged sleep deprivation (SD) could lead to profound negative health consequences, such as impairments in vital biological functions of immunity and cognition, melatonin possesses powerful ameliorating effects against those harmful insults. Melatonin has strong antioxidant and anti-inflammatory effects that help to restore body's immune and cognitive functions. In this study, we investigated the possible role of melatonin in reversing cognitive dysfunction induced by SD in rats. Our experimental results revealed that sleep-deprived animals exhibited spatial memory impairment in the Morris water maze tasks compared with the control groups. Furthermore, there was an increased glial activation most prominent in the hippocampal region of the SD group compared to the normal control (NC) group. Additionally, markers of oxidative stress such as 4-hydroxynonenal (4-HNE) and 7,8-dihydro-8-oxo-deoxyguanine (8-oxo-dG) were significantly increased, while fragile X-mental retardation protein (FMRP) expression was decreased in the SD group. Interestingly, melatonin treatment normalized these events to control levels following SD. Our data demonstrate that SD induces oxidative stress through glial activation and decreases FMRP expression in the neurons. Furthermore, our results suggest the efficacy of melatonin for the treatment of sleep-related neuronal dysfunction, which occurs in neurological disorders such as Alzheimer's disease and autism.

Early immature neuronal death initiates cerebral ischemia-induced neurogenesis in the dentate gyrus.

Throughout adulthood, neurons are continuously replaced by new cells in the dentate gyrus (DG) of the hippocampus, and this neurogenesis is increased by various neuronal injuries including ischemic stroke and seizure. While several mechanisms of this injury-induced neurogenesis have been elucidated, the initiation factor remains unclear. Here, we investigated which signal(s) trigger(s) ischemia-induced cell proliferation and neurogenesis in the hippocampal DG region. We found that early apoptotic cell death of the immature neurons occurred in the DG region following transient forebrain ischemia/reperfusion in mice. Moreover, early immature neuronal death in the DG initiated transient forebrain ischemia/reperfusion-induced neurogenesis through glycogen synthase kinase-3ß/ß-catenin signaling, which was mediated by microglia-derived insulin-like growth factor-1 (IGF-1). Additionally, we observed that the blockade of immature neuronal cell death, early microglial activation, or IGF-1 signaling attenuated ischemia-induced neurogenesis. These results suggest that early immature neuronal cell death initiates ischemia-induced neurogenesis through microglial IGF-1 in mice.

Differential roles of cyclooxygenase isoforms after kainic acid-induced prostaglandin E(2) production and neurodegeneration in cortical and hippocampal cell cultures.

Prostaglandins, which are cyclooxygenase (COX) products, are pathologically up-regulated, and have been proven to be closely associated with neuronal death. In this study, we investigated a role of COX isoforms (COX-1 and COX-2) in kainic acid-induced neuronal death in cultured murine cortical or hippocampal neurons. In primary cortical neurons, both indomethacin (COX-1/-2 nonselective inhibitor) and aspirin (COX-1 preferential inhibitor) reduced basal and kainic acid-induced PGE(2) production significantly and prevented neuronal cell death after kainic acid treatment. In contrast, NS398 (COX-2 selective inhibitor) had no effect on kainic acid-induced neuronal cell death. In hippocampal neurons, however, COX-2 inhibitors prevented both kainic acid-induced neuronal death and PGE(2) production. COX-2 expression was remarkably up-regulated by kainic acid in hippocampal neurons; whereas in cortical neurons, COX-2 expression was comparatively less significant. Astrocytes were unresponsive to kainic acid in terms of PGE(2) production and cell death. In conclusion, we suggest that the release of PGE(2) induced by kainic acid occurred through COX-1 activity rather than COX-2 in cortical neurons. The inhibition of PGE(2) release by COX-1 inhibitors prevented kainic acid-induced cortical neuronal death, while in the hippocampal neurons, COX-2 inhibitors prevented kainic acid-induced PGE(2) release and hippocampal neuronal death.

ARF6 and GASP-1 are post-endocytic sorting proteins selectively involved in the intracellular trafficking of dopamine D2 receptors mediated by GRK and PKC in transfected cells.

BACKGROUND AND PURPOSE: GPCRs undergo both homologous and heterologous regulatory processes in which receptor phosphorylation plays a critical role. The protein kinases responsible for each pathway are well established; however, other molecular details that characterize each pathway remain unclear. In this study, the molecular mechanisms that determine the differences in the functional roles and intracellular trafficking between homologous and PKC-mediated heterologous internalization pathways for the dopamine D2 receptor were investigated. EXPERIMENTAL APPROACH: All of the S/T residues located within the intracellular loops of D2 receptor were mutated, and the residues responsible for GRK- and PKC-mediated internalization were determined in HEK-293 cells and SH-SY5Y cells. The functional role of receptor internalization and the cellular components that determine the post-endocytic fate of internalized D2 receptors were investigated in the transfected cells. KEY RESULTS: T134, T225/S228/S229 and S325 were involved in PKC-mediated D2 receptor desensitization. S229 and adjacent S/T residues mediated the PKC-dependent internalization of D2 receptors, which induced down-regulation and desensitization. S/T residues within the second intracellular loop and T225 were the major residues involved in GRK-mediated internalization of D2 receptors, which induced receptor resensitization. ARF6 mediated the recycling of D2 receptors internalized in response to agonist stimulation. In contrast, GASP-1 mediated the down-regulation of D2 receptors internalized in a PKC-dependent manner. CONCLUSIONS AND IMPLICATIONS: GRK- and PKC-mediated internalizations of D2 receptors occur through different intracellular trafficking pathways and mediate distinct functional roles. Distinct S/T residues within D2 receptors and different sorting proteins are involved in the dissimilar regulation of D2 receptors by GRK2 and PKC.

Adenocarcinoma of the parotid gland with calcification.

A 78-year-old Korean woman was referred to Chonbuk National University Dental Hospital complaining of facial palsy and palpable mass in the right parotid gland area for 4 years. Clinical examination showed an asymmetrical facial appearance due to a 4 cmx5 cm hard, fixed, non-tender mass in the right parotid gland area, incomplete eye closure and a slight tremor at the corner of the mouth. A panoramic radiograph showed an amorphous calcified mass on the posterior mandibular ramus with thinning of the cortical plate adjacent to the mass. A sialogram showed constriction of the main duct and no further filling of striated, intercalated ducts and parenchymal areas. CT indicated an expansile mass with slight contrast enhancement involving the right parotid gland. The large mass showed necrotic areas and calcifications. A bone scan showed marked accumulation of (99)Tc(m)-methylene diphosphonate on the right posterior maxilla. Microscopic findings revealed minimal morphological alterations and rare mitotic figures within tumour cells, and the lesion was diagnosed as adenocarcinoma not otherwise specified (NOS, grade II).

In vivo pharmacologic profile of SK-1080, an orally active nonpeptide AT1-receptor antagonist.

The pharmacologic profile of SK-1080, a newly synthesized AT1-receptor antagonist, was evaluated in conscious normotensive rats, conscious renally (RHRs) and spontaneously (SHRs) hypertensive rats, and conscious furosemide-treated beagle dogs. In angiotensin II-challenged normotensive rats, orally administered SK-1080 had no agonistic effect and dose-dependently inhibited the pressor response to angiotensin II with a slightly weaker potency (ID50: 1.12 and 0.47 mg/kg, respectively), but with a more rapid onset of action than losartan (time to Emax, 30 min and 6 h, respectively). In RHRs, orally given SK-1080 produced a dose-dependent and long-lasting (>24 h) antihypertensive effect with a potency similar to that of losartan (ED20, 5.06 and 3.36 mg/kg, respectively). Intravenously administered SK-1080 exerted a very highly potent antihypertensive effect (ED20, 0.06 mg/kg), thus indicating a poor oral bioavailability in rats. On repeated dosing for 21 days in SHRs, SK-1080 significantly reduced blood pressure without inducing tachycardia and tolerance throughout the dosing period. On repeated dosing, the antihypertensive effect gradually increased from days 1 to 7 (Emax on day 7, 15.0 and 19.7% at 10 and 30 mg/kg, respectively) and remained at a significant level on days 14 and 21. In furosemide-treated dogs, orally given SK-1080 produced a dose-dependent and long-lasting (>8 h) antihypertensive effect with a rapid onset of action (time to Emax, 1-1.5 h) and 10-fold greater potency than losartan (ED20, 0.72 and 8.13 mg/kg, respectively). In furosemide-treated dogs, SK-1080 showed a good oral bioavailability, unlike that in RHRs. These results suggest that SK-1080 is a potent, orally active AT1-receptor antagonist useful for the treatment of hypertension.