Carnosine's (CARN) anti-inflammatory potential in autoimmune diseases has been but scarcely investigated as yet. The aim of this study was to evaluate the therapeutic potential of CARN in rat adjuvant arthritis, in the model of carrageenan induced hind paw edema (CARA), and also in primary culture of chondrocytes under H2O2 injury. The experiments were done on healthy animals, arthritic animals, and arthritic animals with oral administration of CARN in a daily dose of 150 mg/kg b.w. during 28 days as well as animals with CARA treated by a single administration of CARN in the same dose. CARN beneficially affected hind paw volume and changes in body weight on day 14 and reduced hind paw swelling in CARA. Markers of oxidative stress in plasma and brain (malondialdehyde, 4-hydroxynonenal, protein carbonyls, and lag time of lipid peroxidation) and also activity of gamma-glutamyltransferase were significantly corrected by CARN. CARN also reduced IL-1alpha in plasma. Suppression of intracellular oxidant levels was also observed in chondrocytes pretreated with CARN. Our results obtained on two animal models showed that CARN has systemic anti-inflammatory activity and protected rat brain and chondrocytes from oxidative stress. This finding suggests that CARN might be beneficial for treatment of arthritic diseases.
The aim of this study was to evaluate the therapeutic potential of oxidative stress (OS) reduction by using pyridoindole (PI) antioxidants in adjuvant arthritis (AA). The substances tested were stobadine dipalmitate (STB) and SMe1. AA was used as animal model. The experiments included healthy animals, control arthritic animals and arthritic animals with administration of PI in the oral daily dose of 15 mg/kg b.m during 28 experimental days. The rats were sacrificed on day 28. Clinical and biochemical parameters were determined. The effect of PI administration was evaluated on the basis of the following parameters: (a) arthritis (volume of hind paws - HPW, change of animal body mass - CBM), (b) OS (chemiluminescence of whole blood - CWB, levels of thiobarbituric acid reacting substance - TBARS and of HNE- and MDA-protein adducts in plasma and activity of gamma-glutamyltransferase (GGT) in hind paw joint homogenates). The PI studied significantly increased the CBM of animals and corrected the HPW. STB also significantly decreased the activity of GGT in joint homogenates. SMe1 was more effective in decreasing plasmatic TBARS levels, but STB was more effective in reducing plasmatic HNE- and MDA-protein adducts. The assay for HNE- and MDA-adducts in plasma as a function of time was applied for the first time in AA. STB markedly decreased spontaneous and PMA-stimulated CWB and reduced neutrophil count. In summary, STB was more effective than SMe1 in reducing OS in AA. Our results showed that the reduction of OS in arthritis also corrected the clinical manifestations of the disease.
The biochemical link providing effective coordination between the mitochondrial ATP synthetic machinery and the contractile apparatus following transitions in cardiac work remains enigmatic. Studies were designed to determine whether activation of the actomyosin adenosinetriphosphatase (ATPase) is a necessary part of the signaling mechanism to the mitochondrial ATP synthase or whether a rise in cytosolic free Ca2+ is sufficient to activate the synthase. With the use of Langendorff-perfused rat hearts, cardiac work was varied via changes in perfusion pressure and by the inclusion of a beta-adrenergic agent. Furthermore, 2,3-butanedione monoxime and verapamil were used to vary independently either the activity of the actomyosin ATPase or the level of cytosolic free Ca2+. Determinations of the in vivo mitochondrial membrane potential [delta psi m; see Wan et al. Am. J. Physiol. 265 (Heart Circ. Physiol. 34): H445-H452, 1993] and its vectorial displacement during work transitions provide valuable information concerning direct activation of the ATP synthase and proton movement through the membrane domain of the synthase. Increased cardiac work in the presence of the beta-adrenergic agent resulted in a decrease in delta psi m. Addition of 2,3-butanedione monoxime decreased cardiac work but did not change delta psi m. The inclusion of verapamil resulted in similar decreases in cardiac work. However, delta psi m reversed back to a value observed under control, low-work conditions. These results in conjunction with data regarding levels of high-energy phosphates, free Mg2+, and adenosine 3',5'-cyclic monophosphate suggest a Ca(2+)-mediated increase in the activity of the ATP synthase.
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