AbstractBackgroundPerinatal exposure to hyperhomocysteinemia might disturb neurogenesis during brain development and growth. Also, high levels of homocysteine trigger neurodegeneration in several experimental models. However, the putative mechanisms of homocysteine-induced toxicity in the developing nervous system have poorly been elucidated. This study was aimed to investigate homocysteine effects in undifferentiated neuroblastoma cells, Neuro2a.ResultsA 4 h exposure to homocysteine in a concentration range of 10–100 μM did not affect cell viability and ROS production in Neuro2a cell cultures. Instead, ROS levels were increased by two-three folds in cells treated with 250 μM and 500 μM homocysteine, respectively, in comparison with control cells. Also, the highest homocysteine dose significantly reduced the viable cell number by 40%. Notably, the treatment with homocysteine (250 μM–500 μM) in the presence of antioxidants, such as N-acetylcysteine and IRFI 016, a synthetic α-tocopherol analogue, recovered cell viability and significantly reduced homocysteine-evoked increases in ROS production. Moreover, antioxidants, particularly IRFI 016, were able to counteract NF-κB activation induced by 250 μM homocysteine.Cell treatment with 250 μM homocysteine also triggered the onset of apoptosis, as demonstrated by the increased expression of early apoptotic markers such as Bax, caspase-3 and p53. In contrast, Bcl2 expression was not affected by homocysteine exposure. Interestingly, the specific inhibition of NF-κB nuclear translocation by the synthetic peptide SN50 was able to almost completely suppress the homocysteine-evoked rises in pro-apoptotic protein expression as well as in caspase-3 activity. Further, also IRFI 016 and N-acetylcysteine were able to significantly reduce caspase-3 activation induced by homocysteine treatment.ConclusionThese observations suggest an involvement of redox state alterations and activated NF-κB in apoptosis onset triggered by homocysteine in neuroblastoma cells Neuro2a. However, further investigations are needed to characterize molecular events involved in the NF-κB activation induced by homocysteine.

01 Mar 2007·Mini-Reviews in Medicinal ChemistryQ3 · MEDICINE

Raxofelast, (±)5-(Acetyloxy)-2,3-dihydro-4,6,7-trimethyl-2-benzofuranacetic Acid: A New Antioxidant to Modulate the Inflammatory Response During Ischemia-Reperfusion Injury and Impaired Wound Healing

Q3 · MEDICINE

Review

Author: Bitto, A. ; Squadrito, F. ; Altavilla, D. ; Polito, F. ; Minutoli, L.

Raxofelast, also named IRFI 016 or (+/-)5-(acetyloxy)-2,3-dihydro-4,6,7-trimethyl-2-benzofuranacetic acid, belongs to a family of novel molecules designed with the aim to maximize antioxidant potency of phenols related to Vitamin E (alpha-tocopherol). This review will focus on the antioxidant and radical scavenging activity of this new promising compound.

01 Oct 2006·Journal of UrologyQ1 · MEDICINE

Lipid Peroxidation Activates Mitogen-Activated Protein Kinases in Testicular Ischemia-Reperfusion Injury

Q1 · MEDICINE

Article

Author: Nicòtina, Piero Antonio ; Antonuccio, Pietro ; Squadrito, Francesco ; Bitto, Alessandra ; Minutoli, Letteria ; Altavilla, Domenica ; Polito, Francesca ; Zuccarello, Biagio ; Arena, Salvatore ; Romeo, Carmelo

PURPOSETesticular damage after torsion has been attributed to many mechanisms, of which one is lipid peroxidation of the plasma membrane, which could cause the activation of the mitogen-activated protein kinase family. These proteins are of vital importance for signal transduction pathways and 2 of them, extracellular signal-regulated kinase and c-jun N-terminal kinase, participate in the pathogenesis of testicular ischemia. We investigated whether lipid peroxidation may trigger mitogen-activated protein kinase activation in testicular ischemia-reperfusion.MATERIALS AND METHODSAdult male Sprague-Dawley rats were subjected to 1-hour testicular ischemia, followed by 24 hours of reperfusion. Sham testicular ischemia-reperfusion rats served as controls. Animals were randomized to receive raxofelast, an inhibitor of lipid peroxidation (20 mg/kg intraperitoneally administered 15 minutes before detorsion and 15 minutes after detorsion) or vehicle (1 ml/kg 10% dimethyl sulfoxide/NaCl solution). A group of animals was sacrificed 0, 10, 15, 20, 25 and 30 minutes, and 1, 2 and 3 hours, respectively, after detorsion to evaluate testicular c-jun N-terminal kinase, extracellular signal-regulated kinase and tumor necrosis factor-alpha activation by Western blot analysis, and mRNA expression and conjugated dienes using a spectrophotometer technique. Another group was sacrificed 24 hours after detorsion to evaluate histological alterations.RESULTSTesticular ischemia-reperfusion injury caused a significant increase in the conjugated diene levels, extracellular signal-regulated kinase c-jun N-terminal kinase activity and tumor necrosis factor-alpha expression in both testes. Furthermore, histological examination revealed marked damage. Raxofelast inhibited these parameters and decreased histological damage.CONCLUSIONSThese data suggest that lipid peroxidation triggers extracellular signal-regulated kinase and c-jun N-terminal kinase activation. Furthermore, mitogen-activated protein kinase blockade might represent a potential therapeutic approach to treatment in patients with unilateral testicular torsion.

100 Deals associated with Raxofelast

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Indication	Highest Phase	Country/Location	Organization	Date
Atherosclerosis	Phase 2	-	Biomedica Foscama Industria Chimico-Farmaceutic SpA	-
Atherosclerosis	Phase 2	IT	Biomedica Foscama Group SpA	-
Atherosclerosis	Phase 2	GB	Biomedica Foscama Group SpA	-
Diabetes Complications	Phase 2	IT	Biomedica Foscama Group SpA	-
Diabetes Complications	Phase 2	GB	Biomedica Foscama Group SpA	-

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