Antioxidant, antiinflammatory and antiapoptotic effects of dapsone in a model of brain ischemia/reperfusion in rats

Abstract

Although dapsone (4,4'-diaminodiphenylsulfone) has been described as a neuroprotective agent in occlusive focal ischemia in rats, its mechanism of action is still unknown. To explore this mechanism, oxidative, inflammatory and apoptotic processes were evaluated in the striatum of adult rats using a model of ischemia-reperfusion (I/R), either with or without dapsone treatment. Male Wistar rats were submitted to transient middle cerebral artery occlusion for 2 hr, followed by reperfusion. Rats were dosed either with dapsone (12.5 mg/kg i.p.) or vehicle 30 min before or 30 min after the ischemia onset. Lipid peroxidation (LP) and nitrotyrosine contents were measured 22 hr after reperfusion, and myeloperoxidase activity was evaluated 46 hr after I/R. Different markers for apoptosis and necrosis were also evaluated both at 24 and 72 hr after I/R experimental procedure. LP increased by 37% in ischemic animals vs controls, and this effect was reversed by dapsone treatments. A similar effect was observed regarding nitrotyrosine striatal contents. Myeloperoxidase activity, a marker of inflammatory response, increased 3.7-fold in ischemic animals vs. control rats, and dapsone treatment antagonized that effect. Although apoptosis was increased by the effect of ischemia at both evaluation times, dapsone antagonized that effect only at 72 hr after surgery. Dapsone antagonized all of the I/R end points measured, showing a remarkable ability to decrease markers of damage through antioxidant, antiinflammatory, and anti-apoptotic effects.

Delayed administration of dapsone protects from tissue damage and improves recovery after spinal cord injury

“…These results suggest that dapsone may be acting mainly through a mechanism independent of the antiexcitotoxic properties of the sulfone reported by our group (Altagracia et al, 1994;Santamaria et al, 1997;Rodriguez et al, 1999). Recently, we demonstrated the antioxidant, antiinflammatory, and antiapoptotic effects of dapsone in a rat model of brain ischemia and reperfusion (Diaz-Ruiz et al, 2008). Because dapsone was able to prevent the increase of markers of all three processes, we also consider the drug as a candidate to cope with the main mechanisms involved in the secondary damage after SCI.…”

“…Dapsone has been demonstrated to act at multiple key sites to prevent the secondary mechanisms of injury and cellular death, for example, in brain ischemia (Rios et al, 2004) and ischemia/reperfusion (Diaz-Ruiz et al, 2008). In the present study, we tested dapsone for its ability to act as a neuroprotective agent with respect to MPO activity, the lipid peroxidation (LP) process, motor function recovery, and amount of preserved tissue in a rat model of SCI by contusion.…”

Anti-Apoptotic Effects of Dapsone After Spinal Cord Injury in Rats

“…Caspase-9 activity was measured by using a caspase-9 fluorometric protease ELISA Kit that recognizes the sequence LEHD (Chemicon MCH6 kit), according to reported Diaz-Ruiz et al [10]. The assay detects the cleavage of LEHD-AFC (7-amino-4-trifluoromethyl coumarin), as a substrate.…”

“…The enzyme cleaves specifically after aspartate residues in a different peptide sequence (DEVD). The DEVD substrate is also labeled with the fluorescent molecule AFC, so the reaction can be monitored by a blue to green shift in fluorescence upon cleavage of the AFC fluorophore [10]. The results were expressed in arbitrary fluorescence units per milligram of protein of three to eight animals per groups.…”

“…On the other hand, we have reported that dapsone (4,4 0 -diaminodiphenylsulfone, DDS) treatment has anti-oxidant, anti-inflammatory and anti-apoptotic effects in models of ischemia and reperfusion in rat [10,11]. Likewise, dapsone enhanced the functional recovery and increased the amount of tissue preserved in animals with permanent brain ischemia [12].…”