Phytochemicals in ameliorating rheumatoid arthritis therapy: from preclinical studies to clinical applications Acronym: PhytoArt    

Project leaders

Gianluigi Russo, Katarína Bauerová

Agreement

REPUBBLICA SLOVACCA - SAS - Slovak Academy of Sciences

Call

CNR/SAV 2013-2015

Department

Agriculture and Food

Thematic area

Biology, agriculture and food sciences

Status of the project

Extended

Report for renewal

joint-report-russo-bauerova-11102012-allegati.pdf

Research proposal

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting approximately 1% of the population worldwide. Patients with RA have a significantly reduced life quality (degeneration of muscles and joints, muscle weakness, persistent pain) and they need a lifelong therapy. Resistance    and adverse effects frequently occur during antiarthritic therapy. There is thus an urgent need for introduction of new substances into medical practice.
Reactive oxygen and nitrogen species (ROS, RNS) can contribute to the pathogenesis of RA in a variety of ways, including induction of membrane oxidation and instability, irreversible damage to proteins and DNA, cartilage damage and induction of bone resorption. In addition, it has recently been appreciated that ROS/RNS can also modulate a variety of signaling events that control gene expression and affect cellular processes that participate in chronic inflammation.
In the past, our team in the frame of the CNR-SAV bilateral project using an animal model of arthritis induced by adjuvant (AA), monitored oxidative stress (OS) and inflammation, using different clinical and biochemical/immunological markers. We have simultaneously assessed the efficacy of the administered experimental substances with regard to their ability to reduce OS and inflammatory processes. In the experiments on AA rats, we observed a beneficial effect of administration of two endogenous compounds - coenzyme Q10 and chondroitin sulphate - and one compound related to the herbal polyphenols - pinosylvin. A further aim was to find a potential enhancement of the antirheumatic effect of methotrexate (MTX), a basic antirheumatic drug very often used worldwide in rheumatology practice. Coenzyme Q10 and pinosylvin were selected for assessment of a combinatory therapy with MTX. The already performed experiments on AA confirmed the hypothesis of the beneficial effect of adding a suitable immunomodulator/antioxidant compound to the MTX therapy. Safety and efficacy of these approaches calls for further more detailed research not only in preclinical but also in clinical conditions. The socio-economic aim is to provide new knowledge on "traditionally old" natural compounds in medical practice.
The substances of plant origin (arbutin, curcumin, quercetin, pterostilbene and pinosylvin), mostly synthesized, were studied in pilot studies in our AA model. We particularly monitored their ability to reduce the swelling of hind paws, and their effect on some markers of OS, not published in the scientific literature so far. Among the studied compounds, the most effective substance of plant origin was pinosylvin (PIN). Therefore it was selected to test its possible effectiveness in the combination therapy with MTX. In the new project, we would like to study not only PIN, but also other polyphenols as quercetin, N-feruloylserotonin and standardized green tea extract and its main secondary metabolites. Tea polyphenols, known as catechins, usually account for 30-40% of the dry weight of the solids in brewed green tea. The most well described in the literature is the (-)-epigallocatechin gallate (EGCG). It has been already reported that green tea consumed within a balanced controlled diet improves the overall antioxidative status and protects against oxidative damage in humans. Much interest has been centered on the role of green tea antioxidant activity in regards to the aging process and degenerative diseases like cancer, cardiovascular diseases and diabetes. We would like to place the emphasis to study its therapeutic potency in RA at clinical level (as adjuvant therapy of patients treated with MTX) and preclinical level (adjuvant arthritis model and cell cultures of chondrocytes and granulocyte/macrophage lineage cells). The main focus will be given to combinatory therapy with MTX.
PhytoArt is articulated in three years and includes three workpackages: 1. study of combination therapy (MTX plus selected phytochemicals) in Lewis rat, a model of AA; 2. study of combination therapy (MTX plus selected phytochemicals) on primary cell cultures; 3. pilot phase-1 clinical trial on subjects affected by RA treated with a combined therapeutic protocol.
 

Research goals

The work will be distributed within the three years foreseen by the project and will essentially include three workpackages (WPs):
WP-1: Study involving an animal model of AA;
WP-2: Study on primary cell cultures;
WP-3: Clinical studies on subjects affected by RA
 
WP-1: Animal model of AA: to test combination of different natural compounds associated with first line drugs.
WP-2: In vitro study on the protective role of selected phytochemicals on isolated rat primary cells injured with oxidative insults: study of the molecular mechanisms of protection.
WP-3: Combination therapy between methotrexate and phytochemicals against rheumatoid arthritis: from preclinical studies to potential clinical application

Last update: 20/04/2024