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

Abstract

Spinal cord injury (SCI) is a condition producing irreversible damage to the neurological function. Among the leading mechanisms associated to cell death after SCI, excitotoxicity, oxidative stress, inflammatory response and apoptosis are considered potential targets to prevent tissue damage. We recently reported that dapsone an anti-inflammatory drug, decreases the activity of myeloperoxidase, lipid peroxidation, improve neurological function and increase the amount of spared tissue after SCI in rats. In this study, we characterized the anti-apoptotic effect of dapsone administered at 12.5 mg/kg/24 h dose, starting at 3 and 5 h after SCI. We monitored the activity of caspases-8, 9, and 3 and quantitated Annexin V and TUNEL positive cells in the core of the lesion. Results showed increased activities of caspase-8, 9 and 3 at 72 h by SCI to reach increments of 69, 143 and 293 %, respectively, as compared to sham group. Meanwhile, dapsone, administered at 3 and 5 after SCI, reduced caspase-8 activity by 36 and 44 % respectively, whereas the activity of caspase-9 was diminished by 37 %. Likewise, the activity of caspase-3 showed a decrease of 38 %. Finally, both Annexin V and TUNEL-positive cells were significantly reduced by DDS as compared to untreated SCI animals. Results showed that dapsone exerted anti-apoptotic effect after SCI.

4,4′-Diaminodiphenyl Sulfone (DDS) as an Inflammasome Competitor

“…In all measured ischemia‒reperfusion end points, DDS treatment showed a remarkable ability to decrease markers of cell damage by antioxidant, anti-inflammatory, and anti-apoptotic effects [ 64 , 65 ]. DDS is effective in surgical stress induced by brain oxidative damage via downregulating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase level in aged mice [ 65 ], propofol-induced cognitive alterations in aged rats [ 66 ], and an anti-apoptotic effect after spinal cord injury [ 67 ].…”

“…The neurotoxicity of Aβ in brain cells has been linked to H 2 O 2 generation by a study conducted in Seoul. Cu(II) and Fe(III) have been found in abnormally high concentrations in amyloid plaques (0.4 and 1 μM, respectively) and AD-affected neuropil [ 67 ]. Cu(II) markedly potentiates the neurotoxicity exhibited by Aβ in a cell culture.…”

“…Since Cu(II)-glycine alone was not neurotoxic, these results strongly support the possibility that Cu(II) interaction modifies Aβ, leading to enhanced H 2 O 2 -mediated neurotoxicity. Copper, iron, and zinc may be important in exacerbating and perhaps facilitating Aβ-mediated oxidative damage in several diseases [ 67 ]. DDS is a therapeutic preventive substance in AD [ 68 , 69 , 70 , 71 ].…”

Metallothionein‐I + II Reduces Oxidative Damage and Apoptosis after Traumatic Spinal Cord Injury in Rats

“…To characterize the antiapoptotic effect of MT, the activities of caspases 9 and 3 were measured. Ninety-four rats were killed at 24 and 72 hours according to reports by Ríos et al [ 7 ] as the times for maximal activity of the caspases after SCI. Animals were killed by decapitation, and one centimeter (5 mm from the caudal area and 5 mm from the rostral area) of spinal cord wet tissue was obtained from each rat.…”

“…The increased production of ROS and RNS after SCI cause oxidative damage to proteins, DNA, and cellular lipids, polyunsaturated fatty acids in cell membranes, triggering free radical chain reactions to cause lipid peroxidation (LP) [ 6 ]. Furthermore, damage to proteins and DNA activates the mechanisms of cell death by apoptosis [ 7 ]. Apoptosis occurs through intrinsic and extrinsic apoptotic pathways.…”