Ilho Ha

Ulva conglobata, a marine algae, has neuroprotective and anti-inflammatory effects in murine hippocampal and microglial cells

It has been reported that inflammatory processes are associated with the pathophysiology of Alzheimers disease (AD), and the treatment of AD using anti-inflammatory agents slows the progress of AD. Marine algae have been utilized in food products as well as in medicine products for a variety of purposes. In this study, we investigated the neuroprotective effects of methanol extracts of Ulva conglobata (U. conglobata), a marine algae, on glutamate-induced neurotoxicity in the murine hippocampal HT22 cell line and the anti-inflammatory effects on interferon gamma (IFN-gamma)-induced microglial activation in BV2 cells. U. conglobata methanol extracts significantly attenuated the neurotoxicity induced by glutamate in HT22 cells and inhibited nitric oxide production induced by IFN-gamma in BV2 cells. U. conglobata methanol extract treatments were also examined and it was found that they almost completely suppressed the expression of the proinflammatory enzyme cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS). These results suggest that U. conglobata possesses therapeutic potential for combating neurodegenerative diseases associated with neuroinflammation.

Macelignan attenuates LPS-induced inflammation and reduces LPS-induced spatial learning impairments in rats

Previous studies have shown that macelignan has anti-inflammatory and neuroprotective effects. Subsequently, in the current study, we demonstrate that oral administrations of macelignan reduce the hippocampal microglial activation induced by chronic infusions of lipopolysaccharide (LPS) into the fourth ventricle of Fisher-344 rat brains. A Morris water maze was used to evaluate the status of the hippocampal-dependent spatial learning in control rats with an artificial cerebrospinal fluid infusion, rats with chronic LPS infusions, and rats with chronic LPS infusions and oral administrations of macelignan. The rats with chronic LPS infusions showed spatial memory impairments relative to the control rats in the performance of the memory task. Daily administration of macelignan reduced the spatial memory impairments induced by the chronic LPS infusions. The results indicate that macelignan may possess therapeutic potential for the prevention of Alzheimers disease.

Effect of maceligan on the systemic exposure of paclitaxel: In vitro and in vivo evaluation

This study investigated the effect of macelignan on the P-glycoprotein-mediated drug efflux as well as CYP3A4-mediated drug metabolism and subsequently its in vivo implication on the bioavailability of paclitaxel. The inhibition effect of macelignan on the CYP3A4-mediated metabolism was negligible over the concentration range of 0.01-100muM in rat liver microsome while approximately 33% inhibition was observed at 100muM in human liver microsome, implying that the interaction of macelignan with CYP3A4 might be insignificant at the physiologically achievable concentrations. In contrast, macelignan (20muM) increased the cellular accumulation of paclitaxel by approximately 1.7-fold in NCI/ADR-RES cells overexpressing P-gp, while it did not alter the cellular accumulation of paclitaxel in OVCAR-8 cells lacking P-gp. The effect of macelignan on the systemic exposure of paclitaxel was also examined in rats after the intravenous and oral administration of paclitaxel in the presence and the absence of macelignan. The concurrent use of macelignan significantly (p<0.05) enhanced the oral exposure of paclitaxel in rats while it did not affect the intravenous pharmacokinetics of paclitaxel, implying that macelignan might be more effective to improve the intestinal absorption rather than reducing hepatic elimination. In conclusion, macelignan appeared to be effective to improve the cellular accumulation as well as oral exposure of paclitaxel mainly via the inhibition of P-gp-mediated cellular efflux, suggesting that the concomitant use of macelignan may provide a therapeutic benefit in improving the anticancer efficacy of paclitaxel.

Macelignan: A New Modulator of P-Glycoprotein in Multidrug-Resistant Cancer Cells

The effect of macelignan, a phytoestrogen, on P-gp function was investigated using multidrug resistant cancer cells overexpressing P-gp (NCI/ADR-RES) and the fluorescent P-gp substrates, daunorubicin and rhodamine 123. Macelignan (40 μM) increased the cellular accumulation of daunorubicin by approximately threefold in NCI/ADR-RES cells, whereas it did not alter the cellular accumulation of daunorubicin in MCF-7/sensitive cells. Similarly, the presence of macelignan also enhanced significantly (P < 0.05) the cellular accumulation of rhodamine 123 in a concentration-dependent manner in NCI/ADR-RES cells. Furthermore, cancer cells were more susceptible to the cytotoxicity of vinblastine, a P-gp substrate, in the presence of macelignan. Those results suggest that macelignan has inhibitory effects on P-gp mediated cellular efflux. However, P-gp activity did not affect the cellular accumulation of macelignan itself. Taken all together, macelignan was identified as a novel inhibitor of P-gp activity and may be a promising lead compound for the rational design of more efficacious drugs to reverse multidrug resistance in cancer.

Drug Development for Alzheimer's Disease: Recent Progress

Alzheimers disease, the most common cause of dementia, is characterized by two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Based on these two indicators, an amyloid cascade hypothesis was proposed, and accordingly, most current therapeutic approaches are now focused on the removal of β-amyloid peptides (Aβ from the brain. Additionally, strategies for blocking tau hyperphosphorylation and aggregation have been suggested, including the development of drugs that can block the formation of tangles. However, there are no true disease-modifying drugs in the current market, though many drugs based on theories other than Aβ and tau pathology are under development. The purpose of this review was to provide information on the current development of AD drugs and to discuss the issues related to drug development.

Overexpression of BACE1 stimulates spontaneous basal secretion in PC12 cells

Although alterations in the function of the neurotransmitter system have been implicated in the pathology of Alzheimers disease (AD), the mechanisms that underlie this pathological change are not well understood. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is a key protease in the generation of beta-amyloid, an important trigger protein in the pathogenesis of AD. The expression and activity of BACE1 are increased in the brains of sporadic AD patients, and a role for BACE1 in neurotransmission has been suggested recently. This study examines whether BACE1 plays a role in regulated exocytosis in PC12 cells. Treatment of PC12 cells with a beta-secretase inhibitor reduced stimulus-dependent secretion of neurotransmitters, suggesting a potential role of BACE1 in regulated exocytosis. Using transfected human growth hormone as a reporter for a regulated secretory pathway in PC12 cells, we found that the transient overexpression of BACE1 increased basal secretion in the absence of a stimulus and reduced stimulus-dependent secretion in intact PC12 cells. In digitonin-permeabilized PC12 cells, an overexpression of BACE1 enhanced the Ca2+-independent and ATP-independent component of the secretory pathway. Furthermore, expression of the glycosylation-deficient mutant of BACE1, BACE1N354Q, led to an elevation of basal secretions over that by BACE1 wild-type, suggesting a role of BACE1 glycosylation in basal secretion. These results demonstrate an unknown role for BACE1 in secretion, and suggest that elevated levels of BACE1 in AD brains may contribute to the altered neurotransmitter pathology of AD through stimulation of spontaneous basal secretion under resting conditions.