iridoids and Nerve-Degeneration

The amyloid plaques and neurofibrillary tangles found in the Alzheimer's disease (AD) brain arise as a result of self-assembly into fibrillar material of amyloid-β protein (Aβ) and hyperphosphorylated tau, respectively, through a pathological process starting with the appearance of aggregation nuclei and neurotoxic oligomers. Accordingly, the search of inhibitors of oligomer nucleation and growth is considered a promising target to prevent amyloid toxicity. In recent years, a number of dietary factors including antioxidants, vitamins, and polyphenols have been characterized for their ability to protect cells stressed by several factors including the presence of amyloid deposits as well as to inhibit amyloid self-assembly and cytotoxicity and some of them are currently in clinical trial. The present review summarizes the findings on the beneficial effects against neurodegeneration and other peripheral inflammatory and degenerative diseases of oleuropein aglycone (OLE), a natural phenol abundant in the extra virgin olive oil. The data presently available suggest that OLE could provide a protective and therapeutic effect against a number of pathologies, including AD as well as obesity, type 2 diabetes, non-alcoholic hepatitis, and other natural or experimentally-induced pathological conditions. Such a protection could result, at least in part, in a remarkable improvement of the pathological signs arising from stress conditions including oxidative stress, an excessive inflammatory response, and the presence of cytotoxic aggregated material. In particular, the recent data on the cellular and molecular correlates of OLE neuroprotection suggest it could also play a therapeutic role against AD.

Topics: Alzheimer Disease; Anti-Inflammatory Agents; Cognition Disorders; Humans; Inflammation; Iridoid Glucosides; Iridoids; Nerve Degeneration; Plaque, Amyloid

Na(+)-dependent and -independent transport sites were elucidated for glycine and L-leucine, respectively, in Chang liver cells, a human culture cell line. Findings of acceleration of the L-leucine uptake by the cells in the acidic medium and synchronized acidification within the cell membrane vesicles with the uptake by them all suggested contransport of L-leucine and proton and the uptake of L-leucine dependent on the inward proton gradient in Chang liver cells. Cotransport of L-leucine and proton was also demonstrated in human peripheral lymphocytes and accelerated by the addition of concanavalin A, probably accompanied by membrane hyperpolarization. It was shown that the Na(+)-gradient-dependent uptake of glycine can be regulated by insulin and 17 beta-estradiol in the rat uterus and by Ca(2+)-calmodulin and membrane potential in Chang liver cells. D-Aspartate uptake as a model of glutamate transport was characterized in rat hippocampal slices and found to consist of Na(+)-dependent (higher-affinity) and -independent (lower-affinity) components. The vulnerability of hippocampal neurons to the Alzheimer beta-amyloid protein was confirmed in vitro with primary cultured rat hippocampal neurons in the presence of the amyloid protein beta 1-42 or its core fragments. The toxicity of the amyloid protein could be blocked by the addition of insulin and several other growth factors to the medium. The addition of genipin, a plant-derived iridoid, was demonstrated to prevent the toxicity of a synthetic fragment of beta 1-42, beta 25-35. Genipin had a neuritogenic activity in PC12h cells, a rat pheochromocytoma cell line, an activity extremely sensitive to inhibitors of the nitrogen oxide (NO) synthase and soluble guanylate cyclase and an NO scavenger. It was also demonstrated in PC12h cells that the activation of the MAP kinase cascade was essential for the neuritogenesis of genipin. These properties of genipin are very comparable to those of nerve growth factor in the cells. It is considered likely that various useful, neurotrophic substances and their extracts will be found in plants in future.

Topics: Amino Acids; Amyloid beta-Peptides; Animals; Biological Transport; Cell Membrane; Cells, Cultured; Dendrites; Hippocampus; Humans; Hydrocortisone; Iridoid Glycosides; Iridoids; Nerve Degeneration; Neurons; Plants, Medicinal; Pyrans

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by motor neurons degeneration and muscular atrophy. There is no effective SMA treatment. Loganin is a botanical candidate with anti-inflammatory, anti-oxidant, glucose-lowering and anti-diabetic nephropathy activities. The aim of this study is to investigate the potential protective effects of loganin on SMA using two cellular models, SMN-deficient NSC34 cells and SMA patient fibroblasts, and an animal disease model, SMAΔ7 mice. In SMN-deficient NSC34 cells, loganin increased cell viability, neurite length, and expressions of SMN, Gemin2, SMN-Gemin2 complex, p-Akt, p-GSK-3β, p-CREB, BDNF and Bcl-2. However, both AG1024 (IGF-1 R antagonist) and IGF-1 R siRNA attenuated the protective effects of loganin on SMN level and cell viability in SMN-deficient NSC34 cells. In SMA patient fibroblasts, loganin up-regulated levels of SMN, FL-SMN2, and Gemins, increased numbers of SMN-containing nuclear gems, modulated splicing factors, and up-regulated p-Akt. Furthermore, in the brain, spinal cord and gastrocnemius muscle of SMAΔ7 mice, loganin up-regulated the expressions of SMN and p-Akt. Results from righting reflex and hind-limb suspension tests indicated loganin improved muscle strength of SMAΔ7 mice; moreover, loganin activated Akt/mTOR signal and inhibited atrogin-1/MuRF-1 signal in gastrocnemius muscle of SMAΔ7 mice. Loganin also increased body weight, but the average lifespan of loganin (20mg/kg/day)-treated SMA mice was 16.80±0.73 days, while saline-treated SMA mice was 10.91±0.96 days. In conclusion, the present results demonstrate that loganin provides benefits to SMA therapeutics via improving SMN restoration, muscle strength and body weight. IGF-1 plays an important role in loganin neuroprotection. Loganin can be therefore a valuable complementary candidate for treatment of neuromuscular diseases via regulation of muscle protein synthesis and neuroprotection.

Topics: Animals; Apoptosis; Cell Line; Cytoprotection; Disease Models, Animal; Dose-Response Relationship, Drug; Fibroblasts; Genetic Predisposition to Disease; Humans; Insulin-Like Growth Factor I; Iridoids; Mice; Mice, Transgenic; Motor Activity; Motor Neurons; Muscle Proteins; Muscle Strength; Muscle, Skeletal; Muscular Atrophy, Spinal; Mutation; Nerve Degeneration; Neuroprotective Agents; Phenotype; Phosphorylation; Protein Biosynthesis; Proto-Oncogene Proteins c-akt; RNA Interference; Signal Transduction; SKP Cullin F-Box Protein Ligases; Survival of Motor Neuron 1 Protein; Time Factors; TOR Serine-Threonine Kinases; Transfection; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Weight Gain

Parkinson's disease (PD) is a progressive neurodegenerative disorder, primarily affecting dopaminergic neurons in the substantia nigra. There is currently no cure for PD and present medications aim to alleviate clinical symptoms, thus prevention remains the ideal strategy to reduce the prevalence of this disease. The goal of this study was to investigate whether oleuropein (OLE), the major phenolic compound in olive derivatives, may prevent neuronal degeneration in a cellular dopaminergic model of PD, differentiated PC12 cells exposed to the potent parkinsonian toxin 6-hydroxydopamine (6-OHDA). We also investigated OLE's ability to mitigate mitochondrial oxidative stress and modulate the autophagic flux. Our results obtained by measuring cytotoxicity and apoptotic events demonstrate that OLE significantly decreases neuronal death. OLE could also reduce mitochondrial production of reactive oxygen species resulting from blocking superoxide dismutase activity. Moreover, quantification of autophagic and acidic vesicles in the cytoplasm alongside expression of specific autophagic markers uncovered a regulatory role for OLE against autophagic flux impairment induced by bafilomycin A1. Altogether, our results define OLE as a neuroprotective, anti-oxidative and autophagy-regulating molecule, in a neuronal dopaminergic cellular model.

Topics: Animals; Autophagy; Cell Death; Iridoid Glucosides; Iridoids; Mitochondria; Nerve Degeneration; Oxidative Stress; Oxidopamine; Parkinson Disease; PC12 Cells; Rats; Reactive Oxygen Species; Superoxides

The protective effect of an iridoid catalpol extracted and purified from the traditional Chinese medicinal herb Rehmannia glutinosa on the neuronal degeneration of nigral-striatal dopaminergic pathway was studied in a chronic 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP)/probenecid C57BL/6 mouse model and in 1-methyl-4-phenylpyridimium (MPP(+)) intoxicated cultured mesencephalic neurons. Rotarod performance revealed that the locomotor ability of mice was significantly impaired after completion of model production and maintained thereafter for at least 4 weeks. Catalpol orally administered for 8 weeks (starting from the second week of model production) dose dependently improved the locomotor ability. HPLC revealed that catalpol significantly elevated striatal dopamine levels without changing the metabolite/dopamine ratios. Nor did it bind to dopamine receptors. Therefore it is unlikely that catalpol resembles any of the known compounds for treating Parkinsonism. Instead, catalpol dose dependently raised the tyrosine hydroxylase (TH) neuron number in substantia nigra pars compacta (SNpc), the striatal dopamine transporter (DAT) density and the striatal glial cell derived neurotrophic factor (GDNF) protein level. Linear regression revealed that both the TH neuron number and DAT density were positively correlated to the GDNF level. In the cultured mesencephalic neurons, MPP(+) decreased the dopaminergic neuron number and shortened the neurite length, whereas catalpol showed protective effect dose dependently. Furthermore, the expression of GDNF mRNA was up-regulated by catalpol to a peak nearly double of normal control in neurons intoxicated with MPP(+) for 24 h but not in normal neurons. The GDNF receptor tyrosine kinase RET inhibitor 4-amino-5-(4-methyphenyl)-7-(t-butyl)-pyrazolo-[3,4-d]pyrimidine (PP1) abolished the protective effect of catalpol either partially (TH positive neuron number) or completely (neurite length). Taken together, catalpol improves locomotor ability by attenuating the neuronal degeneration of nigral-striatal dopaminergic pathway, and this attenuation is at least partially through elevating the striatal GDNF expression.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Brain; Cells, Cultured; Chronic Disease; Corpus Striatum; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Glial Cell Line-Derived Neurotrophic Factor; Glucosides; Iridoid Glucosides; Iridoids; Male; Mesencephalon; Mice; Mice, Inbred C57BL; Motor Activity; Nerve Degeneration; Neural Pathways; Neurons; Neuroprotective Agents; Probenecid; Substantia Nigra

Our previous study described the neuroprotective effects of catalpol in gerbil ischemic model, in which catalpol was shown to prevent hippocampal neurons from death and ameliorate the cognitive ability of the animals. In the study, we focused on investigating the neuroprotective mechanism of catalpol. Animals were randomly assigned three groups as sham-operated, ischemia-treated with saline and ischemia-treated with catalpol. Transient global ischemia was produced by a 5 min occlusion of the bilateral common carotid arteries. Catalpol was intraperitoneally injected at the dose of 5 mg/kg immediately after reperfusion and repeatedly at 12, 24, 48 and 72 h. Histology as well as immunohistochemistry and TUNEL (the terminal deoxynucleotidyl transferase-mediated UTP nick end label) analysis were performed on serial slices through the dorsal hippocampus after gerbils were sacrificed. The results showed that 5 min transient global ischemia followed by 4 days reperfusion caused significant increases in TUNEL-positive and Bax-positive cells in hippocampal CA1 subfield. Catalpol not only significantly reduced TUNEL-positive and Bax-positive cells but also significantly increased Bcl-2-positive cells. All these suggested that catalpol could effectively inhibit apoptosis by modulating the expressions of Bcl-2 and Bax genes.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Brain Infarction; Brain Ischemia; Disease Models, Animal; Drug Administration Schedule; Drugs, Chinese Herbal; Female; Gene Expression Regulation, Enzymologic; Gerbillinae; Glucosides; Hippocampus; Immunohistochemistry; In Situ Nick-End Labeling; Iridoid Glucosides; Iridoids; Male; Nerve Degeneration; Neuroprotective Agents; Proto-Oncogene Proteins c-bcl-2; Reperfusion Injury; Treatment Outcome

Inflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Microglia, the resident immune cells in the central nervous system, are pivotal in the inflammatory reaction. Activated microglia can induce expression of inducible nitric-oxide synthase (iNOS) and release significant amounts of nitric oxide (NO) and TNF-alpha, which can damage the dopaminergic neurons. Catalpol, an iridoid glycoside, contained richly in the roots of Rehmannia glutinosa, was found to be neuroprotective in gerbils subjected to transient global cerebral ischemia. But the effect of catalpol on inflammation-mediated neurodegeneration has not been examined. In this study, microglia in mesencephalic neuron-glia cultures were activated with lipopolysaccharide (LPS) and the aim of the study was to examine whether catalpol could protect dopaminergic neurons from LPS-induced neurotoxicity. The results showed that catalpol significantly reduced the release of reactive oxygen species (ROS), TNF-alpha and NO after LPS-induced microglial activation. Further, catalpol attenuated LPS-induced the expression of iNOS. As determined by immunocytochemical analysis, pretreatment by catalpol dose-dependently protected dopaminergic neurons against LPS-induced neurotoxicity. These results suggest that catalpol exerts its protective effect on dopaminergic neurons by inhibiting microglial activation and reducing the production of proinflammatory factors. Thus, catalpol may possess therapeutic potential against inflammation-related neurodegenerative diseases.

Topics: Animals; Cells, Cultured; Coculture Techniques; Dopamine; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Glucosides; Inflammation; Iridoid Glucosides; Iridoids; Lipopolysaccharides; Mesencephalon; Mice; Nerve Degeneration; Neurodegenerative Diseases; Neuroglia; Neurons; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase Type II; Reactive Oxygen Species; Tumor Necrosis Factor-alpha