iridoids and Neurodegenerative-Diseases

Central neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are one of the biggest health problems worldwide. Currently, there is no cure for these diseases. The Gardenia jasminoides fruit is a common herbal medicine in traditional Chinese medicine (TCM), and a variety of preparations are used as treatments for central nervous system (CNS) diseases. Pharmacokinetic studies suggest genipin is one of the main effective ingredients of G. jasminoides fruit extract (GFE). Accumulated research data show that genipin possesses a range of key pharmacological properties, such as anti-inflammatory, neuroprotective, neurogenic, antidiabetic, and antidepressant effects. Thus, genipin shows therapeutic potential for central neurodegenerative diseases. We review the pharmacological actions of genipin for the treatment of neurodegenerative diseases of the CNS. We also describe the potential mechanisms underlying these effects.

Topics: Animals; Anti-Inflammatory Agents; Humans; Hypoglycemic Agents; Iridoids; Nerve Growth Factors; Neurodegenerative Diseases; Neuroprotective Agents

Glutamate-induced neurotoxicity is related to excessive oxidative stress accumulation and results in the increase of neuronal cell death. In addition, glutamate has been reported to lead to neurodegenerative diseases, including Parkinson's and Alzheimer's diseases.It is well known that Fraxinus rhynchophylla contains a significant level of oleuropein (Ole), which exerts various pharmacological effects. However, the mechanism of neuroprotective effects of Ole is still poorly defined. In this study, we aimed to investigate whether Ole prevents glutamate-induced toxicity in HT-22 hippocampal neuronal cells. The exposure of the glutamate treatment caused neuronal cell death through an alteration of Bax/Bcl-2 expression and translocation of mitochondrial apoptosis-inducing factor (AIF) to the cytoplasm of HT-22 cells. In addition, glutamate induced an increase in dephosphorylation of dynamin-related protein 1 (Drp1), mitochondrial fragmentation, and mitochondrial dysfunction. The pretreatment of Ole decreased Bax expression, increased Bcl-2 expression, and inhibited the translocation of mitochondrial AIF to the cytoplasm. Furthermore, Ole amended a glutamate-induced mitochondrial dynamic imbalance and reduced the number of cells with fragmented mitochondria, regulating the phosphorylation of Drp1 at amino acid residue serine 637. In conclusion, our results show that Ole has a preventive effect against glutamate-induced toxicity in HT-22 hippocampal neuronal cells. Therefore, these data imply that Ole may be an efficient approach for the treatment of neurodegenerative diseases.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Cell Death; Cell Line; Dynamins; Fraxinus; Gene Expression Regulation; Glutamic Acid; Hippocampus; Iridoid Glucosides; Iridoids; Mice; Mitochondria; Mitochondrial Diseases; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Oxidative Stress; Phosphorylation; Proto-Oncogene Proteins c-bcl-2

Neurodegenerative diseases are becoming prevalent as the population ages. Geniposide could inhibit oxidative stress, reduce apoptosis, protect neuron, and has been used for therapy of the neurodegenerative diseases. The bioavailability of geniposide by nasal route is greater than that by oral administration. However, mucociliary clearance is a rate-limiting factor for nasal route administration. The objective of this study was to develop and evaluate a mucoadhesive, thermoreversible in situ nasal gel of geniposide. The poloxamers (P407, P188) and the hydroxypropyl methylcellulose were used as thermoreversible and mucoadhesive polymers, respectively. Borneol was used as a permeation enhancer. The hydrogel was prepared with the cold method and optimized by the response surface methodology-central composite design. Gelation temperature, pH, clarity, gel strength, mucoadhesive strength, in vitro and ex vivo release kinetics of formulations were evaluated. The optimized amounts of poloxamer407 (P407), poloxamer188 (P188) and hydroxypropyl methylcellulose were determined to be 19.4-20.5%, 1.1-4.0% and 0.3-0.6% respectively. The second-order polynomial equation in terms of actual factors indicated a satisfactory correlation between the independent variables and the response (R2 = 0.9760). An ANOVA of the empirical second-order polynomial model indicated the model was significant (P<0.01). P407, P188, P407×P188, P4072 and P1882 were significant model terms. The effects of P407 on gelation temperature were greater than those of other independent variables. The pH values of all the formulations were found to be within 6.3-6.5 which was in the nasal physiological pH range 4.5-6.5. The drug content, gel strength, mucoadhesive strength of the optimized formulations were 97-101%, 25-50 sec and 4000-6000 dyn/cm2 respectively. The in vitro release kinetics of cumulative release of geniposide was fitted to the zero-order model. The ex vivo cumulative release kinetics of geniposide was fitted to the Weibull model. This study concludes that the release of geniposide is controlled by gel corrosion, and that the permeation of geniposide is time-dependent. The more residence time, mucoadhesive, thermoreversible in situ nasal gel of geniposide for neurodegenerative diseases is of compliance and potential application.

Topics: Administration, Intranasal; Chromatography, High Pressure Liquid; Gels; Humans; Iridoids; Nasal Mucosa; Neurodegenerative Diseases; Temperature

The purpose of this work is to study the effect of catalpol, an iridoid from Rehmannia glutinosa on neurodegenerative changes induced by beta-amyloid peptide Abeta(25-35) or Abeta(25-35)+ibotenic acid and the underlying mechanism. Results showed that catalpol significantly improved the memory deficits in the neurodegenerative mouse model produced by injection of Abeta(25-35)+ibotenic acid to the nucleus magnocellularis basalis, yet it is neither a cholinesterase inhibitor nor a muscarinic (M) receptor agonist. Instead, the choline acetyl transferase (ChAT) activity and the M receptor density in brain were significantly decreased in the model mice and catalpol could significantly elevate their levels. Furthermore, the brain-derived neurotrophic factor (BDNF) content in brain was significantly decreased in the model mice and catalpol elevated it to normal level (83%+/-3% and 102%+/-2% of normal respectively). There is a significant positive correlation between BDNF content and memory. Primary culture of forebrain neurons revealed that aggregated Abeta(25-35) induced significant decrease of ChAT positive neuron number, neurite outgrowth length, and M receptor density, while catalpol added to the culture medium 2 h prior to Abeta addition showed significant dose dependent protective effect. Notably, 24 h and 48 h after the addition of Abeta to the cultured cells, the BDNF mRNA level in the neurons decreased to 76%+/-7% and 66%+/-3% of control without catalpol treatment, but became 128%+/-17% and 131%+/-23% of control with catalpol treatment. When the action of BDNF was inhibited by k252a in the cultured neurons, the protective effect of catalpol was completely (neurite outgrowth length) or partially (ChAT positive neuron number and the M receptor density) abolished. Taken together, catalpol improves memory and protects the forebrain neurons from neurodegeneration through increasing BDNF expression. Whether catalpol could reverse the neurodegenerative changes already present before its application remains to be further studied.

Topics: Amyloid beta-Peptides; Animals; Brain; Brain-Derived Neurotrophic Factor; Cells, Cultured; Choline O-Acetyltransferase; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Glucosides; Iridoid Glucosides; Iridoids; Learning; Memory; Mice; Mice, Inbred ICR; Neurites; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Muscarinic

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