Neuritogenic Activity Research Articles

Linckosides enhance proliferation and induce morphological changes in human olfactory ensheathing cells.

Linckosides are members of the steroid glycoside family isolated from the starfish Linckia laevigata. These natural compounds have notable neuritogenic activity and synergistic effects on NGF-induced neuronal differentiation of PC12 cells. Neurogenic factors or molecules that are able to mimic their activities are known to be involved in the survival, proliferation and migration of neurons and glial cells; however how glial cells respond to specific neurogenic molecules such as linckosides has not been investigated. This study aimed to examine the effect of three different linckosides (linckoside A, B and granulatoside A) on the morphological properties, proliferation and migration of human olfactory ensheathing cells (hOECs). The proliferation rate after all the treatments was higher than control as detected by MTS assay. Additionally, hOECs displayed dramatic morphological changes characterized by a higher number of processes after linckoside treatment. Interestingly changes in microtubule organization and expression levels of some early neuronal markers (GAP43 and βIII-tubulin) were also observed. An increase in the phosphorylation of ERK 1/2 after addition of the compounds suggests that this pathway may be involved in the linckoside-mediated effects particularly those related to morphological changes. These results are the first description of the stimulating effects of linckosides on hOECs and raise the potential for this natural compound or its derivatives to be used to regulate and enhance the therapeutic properties of OECs, particularly for cell transplantation therapies.

Design, Synthesis, and Biological Evaluation of Ganglioside Hp-s1 Analogues Varying at Glucosyl Moiety.

Ganglioside Hp-s1 is isolated from the ovary of sea urchin Diadema setosum. It exhibited better neuritogenic activity than GM1 in pheochromocytoma 12 cells. To explore the roles of glucosyl moiety of Hp-s1 in contributing to the neurogenic activity, we developed feasible procedures for synthesis of Hp-s1 analogues (2a-2f). The glucosyl moiety of Hp-s1 was replaced with α-glucose, α-galactose, β-galactose, α-mannose, and β-mannose, and their biological activities on SH-SY5Y cells and natural killer T (NKT) cells were evaluated. We found that the orientation of C-2 hydroxyl group at glucosyl moiety of Hp-s1 plays an important role to induce neurite outgrowth of SH-SY5Y cells. Surprisingly, compound 2d could activate NKT cells to produce interleukin 2, although it did not show great activity on neurite outgrowth of SH-SY5Y cells. In general, the Hp-s1 might be considered as a lead compound for the development of novel drugs aimed at modulating the activity of neuronal cells.

ChemInform Abstract: Total Synthesis of Linckosides A and B, the Representative Starfish Polyhydroxysteroid Glycosides with Neuritogenic Activities.

ChemInform Abstract: Total Synthesis of Linckosides A and B, the Representative Starfish Polyhydroxysteroid Glycosides with Neuritogenic Activities.

Fermented Saccharina japonica (Phaeophyta) improves neuritogenic activity and TMT-induced cognitive deficits in rats

(FSJ) on the memory deficient rats, which were induced by trimethyltin chloride (TMT), was investigated by assessing the Morris water maze test and by performing choline acetyltransferase (ChAT), cAMP response element binding protein (CREB), and brain derived neuro -trophic factor (BDNF) immunohistochemistry. The neurite outgrowth of Neuro2a cells was assessed in order to examine the underlying mechanisms of the memory enhancing effects of FSJ. Treatment with FSJ tended to shorten the latency to find the platform in the acquisition test of the Morris water maze at the second and fourth day compared to the control group. In the probe trial, the FSJ treated group increased time spent in the target quadrant, compared to that of the con-trol group. Consistent with the behavioral data, these treatments recovered the loss of ChAT, CREB, and BDNF immune-positive neurons in the hippocampus produced by TMT. Treatment with FSJ markedly stimulated neurite outgrowth of the Neuro2a cells as compared to that of the controls. These findings demonstrate that FSJ may be useful for improving the cognitive function via regulation of neurotrophic marker enzyme activity.

Synthesis and SAR Studies of Neuritogenic Gentiside Derivatives.

Tetradecyl 2,3-dihydroxybenzoate (ABG-001) has been designed and synthesised as a lead compound to treat Alzheimer's disease, based on structure-activity relationships of gentisides. In this paper, the alkyl chain and ester linkage group of ABG-001 were modified. Consequently, several series of novel gentiside derivatives were designed and synthesised, and their neuritogenic activity was evaluated in PC12 cells. Among all the tested compounds, S-dodecyl 2,3-dihydroxybenzothioate (15d, named as ABG-199) was the most potent; the compound induced significant neurite outgrowth at 0.1 µM, which was comparable to that of nerve growth factor at the optimal concentration of 40 ng/mL and ABG-001 at 1 µM. A brief study on the mechanism of action of ABG-199 revealed that extracellular signal-regulated kinase phosphorylation was involved in ABG-199-induced neurite outgrowth in PC12 cells.

Structure-Activity Relationship Study of the Neuritogenic Potential of the Glycan of Starfish Ganglioside LLG-3 (‡).

LLG-3 is a ganglioside isolated from the starfish Linchia laevigata. To clarify the structure-activity relationship of the glycan of LLG-3 toward rat pheochromocytoma PC12 cells in the presence of nerve growth factor, a series of mono- to tetrasaccharide glycan derivatives were chemically synthesized and evaluated in vitro. The methyl group at C8 of the terminal sialic acid residue was crucial for neuritogenic activity, and the terminal trisaccharide moiety was the minimum active motif. Furthermore, the trisaccharide also stimulated neuritogenesis in human neuroblastoma SH-SY5Y cells via mitogen-activated protein kinase (MAPK) signaling. Phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was rapidly induced by adding 1 or 10 nM of the trisaccharide. The ratio of phosphorylated ERK to ERK reached a maximum 5 min after stimulation, and then decreased gradually. However, the trisaccharide did not induce significant Akt phosphorylation. These effects were abolished by pretreatment with the MAPK inhibitor U0126, which inhibits enzymes MEK1 and MEK2. In addition, U0126 inhibited the phosphorylation of ERK 1/2 in response to the trisaccharide dose-dependently. Therefore, we concluded that the trisaccharide promotes neurite extension in SH-SY5Y cells via MAPK/ERK signaling, not Akt signaling.

Total Synthesis of Linckosides A and B, the Representative Starfish Polyhydroxysteroid Glycosides with Neuritogenic Activities.

Linckosides A and B, two starfish metabolites with promising neuritogenic activities, are synthesized in a longest linear sequence of 32 steps and 0.5% overall yield; this represents the first synthesis of members of the polyhydroxysteroid glycoside family, which occur widely in starfishes.

Lignosus rhinocerotis (Cooke) Ryvarden mimics the neuritogenic activity of nerve growth factor via MEK/ERK1/2 signaling pathway in PC-12 cells.

The traditional application of the sclerotium of Lignosus rhinocerotis (tiger’s milk mushroom) by the indigenous folks as tonic and remedy to treat a variety of ailments has been documented in Malaysia. Indigenous communities claimed to have consumed the decoction to boost their alertness during hunting. Mental alertness is believed to be related to neuronal health and neuroactivity. In the present study, the cell viability and neuritogenic effects of L. rhinocerotis sclerotium hot aqueous and ethanolic extracts, and crude polysaccharides on rat pheochromocytoma (PC-12) cells were studied. Interestingly, the hot aqueous extract exhibited neuritogenic activity comparable to NGF in PC-12 cells. However, the extracts and crude polysaccharides stimulated neuritogenesis without stimulating the production of NGF in PC-12 cells. The involvements of the TrkA receptor and MEK/ERK1/2 pathway in hot aqueous extract-stimulated neuritogenesis were examined by Trk (K252a) and MEK/ERK1/2 (U0126 and PD98059) inhibitors. There was no significant difference in protein expression in NGF- and hot aqueous extract-treated cells for both total and phosphorylated p44/42 MAPK. The neuritogenic activity in PC-12 cells stimulated by hot aqueous and ethanolic extracts, and crude polysaccharides of L. rhinocerotis sclerotium mimicking NGF activity via the MEK/ERK1/2 signaling pathway is reported for the first time.

Evaluation of neuritogenic activity of cultivated, wild and commercial roots of Gentiana lutea L.

Several natural products have been proven to prevent neurodegenerative disorders by potentiating the action of nerve growth factor (NGF). Among them, secoiridoids have recently attracted interest for their potential use as neuritogenic compounds. A source of these compounds is the root of Gentiana lutea L. used in food products to improve digestion. The aim of this work was to evaluate the neuritogenic activity of methanolic extracts of cultivated, wild and commercial roots of G. lutea using rat pheochromocytoma (PC12) cells. Neuritogenic activity was assessed by xCELLigence real time cell analysis system (RTCA DP), neurite outgrowth image analysis and immunofluorescence staining. Extracts at 12.5 and 25 µg/ml with or without NGF showed a marked stimulation of neuritogenesis, without cytotoxic effects, and their neuritogenic action was synergistic to NGF activity. These results represent the first evidence of the neuritogenic effects of G. lutea and of its potential use as a functional food ingredient.

Rice panicles: New promising unconventional cereal product for health benefits

Historically, rice has been served as a food and as an herbal remedy. The claimed therapeutic properties of rice-derived products have attracted a considerable amount of attention, but these therapeutic properties are currently underestimated. Rice panicles of Phitsanulok 2 (PL), Suphan Buri 1 (SP) and San Pa Tong 1 (ST) varieties were compared based on their antioxidant activities and total phenolic content (TPC). The crude fiber, fat and mineral contents of PL were significantly (p < 0.05) greater than those of SP and ST. Phenolics were particularly found in PL, including insoluble phenolics in the PL_50%EtOH_EtOAc (Ins), PL_EtOAc_Direct (Ins) and PL_EtOAc (Ins) extracts. These extracts were comparable in their TPC, and ABTS and DPPH scavenging activities. The FRAP reducing power of PL_EtOAc_Direct (Ins) was significantly (p < 0.05) greater than those of the others, and it was similar to the anti-tyrosinase effect. All of the extracts were non-cytotoxic in fibroblasts and cultured neurons. The neuroprotective and neuritogenic activities were significant (p < 0.05) in PL_50%EtOH_EtOAc (Ins). The extracts contained health-promoting phenolics, particularly p-coumaric (2477–3153 μg/ml), ferulic (329–347 μg/ml) and caffeic (387–413 μg/ml) acids. Rice panicle extracts are therefore highlighted as potential antioxidants for health promotion products.

Total Synthesis and Neuritogenic Activity Evaluation of Ganglioside PNG‐2A from the Starfish Protoreaster nodosus

AbstractThe total synthesis of ganglioside PNG‐2A from the starfish Protoreaster nodosus and its neuritogenic activity toward neuron‐like cells is described. The unique galactose‐enriched glycan moiety, in which an 8‐O‐methyl sialic acid residue is sandwiched between galactose residues, was constructed through an efficient 8‐O‐methylation and subsequent di‐tert‐butylsilylene‐assisted α‐glycosylation at the 4‐OH of the sialic acid residue with a Galfβ(1,3)Gal donor. In vitro biological evaluation in a rat adrenal pheochromocytoma (PC12) cell line revealed that the synthesized PNG‐2A potentiated the neurite outgrowth of PC12 cells in the presence of nerve growth factor (NGF).

Isofuranodiene: A neuritogenic compound isolated from wild celery (Smyrnium olusatrum L., Apiaceae)

In the search for neuroactive compounds that mimic the nerve growth factor (NGF) activity for the protection against neurodegenerative diseases, the potential medicinal values of foods and plants attracts intense interest. Isofuranodiene is the major constituent of the essential oil of wild celery (Smyrnium olusatrum L., Apiaceae). The cytotoxic effects of isofuranodiene towards rat neuronal PC-12 pheochromocytoma cells were determined by MTT assay, while the cell differentiation was evaluated with xCELLigence real time cell analysis system (RTCA DP), and the neuritogenic activity was assessed by neurite outgrowth image analysis. Isofuranodiene at concentrations of 25 and 12.5μM alone, or in combination with 50nM NGF, showed a marked stimulation of neuritogenesis, but it was more effective at 12.5μM with or without NGF. The present study reports the first evidence of the neuritogenic effects of isofuranodiene, which appears to be a promising neurotrophic and neuroprotective agent deserving further investigation.

First Total Synthesis of Ganglioside GAA‐7 from Starfish Asterias amurensis versi­color

AbstractThe first total synthesis of neuritogenic ganglioside GAA‐7 was achieved using the glucosyl ceramide (Glc‐Cer) cassette approach. The stereocenter triad within the ceramide moiety of the target molecule was efficiently established from D‐lyxose. The assembly of the ceramide moiety was followed by glycosylation with glucosyl donors to give Glc‐Cer cassettes, which underwent conjugation with the oligosaccharide moiety, followed by global deprotection. By using the most suitable Glc‐Cer cassette, the target molecule was successfully synthesized. In vitro evaluation indicated that the synthesized GAA‐7 and its glycan moiety both showed strong neuritogenic activity towards neuron‐like rat adrenal pheochromocytoma (PC12) cells in the presence of neurite growth factor.

Releasing Nrf2 to promote neurite outgrowth.

Releasing Nrf2 to promote neurite outgrowth.

Proteomic identification of calcium-binding chaperone calreticulin as a potential mediator for the neuroprotective and neuritogenic activities of fruit-derived glycoside amygdalin

Amygdalin is a fruit-derived glycoside with the potential for treating neurodegenerative diseases. This study was designed to identify the neuroprotective and neuritogenic activities of amygdalin. We initially demonstrated that amygdalin enhanced nerve growth factor (NGF)-induced neuritogenesis and attenuated 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in rat dopaminergic PC12 cells. To define protein targets for amygdalin, we selected a total of 11 mostly regulated protein spots from two-dimensional sodium dodecyl sulfate–polyacrylamide gel electrophoresis gels for protein identification by matrix-assisted laser desorption/ionization–time-of-flight–mass spectrometry. We verified the effect of amygdalin on six representative proteins (i.e., calreticulin, Hsp90β, Grp94, 14-3-3η, 14-3-3ζ/δ and Rab GDI-α) for biological relevance to neuronal survival and differentiation. Calcium-binding chaperone calreticulin is of special interest for its activities to promote folding, oligomeric assembly and quality control of proteins that modulate cell survival and differentiation. We transiently knocked down calreticulin expression by specific siRNA and studied its effect on the neuroprotective and neuritogenic activities of amygdalin. We found that amygdalin failed to enhance NGF-induced neuritogenesis in calreticulin-siRNA transfected cells. On the other hand, amygdalin rescued 6-OHDA-induced loss of calreticulin expression. We also found that amygdalin increased the intracellular calcium concentration possibly via inducing calreticulin. Collectively, our results demonstrated the role of calreticulin in mediating the neuroprotective and neuritogenic activities of amygdalin.

Botanical Drug Puerarin Coordinates with Nerve Growth Factor in the Regulation of Neuronal Survival and Neuritogenesis via Activating ERK1/2 and PI3K/Akt Signaling Pathways in the Neurite Extension Process

Nerve growth factor (NGF) regulates neuronal survival and differentiation by activating extracellular signal-regulated-kinases (ERK) 1/2 and phosphoinositide-3-kinase (PI3K)/Akt pathways in two distinct processes: latency process and neurite extension process. This study was designed to investigate whether botanical drug C-glucosylated isoflavone puerarin coordinates with NGF to regulate neuritogenesis via activating ERK1/2 and PI3K/Akt in neurite extension process. We investigated the neuroprotective and neurotrophic activities of puerarin in MPTP-lesioned mice and dopaminergic PC12 cells. The effects of puerarin on ERK1/2, Akt, Nrf2, and HO-1 were assessed by Western blotting. The neurite outgrowth was assayed by neurite outgrowth staining kit. Puerarin protected dopaminergic cells and ameliorated the behavioral impairments in MPTP-lesioned mice. Puerarin potentiated the effect of NGF on neuritogenesis in PC12 cells by >10-fold. Mechanistic studies revealed: (1) puerarin rapidly activated ERK1/2 and Akt, leading to the activation of Nrf2/heme oxygenase-1 (HO-1) pathways; (2) ERK1/2, PI3K/Akt, and HO-1 inhibitors attenuated the neuritogenic activity of puerarin. Notably, puerarin enhanced NGF-induced neuritogenesis in a timing-dependent manner. Puerarin effectively coordinated with NGF to stimulate neuritogenesis via activating ERK1/2 and PI3K/Akt pathways in neurite extension process. These results demonstrated a general mechanism supporting the therapeutic application of puerarin-related compounds in neurodegenerative diseases.

ChemInform Abstract: Chemical Construction and Structural Permutation of Neurotoxic Natural Product, Antillatoxin: Importance of the Three‐Dimensional Structure of the Bulky Side Chain

AbstractReview: 51 refs.

Molecular species analysis of monosialogangliosides from sea urchin Strongylocentrotus nudus by RPLC-ESI-MS/MS

Sea urchin gangliosides have been proved to contain neuritogenic activities, which related to their molecular compositions. This study reports a method utilizing reversed-phase chromatography coupled to mass spectrometry for structure investigation and molecular species determination of the monosialogangliosides from sea urchin Strongylocentrotus nudus. Two types of sulfated and nonsulfated monosialogangliosides were isolated from the sea urchin ovary. In MS2 spectra of both nonsulfated monosialoganglioside and sulfated monosialoganglioside, 2-6 linked sialic acids were identified by the characteristic fragments of 0,4A2-CO2 and 0,2A1. Fragment ions at m/z 139.1 and m/z 169.1 of nonsulfated monosialoganglioside might be characteristic for 8-sulfated sialic acid residue. Retention time of the molecules was effectively used in the characterization of unknown molecules, and molecules that differ in mass by only 0.04Da were easily differentiated.

Langaside, a novel secoiridolactone glycoside derivative from Tachiadenus longiflorus Griseb. (Gentianaceae) formed by a [2+2] cycloaddition reaction

Langaside (1), a secoiridoid lactone glucoside possessing a novel skeleton formed by a [2+2] cycloaddition reaction between the secoiridolactone glucoside, 1,9-trans-9,5-cis-sweroside, and p-coumaric acid was isolated from the fruits and flowers of the Malagasy Tachiadenus longiflorus Griseb. (Gentianaceae), alongside another seven known compounds. The structure of langaside was established using HRESIMS, IR and NMR spectroscopy and comparison of experimental and calculated electronic circular dichroism (ECD) spectra. Langaside was screened for its neuritogenic activity against SHSY-5Y cells and anticancer activity against the NCI59 human tumour cell panel but not found to be active.

Synthesis of caffeic acid phenethyl ester derivatives, and their cytoprotective and neuritogenic activities in PC12 cells.

Twenty-one caffeic acid phenethyl ester (CAPE) derivatives were synthesized, and characterized by IR, HR-MS, (1)H and (13)C NMR analyses. All compounds were evaluated for their cytoprotective effects against H2O2-induced cytotoxicity and neuritogenic activities in the neurite outgrowth in PC12 cells. Compounds 1 and 20 exhibited stronger cytoprotective activities than their parent compound CAPE at 4 nM. Compounds 1, 4, 12 and 13 showed potential neuritogenic activities at 0.5 nM, while compounds 19 and 20 induced neurite outgrowth at 10 nM. The results from this study suggested that CAPE and its derivatives may be potential functional food ingredients for the prevention of neurodegenerative diseases.