rosmarinic-acid and Parkinson-Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. The main therapeutic approach available nowadays relieves motor symptoms but does not prevent or stop neurodegeneration. Rosmarinic acid (RA), an ester of caffeic and 3,4-dihydroxyphenylacetic acids, is obtained from numerous plant species such as Salvia officinalis L. (sage) and Rosmarinus officinalis (rosemary). This compound has a wide spectrum of biological activities, such as antioxidant and anti-inflammatory, and could be an additional therapy for neurodegenerative disorders. Here we evaluated the potential neuroprotective effects of RA treatment in a murine model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Mice were separated into four groups: CN, Control/saline; RA, Rosmarinic acid/vehicle; MPTP, MPTP/saline; MPTP+RA, MPTP/RA. RA (20 mg/kg, or vehicle) was administered orally by intra-gastric gavage for 14 days, one hour before MPTP or saline injection. MPTP groups received the drug (30 mg/kg, intraperitoneally) once a day for five days (fourth to the eighth day of the experiment). MPTP-treated animals displayed hyperlocomotion behavior, which was significantly prevented by RA treatment. In addition, RA treatment increased dopaminergic signaling in the parkinsonian mice and improved the monoaminergic system in healthy animals. Analysis of alterations in the striatal mRNA expression of dopaminergic system components showed that MAO-A expression was increased in the MPTP+AR group. Overall, this study brings new evidence of the potential neuroprotective properties of RA not only in preventing behavioral features observed in PD, but also by improving neurotransmission in the healthy brain.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Dopamine; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Neuroprotective Agents; Parkinson Disease; Rosmarinic Acid

Intracellular aggregation of α-synuclein is a major pathological feature of Parkinson's disease. In this study, we show that the polyphenols delphinidin and rosmarinic acid suppress intracellular aggregation of α-synuclein in a mouse neuron cell model when added under oxidative stress conditions. To enhance the detection threshold of this preventive effect of the two polyphenols, we generated a new strain of "aggregation prone model cells" that tended to show prominent α-synuclein aggregation even under normal conditions. Using this new highly sensitive cell line, we demonstrate that addition of delphinidin to model cell cultures effectively suppresses the formation of intracellular α-synuclein aggregates. Flow cytometric analysis shows that adding delphinidin decreases the fraction of "dying cells," cells that were alive but in a damaged state. Our findings suggest the possibility of using polyphenols to prevent and treat the symptoms correlated with the onset of Parkinson's disease. Additionally, our aggregation-prone cell model may be used in future studies to probe numerous neurodegenerative diseases with high sensitivity.

Topics: alpha-Synuclein; Animals; Mice; Neurons; Parkinson Disease; Polyphenols; Rosmarinic Acid

Rosmarinic acid (RA) is a natural polyphenolic compound with antioxidative property. With the present study, we aimed to evaluate the neuroprotective role of RA on Parkinson's disease using rotenone induced SH-SY5Y cell model of Parkinson's disease, the underlying mechanism of action of RA was also investigated. Cell viability, cell morphology, apoptosis, signaling protein phosphorylation and expression, cellular reactive oxygen species (ROS) production, ATP content, and mitochondrial membrane potential were tested in SH-SY5Y cells. RA showed a neuroprotective effect in a rotenone-induced SH-SY5Y cell model of Parkinson's disease with dose-dependent manner, it reduced cell apoptosis and restored normal cell morphology. RA not only decreased levels of α-synuclein and Tau phosphorylation but also elevated the contents of AMPK phosphorylation, Akt phosphorylation, and PGC-1α. RA restored the reduced mitochondrial membrane potential and ATP content as well as inhibited rotenone-induced ROS overproduction. Further findings demonstrated that the neuroprotective role of RA was partially due to the inhibition of Abl tyrosine kinase. RA treatment suppressed the hyperphosphorylation of Abl Y412 and CrkII Y221 induced by rotenone. Nilotinib, a specific inhibitor of Abl, elicited a similar neuroprotective effect as that of RA. The present study indicates that RA has a property of neuroprotection against rotenone, and the neuroprotective effect is partially attributed to the inhibition of Abl.

Topics: Adenosine Triphosphate; Apoptosis; Cell Line, Tumor; Cell Survival; Cinnamates; Depsides; Humans; Neuroblastoma; Neuroprotective Agents; Neurotoxicity Syndromes; Parkinson Disease; Reactive Oxygen Species; Rosmarinic Acid; Rotenone

Topics: Animals; Apoptosis; Cinnamates; Depsides; Inflammation; Mice; Mice, Inbred C57BL; MicroRNAs; Neurodegenerative Diseases; Oxidative Stress; Parkinson Disease; Rosmarinic Acid

Caspase-3 has been identified as a key mediator of neuronal apoptosis. The present study identifies caspase-3 as a common player involved in the regulation of multineurodegenerative disorders, namely, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The protein interaction network prepared using STRING database provides a strong evidence of caspase-3 interactions with the metabolic cascade of the said multineurodegenerative disorders, thus characterizing it as a potential therapeutic target for multiple neurodegenerative disorders. In silico molecular docking of selected nonpeptidyl natural compounds against caspase-3 exposed potent leads against this common therapeutic target. Rosmarinic acid and curcumin proved to be the most promising ligands (leads) mimicking the inhibitory action of peptidyl inhibitors with the highest Gold fitness scores 57.38 and 53.51, respectively. These results were in close agreement with the fitness score predicted using X-score, a consensus based scoring function to calculate the binding affinity. Nonpeptidyl inhibitors of caspase-3 identified in the present study expeditiously mimic the inhibitory action of the previously identified peptidyl inhibitors. Since, nonpeptidyl inhibitors are preferred drug candidates, hence, discovery of natural compounds as nonpeptidyl inhibitors is a significant transition towards feasible drug development for neurodegenerative disorders.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Apoptosis; Caspase 3; Caspase Inhibitors; Cinnamates; Curcumin; Depsides; Humans; Huntington Disease; Ligands; Molecular Docking Simulation; Neurodegenerative Diseases; Parkinson Disease; Rosmarinic Acid

Rosmarinic acid (RA) is a naturally occurring polyphenolic compound found in various plant families. We previously reported that RA exerted protective effects against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity through antioxidative properties. In this study, we investigated whether RA could prevent effects of 1-methyl-4-phenylpyridinium (MPP(+))-induced insult in MES23.5 dopamineric cells. 1-Methyl-4-phenylpyridinium treatment decreased cell viability and dopamine content, as well as caused apoptotic morphological changes. 1-Methyl-4-phenylpyridinium-induced mitochondrial dysfunction, indicated by inhibition of activity associated with mitochondrial respiratory chain complex I, suggested mitochondrial transmembrane potential collapse and generation of reactive oxygen species. Decreased Bcl-2/Bax ratio and caspase 3 activation were also observed. Rosmarinic acid pretreatment restored the complex I activity of the mitochondrial respiratory chain and partially reversed the other damaging effects of MPP(+). Our results indicate that RA plays a neuroprotective role by ameliorating mitochondrial dysfunction against MPP(+)-induced cell apoptosis and suggest that RA has the potential to be considered an aid for prevention of Parkinson's disease.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Antioxidants; Apoptosis; Apoptosis Regulatory Proteins; Cell Line; Cell Survival; Cinnamates; Depsides; Dopamine; Electron Transport Complex I; Gene Expression Regulation; Herbicides; Membrane Potential, Mitochondrial; Mice; Neurons; Neuroprotective Agents; Parkinson Disease; Rats; Reactive Oxygen Species; RNA, Messenger; Rosmarinic Acid