Dietary conjugated linoleic acid as dietary medicament for the treatment of neurodegenerative disorders

Dietary conjugated linoleic acid as dietary medicament for the treatment of neurodegenerative disorders A. Petroni1 , M. Cappa2 , C. Bizzarri2 , C. Vacca3 , A.R. Sirigu3 , M.Blasevich1 , A. Piras3 and S. Banni3 1 Department of Pharmacological Sciences, via Balzaretti 9, Milan; 2 Department of Pediatrics Medicine, Endocrinology Unit, Children\u2019s Hospital \u201cBambino Ges\uf9\u201d, Rome; 3 Department of Experimental Biology, University of Cagliari, Italy. Neurodegenerative disorders are often associated to lipid metabolic alterations and secondary inflammatory processes. X-linked Adrenoleukodystrophy (X-ALD), a demyelinating disorder, is characterized by the abnormal accumulation of very long chain fatty acids (VLCFA). Lorenzo's Oil (LO), a mixture of glyceryl trioleate and glyceryl trierucate, is able to normalize lipid metabolic alterations in patients although not always the progression of the disease. Our objective was to introduce conjugated linoleic acid isomers (CLA) as therapeutic approach for X-ALD and for other neurodegenerative disorders. We tested a mixture of LO (40 g/day) with CLA (5 g/day) for 2 months, in female heterozygous X 12ALD individuals, to determine whether CLA crosses the blood-brain barrier and exerts a synergistic effect with LO. After the treatment, CLA was detected in the liquor indicating the passage through the blood-brain barrier and the mixture decreased the VLCFA 26:0 and the ratio 26:0/22:0 in plasma. Somatosensory evoked potentials were improved after the treatment with the mixture, whereas with dietary LO, were found unchanged. We conclude that the synergistic action of LO with CLA, besides inhibiting elongases and preventing the formation of 26:0, it enhances peroxisomal beta-oxidation both in peripheral tissues and in the brain, partially re-establishing the physiologic neurological function which in turn might improve the somatosensory evoked potentials. Our results are opening the field for a novel promising therapeutic strategy for X-ALD and other neurodegenerative disorders. Sponsor: Biomedicine and Nutrition Association, Italy (www.biomedicinanutrizione.org)

Design of noncompetitive interleukin-8 inhibitors acting on CXCR1 and CXCR2

Chemokines CXCL8 and CXCL1 play a key role in the recruitment of neutrophils at the site of inflammation. CXCL8 binds two membrane receptors, CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated. A novel class of small molecular weight allosteric CXCR1 inhibitors was identified, and reparixin, the first drug candidate, is currently under clinical investigation in the prevention of ischemia/reperfusion injury in organ transplantation. Reparixin binding mode to CXCR1 has been studied and used for a computer-assisted design program of dual allosteric CXCR1 and CXCR2 inhibitors. In this paper, the results of modeling-driven SAR studies for the identification of potent dual inhibitors are discussed, and three new compounds (56, 67, and 79) sharing a common triflate moiety have been selected as potential leads with optimized pharmacokinetic characteristic