No abstract

Alzheimer’s disease (AD) is the most common form of dementia among the elderly. Neuritic plaques whose primary component is amyloid beta peptide (Aβ) and neurofibrillary tangles which are composed of hyperphosphorylated tau, are known to be the neuropathological hallmarks of AD. In addition, impaired synaptic plasticity in neuronal networks is thought to be important mechanism underlying for the cognitive deficits observed in AD. Although various causative factors, including excitotoxicity, mitochondrial dysregulation and oxidative damage caused by Aβ, are involved in early onset of AD, fundamental therapeutics that can modify the progression of this disease are not currently available. In the present study, we investigated whether phloroglucinol (1, 3, 5—trihydroxybenzene), a component of phlorotannins, which are plentiful in Ecklonia cava, a marine brown alga species, displays therapeutic activities in AD. We found that phloroglucinol attenuates the increase in reactive oxygen species (ROS) accumulation induced by oligomeric Aβ1–42 (Aβ1–42) treatment in HT-22, hippocampal cell line. In addition, phloroglucinol was shown to ameliorate the reduction in dendritic spine density induced by Aβ1–42 treatment in rat primary hippocampal neuron cultures. We also found that the administration of phloroglucinol to the hippocampal region attenuated the impairments in cognitive dysfunction observed in 22-week-old 5XFAD (Tg6799) mice, which are used as an AD animal model. These results indicate that phloroglucinol displays therapeutic potential for AD by reducing the cellular ROS levels.

Gb3 accumulation reduces K(Ca)3.1 channel expression by down-regulating ERK and AP-1 and up-regulating REST and the channel activity by decreasing intracellular levels of PI(3)P. Gb3 thereby evokes K(Ca)3.1 channel dysfunction, and the channel dysfunction in vascular endothelial cells may contribute to vasculopathy in Fabry disease.

Objective— Globotriaosylceramide (Gb3) induces K Ca 3.1 downregulation in Fabry disease (FD). We investigated whether Gb3 induces K Ca 3.1 endocytosis and degradation. Approach and Results— K Ca 3.1, especially plasma membrane–localized K Ca 3.1, was downregulated in both Gb3-treated mouse aortic endothelial cells (MAECs) and human umbilical vein endothelial cells. Gb3-induced K Ca 3.1 downregulation was prevented by lysosomal inhibitors but not by a proteosomal inhibitor. Endoplasmic reticulum stress–inducing agents did not induce K Ca 3.1 downregulation. Gb3 upregulated the protein levels of early endosome antigen 1 and lysosomal-associated membrane protein 2 in MAECs. Compared with MAECs from age-matched wild-type mice, those from aged α-galactosidase A (Gla)-knockout mice, an animal model of FD, showed downregulated K Ca 3.1 expression and upregulated early endosome antigen 1 and lysosomal-associated membrane protein 2 expression. In contrast, no significant difference was found in early endosome antigen 1 and lysosomal-associated membrane protein 2 expression between young Gla-knockout and wild-type MAECs. In aged Gla-knockout MAECs, clathrin was translocated close to the cell border and clathrin knockdown recovered K Ca 3.1 expression. Rab5, an effector of early endosome antigen 1, was upregulated, and Rab5 knockdown restored K Ca 3.1 expression, the current, and endothelium-dependent relaxation. Conclusions —Gb3 accelerates the endocytosis and lysosomal degradation of endothelial K Ca 3.1 via a clathrin-dependent process, leading to endothelial dysfunction in FD.

The increasing prevalence of diabetes heightens concerns over diabetic complications such as neuropathy. Diabetic neuropathy is one of the most debilitating complications of type 1 and type 2 diabetes.1) The histopathology of the condition is characterized by axonal degeneration, demyelination, and atrophy in association with failed axonal regeneration, remyelination, and impaired synaptogenesis. 2)Previous reports have suggested that reduced availability of nerve growth factor (NGF) plays a significant role in the pathogenesis of diabetic polyneuropathy.3) Retrograde axonal transport of NGF is impaired in animals with diabetes mellitus (DM), 4) and its transcription in neuronal target tissues is reduced.5) NGF itself has been considered an option for the treatment of diabetic peripheral neuropathy. Although systemic administration of exogenous recombinant human NGF was found to prevent neuropathy in a phase II clinical trial, 6) unfortunately efficacy of NGF was not demonstrated in a completed phase III trial due to its limited delivery to the nervous system and adverse effects after subcutaneous injection.7) An alternative therapeutic approach is the use of small molecules to induce or enhance neurotropic factor production. Saito and colleagues reported that the orally active small molecule MCC-257, a sialic acid derivative, elevated NGF levels in the sciatic nerve and improved nerve conduction velocity in a diabetic rodent model. 8) Also, retinoic acid can revert functional and ultrastructural changes and induce neural regeneration after the establishment of diabetic neuropathy, possibly because of increased NGF concentrations in nerve terminals. 9)Our study focused on diosgenin (DG), a major steroidal sapogenin isolated from Dioscoreaceae. DG is the primary spirostane-type sapogenin found in several plants, including fenugreek, Costus speciosus, and the Dioscorea species. 10) DG has been shown to be useful in maintaining healthy blood cholesterol levels, 11) and is a precursor for several hormones such as dehydroepiandrosterone.12)The present study examined the neuroprotective effect of DG on diabetic peripheral neuropathy through increasing NGF levels in a diabetic rodent model. MATERIALS AND METHODS Isolation of Diosgenin from Dioscorea nipponicaRhizomes of Dioscorea nipponica (DN) MAKINO (Dioscoreaceae), referred to as Cheonsangyong in China and as Buchema in Korea, were obtained from the Kyungdong Herb Market in Seoul, Korea. They were identified by Dr. C. S. Yook, Department of Pharmacy, Kyung Hee University. Dried DN rhizomes (1 kg) were extracted 3 times using 85% methanol under ultrasonic apparatus for each 2 h and evaporated to dryness. Such an extraction process was repeated twice. The residue (147 g) was then partitioned between water-saturated n-butanol and water, and the n-butanol layer was separated, which was repeated 5 times, and evaporated to dryness. The yield was 3.4%. The residue was subsequently taken up into 2.5 N HCl for 4 h at 94°C, extracted using CHCl 3 , filtered, and evaporated to...