rhyncophylline and Alzheimer-Disease

Alzheimer's disease (AD), the most common neurodegenerative disease, has limited treatment options. As such, extensive studies have been conducted to identify novel therapeutic approaches. We previously reported that rhynchophylline (Rhy), a small molecule EphA4 inhibitor, rescues impaired hippocampal synaptic plasticity and cognitive dysfunctions in APP/PS1 mice, an AD transgenic mouse model. To assess whether Rhy can be developed as an alternative treatment for AD, it is important to examine its pharmacokinetics and effects on other disease-associated pathologies. Here, we show that Rhy ameliorates amyloid plaque burden and reduces inflammation in APP/PS1 mice. Transcriptome analysis revealed that Rhy regulates various molecular pathways in APP/PS1 mouse brains associated with amyloid metabolism and inflammation, specifically the ubiquitin proteasome system, angiogenesis, and microglial functional states. These results show that Rhy, which is blood-brain barrier permeable, is beneficial to amyloid pathology and regulates multiple molecular pathways.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative Diseases; Oxindoles; Plaque, Amyloid; Presenilin-1

Alzheimer's disease (AD) is a growing concern in the modern society. The current drugs approved by FDA are not very promising. Rhynchophylline (RIN) is a major active tetracyclic oxindole alkaloid stem from traditional Chinese medicine uncaria species, which has potential activities beneficial for the treatment of AD. However, the application of rhynchophylline for AD treatment is restricted by the low water solubility, low concentration in brain tissue and low bioavailability. And there is no study of brain-targeting therapy with RIN. In this work, we prepared rhynchophylline loaded methoxy poly (ethylene glycol)-poly (dl-lactide-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPS-RIN), which coupled with Tween 80 (T80) further for brain targeting delivery (T80-NPS-RIN).. Preparation and characterization of T80-NPS-RIN were followed by the detection of transportation across the blood-brain barrier (BBB) model in vitro, biodistribution and neuroprotective effects of nanoparticles.. The results indicated T80-NPS-RIN could usefully assist RIN to pass through the BBB to the brain. T80-NPS-RIN treatment regulated the activity of neurons in vitro.. The presented data confirmed that rhynchophylline encapsulated mPEG-PLGA nanoparticles coated with Tween 80 could across through the BBB and exhibited efficient neuroprotective effects. The T80-NPS-RIN nanoparticles have a chance to be an alternative drug to the therapy of AD.

Topics: Alzheimer Disease; Animals; Blood-Brain Barrier; Disease Models, Animal; Male; Mice, Inbred C57BL; Nanoparticles; Neurons; Neuroprotective Agents; Oxindoles; PC12 Cells; Polyesters; Polyethylene Glycols; Polysorbates; Rabbits; Rats; Rats, Sprague-Dawley; Tissue Distribution

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cognition Disorders; Cognitive Dysfunction; Disease Models, Animal; Female; Hippocampus; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroimmunomodulation; Oxindoles; Presenilin-1; tau Proteins

The progressive accumulation of amyloid-β (Aβ) in the form of senile plaques has been recognized as a key causative factor leading to the cognitive deficits seen in Alzheimer's disease (AD). Recent evidence indicates that Aβ induces neurotoxicity in the primary neuronal cultures as well as in the brain. Previously, we have demonstrated that isorhynchophylline (IRN), the major chemical ingredient of Uncaria rhynchophylla, possessed potent neuroprotective effects. In the present study, we aimed to investigate the effect of IRN on cognitive function, neuronal apoptosis, and tau protein hyperphosphorylation in the hippocampus of the Aβ25-35-treated rats and to elucidate its action mechanisms. We showed that Aβ25-35 injection caused spatial memory impairment, neuronal apoptosis, and tau protein hyperphosphorylation. Treatment with IRN (20 or 40 mg/kg) for 21 days could significantly ameliorate the cognitive deficits induced by Aβ25-35 in the rats. In addition, IRN attenuated the Aβ25-35-induced neuronal apoptosis in hippocampus by down-regulating the protein and mRNA levels of the ratio of Bcl-2/Bax, cleaved caspase-3 and caspase-9, as well as suppressing the tau protein hyperphosphorylation at the Ser396, Ser404, and Thr205 sites. Mechanistic study showed that IRN could inhibit the glycogen synthase kinase 3β (GSK-3β) activity, and activate the phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. These results indicate that down-regulation of GSK-3β activity and activation of PI3K/Akt signaling pathway are intimately involved in the neuroprotection of IRN. The experimental findings provide further evidence to affirm the potential of IRN as a worthy candidate for further development into a therapeutic agent for AD and other tau pathology-related neurodegenerative diseases.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apoptosis; bcl-2-Associated X Protein; Caspases; Cognition Disorders; Cytochromes c; Disease Models, Animal; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hippocampus; Indole Alkaloids; Male; Maze Learning; Neurons; Neuroprotective Agents; Oxindoles; Peptide Fragments; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Space Perception; tau Proteins

The major medicinal alkaloids isolated from Uncaria rhynchophylla (gouteng in chinese) capsules are rhynchophylline (RIN) and isorhynchophylline (IRN). Extracts containing these terpene indole alkaloids (TIAs) can inhibit the formation and destabilize preformed fibrils of amyloid β protein (a pathological marker of Alzheimer's disease), and have been shown to improve the cognitive function of mice with Alzheimer-like symptoms. The biosynthetic pathways of RIN and IRN are largely unknown.. In this study, RNA-sequencing of pooled Uncaria capsules RNA samples taken at three developmental stages that accumulate different amount of RIN and IRN was performed. More than 50 million high-quality reads from a cDNA library were generated and de novo assembled. Sequences for all of the known enzymes involved in TIAs synthesis were identified. Additionally, 193 cytochrome P450 (CYP450), 280 methyltransferase and 144 isomerase genes were identified, that are potential candidates for enzymes involved in RIN and IRN synthesis. Digital gene expression profile (DGE) analysis was performed on the three capsule developmental stages, and based on genes possessing expression profiles consistent with RIN and IRN levels; four CYP450s, three methyltransferases and three isomerases were identified as the candidates most likely to be involved in the later steps of RIN and IRN biosynthesis.. A combination of de novo transcriptome assembly and DGE analysis was shown to be a powerful method for identifying genes encoding enzymes potentially involved in the biosynthesis of important secondary metabolites in a non-model plant. The transcriptome data from this study provides an important resource for understanding the formation of major bioactive constituents in the capsule extract from Uncaria, and provides information that may aid in metabolic engineering to increase yields of these important alkaloids.

Topics: Alzheimer Disease; Gene Expression Profiling; Genes, Plant; High-Throughput Nucleotide Sequencing; Indole Alkaloids; Molecular Sequence Annotation; Oxindoles; Sequence Analysis, RNA; Sequence Homology, Nucleic Acid; Uncaria