So-Young Jeon

β-secretase (BACE1) inhibitors from Pomegranate (Punica granatum) husk

In the course of screening for anti-dementia agents from natural products, two β-secretase (BACE1) inhibitors were isolated from the husk of pomegranate(Punica granatum) by activity-guided purification. They were identified as ellagic acid and punicalagin with IC50 values of 3.9 x10-6 and 4.1x10-7 M andKi values of 2.4x10-5 and 5.9x10-7 M, respectively. The compounds were non-competitive inhibitors with a substrate in the Dixon plot. Ellagic acid and punicalagin were less inhibitory to α-secretase (TACE) and other serine proteases such as chymotrypsin, trypsin, and elastase, thus indicating that they were relatively specific inhibitors of BACE1.

3,4-Dihydroxybenzoic acid from Smilacis chinae rhizome protects amyloid β protein (25–35)-induced neurotoxicity in cultured rat cortical neurons

The neuroprotective effect of 3,4-dihydroxybenzoic acid (3,4-DHBA) isolated from Smilacis chinae rhizome against Abeta (25-35)-induced neurotoxicity on cultured rat cortical neurons was found in this study. The protective effect of 3,4-DHBA against Abeta (25-35)-induced neuronal cell death was investigated by measuring cell viability via a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) assay and Hoechst 33342 staining. 3,4-DHBA (1 and 10 microM) concentration-dependently inhibited 10 microM Abeta (25-35)-induced neuronal apoptotic death. 3,4-DHBA (1 and 10 microM) inhibited 10 microM Abeta (25-35)-induced elevation of cytosolic Ca(2+) concentration ([Ca(2+)](c)), which was measured by a fluorescent dye, Fluo-4 AM. 3,4-DHBA also inhibited glutamate release into medium, reactive oxygen species (ROS) generation, and caspase-3 activation, which were induced by 10 microM Abeta (25-35). These results suggest that 3,4-DHBA prevents Abeta (25-35)-induced neuronal cell damage by interfering with the increase of [Ca(2+)](c), and then by inhibiting glutamate release, generation of ROS and caspase-3 activity.

A prolyl endopeptidase-inhibiting antioxidant from Phyllanthus ussurensis.

A prolyl endopeptidase inhibitor was isolated from the ethyl acetate soluble fraction ofPhyllanthus ussurensis. The active compound was identified as an ellagitannin, corilagin. It was shown to non-competitively inhibit prolyl endopeptidase (PEP) with the IC50 value of 1.17x10-6 μM. TheKi value was 6.70x10-7 M. Corilagin was less inhibitory to other serine proteases such as chymotrypsin, trypsin, and elastase, indicating that it was relatively a specific inhibitor of PEP. Corilagin also effectively inhibited reactive oxygen species such as hydroxide and superoxide anion radical, hydrogen peroxide, and DPPH. Especially, corilagin showed potent scavenging activity on the superoxide anion radical in the ESR method (IC50 = 3.79x10-6 M) as well as xanthine oxidase system.

Expression of monocyte chemoattractant protein-1 and its induction by tumor necrosis factor receptor 1 in sensory neurons in the ventral rhizotomy model of neuropathic pain

The expression and role of monocyte chemoattractant protein-1 (MCP-1) in the rat dorsal root ganglion (DRG) and spinal cord was evaluated in the lumbar 5 ventral rhizotomy (L5 VR) model of neuropathic pain. MCP-1 protein expression in the L4/L5 DRG neurons following L5 VR peaked after 3 days, and then declined. Immunohistochemistry showed that no MCP-1 immunoreactivity was observed in the spinal cord after L5 VR, while enzyme-linked immunosorbent assay (ELISA) revealed a small but significant increase in MCP-1 protein content. L5 VR resulted in robust and prolonged mechanical allodynia and thermal hyperalgesia. Administration of anti-MCP-1 neutralizing antibody before and at early time points after L5 VR resulted in a significant attenuation of mechanical allodynia and thermal hyperalgesia, while post-treatment had a weaker effect on established neuropathic pain. Extensive colocalization of tumor necrosis factor receptor 1 (TNFR1) and MCP-1 was observed in the L5 DRG following L5 VR, and treatment with TNFR1 antisense oligonucleotide reduced L5 VR-induced MCP-1 expression in L5 DRG neurons and neuropathic pain behaviors. MCP-1/chemokine (C-C motif) receptor 2 signaling has been proposed as a major regulator of macrophage trafficking. In contrast to the effect on pain behaviors, however, intrathecal administration of anti-MCP-1 neutralizing antibody had no effect on the L5 VR-induced increase in ED-1-immunoreactive macrophages in the L5 DRG and the distal stump of the transected L5 ventral root. These data indicate that increased MCP-1 in DRG neurons might participate in the initiation, rather than the maintenance, of neuropathic pain induced by L5 VR. Furthermore, increased MCP-1 in the DRG is induced by TNF-α/TNFR1 and has no effect on the infiltration of macrophages into the DRG following L5 VR.

Expression of brain-derived neurotrophic factor in the rat forebrain and upper brain stem during postnatal development: An immunohistochemical study

The present study was undertaken to characterize the regional and temporal patterns of brain-derived neurotrophic factor (BDNF) in the rat forebrain and upper brain stem during postnatal development using an immunohistochemical approach. Results indicated that BDNF-immunoreactive (IR) cells could be divided into three groups based on their postnatal developmental patterns: (group 1) BDNF-IR cells were first detected between postnatal days (PND) 1 and 7, and thereafter they increased in number and remained stable during later stages of ontogeny; (group 2) BDNF-IR cells progressively increased in number with age, and then decreased in adults; (group 3) numerous BDNF-IR cells detected between PND 1 and 7 showed a dramatic reductions in number with few IR cells in adults. In contrast, the developmental pattern of most BDNF-IR fibers differed from that of IR neurons, i.e. they appeared between PND 1-28 and thereafter continued to increase in number showing a maximum level in adults. Additionally, BDNF-IR cells in the superficial layer of the neocortex and IR fibers in the stratum oriens of CA2 first appeared as late as PND 28 and in adults, respectively. After colchicine treatment, reexpression or a marked increase in the number of BDNF-IR neurons was observed in many areas of the adult brain where a progressive decrease in BDNF-IR cell numbers during development and scant or some IR neurons in adults were shown. These results showed both transient and persistent expression of BDNF in various regions of the developing rat brain.