ABSTRACT
Title
Protective effects of the poliaminocarboxylic compound Mn(II)Me2DO2A in osteoarticular pain models.
Authors
1Di Cesare Mannelli L., 2Bani D., 3Bencini A., 3Valtancoli B., 1Biffi Gentili G., 1Zanardelli M., 1Ghelardini C., 1Failli P.
1Dept. of Pharmacology, 2 Dept. of Anatomy, Histology and Forensic Medicine, and 3Dept. of Chemistry, University of Florence.
1Dept. of Pharmacology, 2 Dept. of Anatomy, Histology and Forensic Medicine, and 3Dept. of Chemistry, University of Florence.
Abstract
Reactive oxygen species (ROS) are normal by-products of cellular metabolism and achieve as second messengers in physiological conditions. However, in numerous degenerative and inflammatory diseases, ROS production is dramatically increased and this excess can induce cell, tissue and organ toxicity [1]. Among other pathological conditions, their over-production is well described in rheumatoid arthritis [2], osteoarthritis and osteoarticular pathologies [3]. In addition, ROS are an important determinant of pain [4]. On this basis, anti-oxidant compounds and in particular superoxide dismutase (SOD) mimetics have been proposed as therapeutic agents in the treatment of osteoarticular diseases and inflammatory pain syndromes.
The manganese(II) complex with the organic ligand 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (Mn(II)Me2DO2A) is an effective, potent scavenger for superoxide anion in cell lines ([5]; patent application PCT/IB2009/053859, Sept. 4, 2009). Therefore, in this work Mn(II)Me2DO2A has been tested as anti-inflammatory/analgesic compound in several experimental models of osteoarticular pain.
All experiments were performed on rats and were approved by the Ethical Committee for animal experimental procedure. Pain threshold was evaluated by measuring the mechanical hyperalgesia by paw pressure test. Plasma TNF-α was measured by ELISA; carbonylated plasma proteins were quantified by western blot followed by densitometric analysis.
Three hours after carrageenan edema induction (carrageenan: 1%, 0.1 ml, intraplantary), Mn(II)Me2DO2A at the doses 5 mg/kg and 15 mg/kg i.p. (acutely administered), reduced inflammatory pain. Moreover, acutely administered at the same doses, it reduced the chronic pain induced by complete Freund’s adjuvant intraarticular injection (CFA; 50 μl, 7 days before pain evaluation) or monoiodoacetate (MIA; 2mg/25 μl, 14 days before pain evaluation). In chronic administration (15mg/kg subcutaneous infusion for 14 days), Mn(II)Me2DO2A prevented the increase in plasma TNF-α and reduced the histological modification of tibio-tarsal joint induced by MIA. At the doses tested, Mn(II)Me2DO2A was well tolerated in acute and chronic administration .
These data suggest that Mn(II)Me2DO2A can be used as a valuable tool in pain relieve and it could be a promising therapeutic agent in the treatment and cure of osteoarticular diseases.
[1] Halliwell B. (1987) FASEB J., 1:358-364.
[2] Weissmann G. (2004) J Clin Rheumatol, 10: S26-31.
[3] Henrotin Y., Kurz B. & Aigner T. (2005) OsteoArthritis Cartilage,13, 643-654.
[4] Tal M. (1996) NeuroReport 7, 1382–1384.
[5] Failli P., Bani D., Bencini A., Cantore M., Di Cesare Mannelli L., Ghelardini C., Giorgi C., Innocenti M., Rugi F., Spepi A., Udisti R., Valtancoli B.(2009) J. Med. Chem., 52, 7273–7283.
The manganese(II) complex with the organic ligand 4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (Mn(II)Me2DO2A) is an effective, potent scavenger for superoxide anion in cell lines ([5]; patent application PCT/IB2009/053859, Sept. 4, 2009). Therefore, in this work Mn(II)Me2DO2A has been tested as anti-inflammatory/analgesic compound in several experimental models of osteoarticular pain.
All experiments were performed on rats and were approved by the Ethical Committee for animal experimental procedure. Pain threshold was evaluated by measuring the mechanical hyperalgesia by paw pressure test. Plasma TNF-α was measured by ELISA; carbonylated plasma proteins were quantified by western blot followed by densitometric analysis.
Three hours after carrageenan edema induction (carrageenan: 1%, 0.1 ml, intraplantary), Mn(II)Me2DO2A at the doses 5 mg/kg and 15 mg/kg i.p. (acutely administered), reduced inflammatory pain. Moreover, acutely administered at the same doses, it reduced the chronic pain induced by complete Freund’s adjuvant intraarticular injection (CFA; 50 μl, 7 days before pain evaluation) or monoiodoacetate (MIA; 2mg/25 μl, 14 days before pain evaluation). In chronic administration (15mg/kg subcutaneous infusion for 14 days), Mn(II)Me2DO2A prevented the increase in plasma TNF-α and reduced the histological modification of tibio-tarsal joint induced by MIA. At the doses tested, Mn(II)Me2DO2A was well tolerated in acute and chronic administration .
These data suggest that Mn(II)Me2DO2A can be used as a valuable tool in pain relieve and it could be a promising therapeutic agent in the treatment and cure of osteoarticular diseases.
[1] Halliwell B. (1987) FASEB J., 1:358-364.
[2] Weissmann G. (2004) J Clin Rheumatol, 10: S26-31.
[3] Henrotin Y., Kurz B. & Aigner T. (2005) OsteoArthritis Cartilage,13, 643-654.
[4] Tal M. (1996) NeuroReport 7, 1382–1384.
[5] Failli P., Bani D., Bencini A., Cantore M., Di Cesare Mannelli L., Ghelardini C., Giorgi C., Innocenti M., Rugi F., Spepi A., Udisti R., Valtancoli B.(2009) J. Med. Chem., 52, 7273–7283.