Neurochemical Research

, Volume 40, Issue 6, pp 1243–1251 | Cite as

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

  • Camilo Ríos
  • Sandra Orozco-Suarez
  • Hermelinda Salgado-Ceballos
  • Marisela Mendez-Armenta
  • Concepción Nava-Ruiz
  • Iván Santander
  • Veronica Barón-Flores
  • Nadia Caram-Salas
  • Araceli Diaz-Ruiz
Original Paper


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.


Dapsone Spinal cord injury Anti-apoptotic effect Caspases 



Supported by CONACYT Grant 183667.

Conflict of interest

The authors declare no conflict of interest associated with the present study.


  1. 1.
    Torres S, Salgado-Ceballos H, Torres JL, Orozco-Suarez S, Díaz-Ruíz A, Martínez A, Rivera-Cruz M, Ríos C, Lara A, Collado C, Guizar-Sahagún G (2010) Early metabolic reactivation versus antioxidant therapy after a traumatic spinal cord injury in adult rats. Neuropathology 30:36–43PubMedCrossRefGoogle Scholar
  2. 2.
    Park E, Velumian AA, Fehlings MG (2004) The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration. J Neurotrauma 21:754–774PubMedCrossRefGoogle Scholar
  3. 3.
    Diaz-Ruiz A, Rios C, Duarte I, Correa D, Guizar-Sahagun G, Grijalva I, Ibarra A (1999) Cyclosporin-A inhibits lipid peroxidation after spinal cord injury in rats. Neurosci Lett 266:61–64PubMedCrossRefGoogle Scholar
  4. 4.
    Hausmann ON (2003) Post-traumatic inflammation following spinal cord injury. Spinal Cord 41:369–378PubMedCrossRefGoogle Scholar
  5. 5.
    Beattie MS, Hermann GE, Rogers RC, Bresnahan JC (2002) Cell death in models of spinal cord injury. Prog Brain Res 137:37–47PubMedGoogle Scholar
  6. 6.
    Precht TA, Phelps RA, Linseman DA, Butts BD, Le SS, Laessig TA, Bouchard RJ, Heidenreich KA (2005) The permeability transition pore triggers Bax translocation to mitochondria during neuronal apoptosis. Cell Death Differ 12:255–265PubMedCrossRefGoogle Scholar
  7. 7.
    Choi C, Benveniste EN (2004) Fas ligand/Fas system in the brain: regulator of immune and apoptotic responses. Brain Res Brain Res Rev 44:65–81PubMedCrossRefGoogle Scholar
  8. 8.
    Badiola N, Malagelada C, Llecha N, Hidalgo J, Comella JX, Sabriá J, Rodríguez-Alvarez J (2009) Activation of caspase-8 by tumour necrosis factor receptor 1 is necessary for caspase-3 activation and apoptosis in oxygen-glucose deprived cultured cortical cells. Neurobiol Dis 35:438–447PubMedCrossRefGoogle Scholar
  9. 9.
    Yip PK, Malaspina A (2012) Spinal cord trauma and the molecular point of no return. Mol Neurodegener 7:6PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Diaz-Ruiz A, Zavala C, Montes S, Ortiz-Plata A, Salgado-Ceballos H, Orozco-Suarez S, Nava-Ruiz C, Pérez-Neri I, Perez-Severiano F, Ríos C (2008) Antioxidant, antiinflammatory and antiapoptotic effects of dapsone in a model of brain ischemia/reperfusion in rats. J Neurosci Res 86:3410–3419PubMedCrossRefGoogle Scholar
  11. 11.
    Wozel G, Blasum C (2014) Dapsone in dermatology and beyond. Arch Dermatol Res 306:103–124PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Ríos C, Nader-Kawachi J, Rodriguez-Payán AJ, Nava-Ruiz C (2004) Neuroprotective effect of dapsone in an occlusive model of focal ischemia in rats. Brain Res 999:212–215PubMedCrossRefGoogle Scholar
  13. 13.
    Diaz-Ruiz A, Salgado-Ceballos H, Montes S, Guizar-Sahagún G, Gelista-Herrera N, Mendez-Armenta M, Diaz-Cintra S, Ríos C (2011) Delayed administration of dapsone protects from tissue damage and improves recovery after spinal cord injury. J Neurosci Res 89:373–380PubMedCrossRefGoogle Scholar
  14. 14.
    Diaz-Ruiz A, Mendez-Armenta M, Galván-Arzate S, Manjarrez J, Nava-Ruiz C, Santander I, Balderas G, Ríos C (2013) Antioxidant, anticonvulsive and neuroprotective effects of dapsone and phenobarbital against kainic acid-induced damage in rats. Neurochem Res 38:1819–1827PubMedCrossRefGoogle Scholar
  15. 15.
    Basso DM, Beattie MS, Bresnahan JC (1996) Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol 139:244–256PubMedCrossRefGoogle Scholar
  16. 16.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  17. 17.
    Ling X, Bao F, Qian H, Liu D (2013) The temporal and spatial profiles of cell loss following experimental spinal cord injury: effect of antioxidant therapy on cell death and functional recovery. BMC Neurosci 14:146PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    West MJ, Slomianka L, Gundersen HJ (1991) Unbiased stereological estimation of the total number of neurons in the subdivisions of the rat hippocampus using the optical fractionator. Anat Rec 231:482–497PubMedCrossRefGoogle Scholar
  19. 19.
    West MJ (1993) New stereological methods for counting neurons. Neurobiol Aging 14:275–285PubMedCrossRefGoogle Scholar
  20. 20.
    Besio W, Cuellar-Herrera M, Luna-Munguia H, Orozco-Suárez S, Rocha L (2013) Effects of transcranial focal electrical stimulation alone and associated with a sub-effective dose of diazepam on pilocarpine-induced status epilepticus and subsequent neuronal damage in rats. Epilepsy Behav 28:432–436PubMedCrossRefGoogle Scholar
  21. 21.
    Takagi T, Takayasu M, Mizuno M, Yoshimoto M, Yoshida J (2003) Caspase activation in neuronal and glial apoptosis following spinal cord injury in mice. Neurol Med Chir (Tokyo) 43:20–29CrossRefGoogle Scholar
  22. 22.
    Knoblatch SM, Huang X, VanGelderen J, Calva-Cerqueira D, Faden AI (2005) Selective caspase activation may contribute to neurological dysfunction after experimental spinal cord trauma. J Neurosci Res 80:369–380CrossRefGoogle Scholar
  23. 23.
    Baumgartner HK, Gerasimenko JV, Thorne C, Ferdek P, Pozzan T, Tepikin AV, Petersen OH, Sutton R, Watson AJ, Gerasimenko OV (2009) Calcium elevation in mitochondria is the main Ca2+ requirement for mitochondrial permeability transition pore (mPTP) opening. J Biol Chem 284:20796–20803PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Santamaría A, Ordaz-Moreno J, Rubio-Osornio M, Solís-Hernández F, Ríos C (1997) Neuroprotective effect of dapsone against quinolinate- and kainate-induced striatal neurotoxicities in rats. Pharmacol Toxicol 81:271–275PubMedGoogle Scholar
  25. 25.
    Rodríguez E, Méndez-Armenta M, Villeda-Hernández J, Galván-Arzate S, Barroso-Moguel R, Rodríguez F, Ríos C, Santamaría A (1999) Dapsone prevents morphological lesions and lipid peroxidation induced by quinolinic acid in rat corpus striatum. Toxicology 139:111–118PubMedCrossRefGoogle Scholar
  26. 26.
    Wrathall JR, Choiniere D, Teng YD (1994) Dose-dependent reduction of tissue loss and functional impairment after spinal cord trauma with the AMPA/kainate antagonist NBQX. J Neurosci 14:6598–6607PubMedGoogle Scholar
  27. 27.
    Wrathall JR, Teng YD, Marriott R (1997) Delayed antagonism of AMPA/kainate receptors reduces long-term functional deficits resulting from spinal cord trauma. Exp Neurol 145:565–573PubMedCrossRefGoogle Scholar
  28. 28.
    Lee JM, Yan P, Xiao Q, Chen S, Lee KY, Hsu CY, Xu J (2008) Methylprednisolone protects oligodendrocytes but not neurons after spinal cord injury. J Neurosci 28:3141–3149PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Bao F, Liu D (2004) Hydroxyl radicals generated in the rat spinal cord at the level produced by impact injury induce cell death by necrosis and apoptosis: protection by a metalloporphyrin. Neuroscience 126:285–295PubMedCrossRefGoogle Scholar
  30. 30.
    Chen KB, Uchida K, Nakajima H, Yayama T, Hirai T, Watanabe S, Guerrero AR, Kobayashi S, Ma WY, Liu SY, Baba H (2011) Tumor necrosis factor-α antagonist reduces apoptosis of neurons and oligodendroglia in rat spinal cord injury. Spine 36:1350–1358PubMedCrossRefGoogle Scholar
  31. 31.
    Niwa Y, Sakane T, Miyachi Y (1984) Dissociation of the inhibitory effect of dapsone on the generation of oxygen intermediates-in comparison with that of colchicine and various scavengers. Biochem Pharmacol 33:2355–2360PubMedCrossRefGoogle Scholar
  32. 32.
    Suda T, Suzuki Y, Matsui T, Inoue T, Niide O, Yoshimaru T, Suzuki H, Ra C, Ochiai T (2005) Dapsone suppresses human neutrophil superoxide production and elastase release in a calcium-dependent manner. Br J Dermatol 152:887–895PubMedCrossRefGoogle Scholar
  33. 33.
    Ren Y, Young W (2013) Managing inflammation after spinal cord injury through manipulation of macrophage function. Neural Plast 2013:945034PubMedCentralPubMedGoogle Scholar
  34. 34.
    Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964PubMedCrossRefGoogle Scholar
  35. 35.
    Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29:13435–13444PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Chen HC, Hsu PW, Tzaan WC, Lee AW (2014) Effects of the combined administration of vitamins C and E on the oxidative stress status and programmed cell death pathways after experimental spinal cord injury. Spinal Cord 52:24–28PubMedCrossRefGoogle Scholar
  37. 37.
    Abe M, Shimizu A, Yokoyama Y, Takeuchi Y, Ishikawa O (2008) A possible inhibitory action of diaminodiphenyl sulfone on tumour necrosis factor-alpha production from activated mononuclear cells on cutaneous lupus erythematosus. Clin Exp Dermatol 33:759–763PubMedCrossRefGoogle Scholar
  38. 38.
    Hermann GE, Rogers RC, Bresnahan JC, Beattie MS (2001) Tumor necrosis factor-alpha induces cFOS and strongly potentiates glutamate-mediated cell death in the rat spinal cord. Neurobiol Dis 8:590–599PubMedCrossRefGoogle Scholar
  39. 39.
    Maloff BL, Fox D, Bruin E, Di Meo TM (1988) Dapsone inhibits LTB4 binding and bioresponse at the cellular and physiologic levels. Eur J Pharmacol 158:85–89PubMedCrossRefGoogle Scholar
  40. 40.
    Saiwai H, Ohkawa Y, Yamada H, Kumamaru H, Harada A, Okano H, Yokomizo T, Iwamoto Y, Okada S (2010) The LTB4-BLT1 axis mediates neutrophil infiltration and secondary injury in experimental spinal cord injury. Am J Pathol 176:2352–2366PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Altagracia M, Monroy-Noyola A, Osorio-Rico L, Kravzov J, Alvarado-Calvillo R, Manjarrez-Marmolejo J, Ríos C (1994) Dapsone attenuates kainic acid-induced seizures in rats. Neurosci Lett 176:52–54PubMedCrossRefGoogle Scholar
  42. 42.
    Tristán-López L, Pérez-Álvarez V, Pérez-Severiano F, Montes S, Pérez-Neri I, Rivera-Espinosa L, Ríos C (2012) Protective effect of N,N′-dialkylated analogs of 4,4′-diaminodiphenylsulfone in a model of intrastriatal quinolinic acid induced-excitotoxicity. Neurosci Lett 528:1–5PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang N, Yin Y, Xu SJ, Wu YP, Chen WS (2012) Inflammation & apoptosis in spinal cord injury. Indian J Med Res 135:287–296PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Camilo Ríos
    • 1
    • 5
  • Sandra Orozco-Suarez
    • 2
  • Hermelinda Salgado-Ceballos
    • 2
  • Marisela Mendez-Armenta
    • 3
  • Concepción Nava-Ruiz
    • 3
  • Iván Santander
    • 1
  • Veronica Barón-Flores
    • 5
  • Nadia Caram-Salas
    • 4
  • Araceli Diaz-Ruiz
    • 1
  1. 1.Departamento de NeuroquímicaInstituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez S.S.A.Mexico CityMexico
  2. 2.Unidad de Investigación Médica en Enfermedades Neurológicas, Hospital de EspecialidadesCentro Médico Nacional Siglo XXIMexicoMexico
  3. 3.Laboratorio de NeuropatologíaInstituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez S.S.A.MexicoMexico
  4. 4.Laboratorio de Investigación en AdiccionesInstituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez S.S.A.MexicoMexico
  5. 5.Departamento de Sistemas BiológicosUniversidad Autónoma Metropolitana Unidad XochimilcoMexicoMexico

Personalised recommendations