- Email: [email protected]
Bupropion Reduces the Inflammatory Response and Intestinal Injury Due to Ischemia-Reperfusion
Bupropion Reduces the Inflammatory Response and Intestinal Injury Due to Ischemia-Reperfusion C.R. Cámara-Lemarroy, F.J. Guzmán-de la Garza, P. Cordero-Pérez, G. Alarcón-Galván, J.M. Ibarra-Hernández, L.E. Muñoz-Espinosa, and N.E. Fernández-Garza ABSTRACT Intestinal ischemia-reperfusion (I/R) causes severe organ failure and intense inflammatory responses, which are mediated in part by the cytokine tumor necrosis factor-alpha (TNFalpha). Bupropion is an antidepressant known to inhibit TNF-alpha production. We sought to examine the protective effects of bupropion on intestinal I/R injury in 15 male SpragueDawley rats that were randomized to sham surgery, 45 minutes of intestinal ischemia followed by 180 minutes reperfusion, or bupropion (100 mg/kg) before the intestinal I/R injury. To evaluate the systemic inflammatory response induced by intestinal I/R, we measured serum levels of TNF-alpha, interleukins-1 and -6, lipid peroxidation, and transaminases. Histologic analysis evaluated intestinal injury using the Chiu muscosal injury score. After I/R, Chiu score in control animals was 3.6 1.2 vs 2.6 0.53 in animals that received bupropion (P < .05). Bupropion pretreatment reduced intestinal. I/R injury and blunted serum elevations of TNF-alpha (0.96 1.1 ng/mL vs 0.09 0.06 ng/mL, P < .05) and interleukin-1 (0.53 0.24 ng/mL vs 0.2 0.11 ng/mL, P < .05). Bupropion in reduced intestinal I/R injury through immunomodulatory machanisms that involve inflammatory cytokines such as TNF-alpha.
I
NTESTINAL ISCHEMIA occurs when the intestinal blood supply is interrupted, or when there is inadequate perfusion due to shock or hypovolemia.1 This condition is ubiquitous during transplantation and other surgical procedures. The initial damage caused by ischemia is worsened by reperfusion, the ischemia-reperfusion (I/R) injury. I/R adversely affects transplant outcomes, and induces a systemic life-threatening inflammatory response. Multiple mechanisms are involved in I/R injury, such as production of reactive oxygen species, intravascular thrombosis, inflammatory cell infiltration, and cytokine production.2 Novel protective strategies, such as pharmacologic preconditioning, are active fields of research.l One of the main orchestrators of I/R injury as well as graft rejection is the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha). TNF-alpha participates in all levels of the physiopathology of I/R injury; it promotes leukocyte infiltration, induced cell death and endothelial dysfunction, as well as activates an inflammatory cascade that results in further production of cytokines and chemokines, mediating remote organ injury.3,4 Pharmacologic modulation of TNF-alpha production is a promising strategy to prevent I/R injury.5
Bupropion is an antidepressant whose main mechanism of action is believed to be inhibition of dopamine and noradrenalin reuptake. Recent evidence suggests bupropion can act as an anti-TNF-alpha agent.6,7 In a recent study, Brustolim et al showed that bupropion dose-dependently reduced TNF-alpha production in a mouse lipopolysaccharideinduced inflammation model.8 Our aim was to investigate whether bupropion could reduce intestinal I/R injury as well. From the Departamento de Fisiología, (C.R.C.-L., F.J-G.-G., J.M.I.-H., N.E.F.-G.) and Unidad de Hígado, Departamento de Medicina Interna (P.C.-P., L.E.M.-E.), Universidad Autónoma de Nuevo León, School of Medicine and Servicio de Anatomía Patológica y Citopatología (G.A.-G.) and Departamento de Medicina Interna (C.R.C.-L.), Hospital Universitario “José Eleuterio González”, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México. Address reprint requests to Carlos Rodrigo Cámara Lemarroy, Departamento de Medicina Interna, Hospital Universitario “José Eleuterio González,” U.A.N.L., Av Francisco I. Madero y Dr. Eduardo Aguirre Pequeño S/No, Col Mitras Centro, 64460, Monterrey, Nuevo León, México. E-mail: crcamara83@hotmail. com
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.04.010
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2502
Transplantation Proceedings, 45, 2502e2505 (2013)
BUPROPION REDUCES INFLAMMATORY RESPONSE
MATERIALS AND METHODS Animal procedures were performed in accordance with the proper use and care of laboratory animals and approved by our ethics committee. Experiments were performed on 15 male Sprague-Dawley rats weighing 200 to 250 g. Animals were maintained under standard conditions, of stable room temperature (24 C 3 C) 12 hour light/12 hour dark cycles, and access to commercial rat pellets and water ad libitum. Briefly, after ketamine/xylazine anesthesia (Anesket, Pfizer Inc, Mexico; 50/10 mg/kg, intraperitoneally) we performed a midline laparotomy. Animals were placed under heating lamp to preserve core body temperature at 37 C. Ischemia was induced by crossclamping the superior mesenteric artery for 45 minutes (ischemia), followed by its removal to allow 180 minutes of reperfusion. Rats were randomly divided into 5 groups (n ¼ 5): (1) shamoperated that underwent laparotomy with intestines manipulated but not rendered ischemic; (2), controls subjected to I/R; (3), bupropion group, (100 mg/kg; Wellbutrin, GlaxoSmithKline) as described by Brustolim et al8 and administered orally via gavage, at 60 minutes before the I/R procedure.
Tissue Examination Immediately after concluding the reperfusion period, rats were sacrificed by exsanguination from the aorta to obtaine intestinal tissue samples. The samples fixed in 10% neutral buffered formalin overnight were embedded in paraffin to obiaim 4-mm-thick sections that were stained with hematoxylin and eosin for light microscopy examination by a blinded pathologist. The Chiu score of mucosa injury to evaluate the degree of histologic damage9 consists of values from 0 to 5: 0, normal mucosa; 1, subepithelial (Gruenhagen’s) spaces; 2, extension of the subepithelial spaces with moderate epithelial lifting from the lamina propria; 3, extensive epithelial lifting with occasional denuded villi tips; 4, denuded villi with exposed lamina propria and dilated capillaries; and 5, disintegration of the lamina propria with hemorrhage and ulceration.
Serum Analysis Blood samples were used to determine serum levels of AST (aspartate aminotransferase) and ALT (alanine aminotransferase) by standard biochemical automated methods, using commercially available kits on DT6011 and DTSC11 analyzers (System Vitros Chemical, Johnson and Johnson, USA). AST serum levels serve as indirect markers of intestinal injury, while ALT is more specific for hepatic injury. Serum concentrations of TNF-alpha, interleukin-1
2503 (IL-1) and interleukin-6 (IL-6) were determined using a rat enzymelinked immunosorbent assay kit (PeproTech, Mexico). Lipid peroxidation, expressed as malonaldehyde (MDA) levels, was assessed by the TBARS method using a commercially available colorimetric assay kit (Cayman chemicals, USA).
Survival To assess survival, additional groups of rats (n ¼ 10 per group) underwent the study protocol (control and bupropion). Since a period of 45 minutes of mesenteric ischemia resulted in neglible mortality, we used an ischemia time of 70 minutes. The animals were observed for 3 days to record mortality rates.
Statistical Analysis SPSS 11.0 statistical software (SPSS Inc, Software, Chicago, Ill, USA) was employed to analyze data by one-way analysis of variance, and LSD post hoc test (when data were normally distributed), or Kruskal-Wallis (when data were not normally distributed). Survival curves were determined using the Kaplan-Meier method with the log-rank test to compare the curves. All results are expressed as mean values standard deviations with P < .05 considered to be statistically significant.
RESULTS ALT and AST
In both the control and bupropion groups AST values were significantly elevated after I/R, with no difference between them. ALT levels elevated after I/R (88.4 21 IU/L), were reduced by bupropion (52.6 23.3 IU/L, P < .05; Fig 1). Morphologic Examination
The sham group revealed a Chiu score of mucosal injury of 0.6 0.53, indicating a negligible effects. Severe mucosal injury was evident the control group after I/R (Fig 2), a Chiu score of 3.6 1.2. The bupropion group displayed some injury, as significantly less than the controls (Chiu score: 2.6 0.53; P < .05). Serum Cytokine Levels
There was no difference among the groups in IL-6 levels (data not shown). Both TNF-alpha and IL-1 serum levels
Fig 1. Serum levels of interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malonaldehyde (MDA). Both cytokines and ALT elevations after ischemia-reperfusion (l/R) were attenuated by bupropion pretreatment. (*P < .05 vs sham ** P < .05 vs control). There were no significant differences in MDA levels between groups.
2504
CÁMARA-LEMARROY, GUZMÁN-DE LA GARZA, CORDERO-PÉREZ ET AL
Fig 2. Hematoxylin and eosinestained images of intestinal mucosa (100). Tissue injury (ulceration, hemorrhage, and epithelial loss) after ischemia-reperfusion was evident in control group (C) compared with sham operated animals (A). In bupropion group (B), morphologic alterations were less severe.
were elevated significantly after I/R injury in the control group (0.96 1.1 and 0.53 0.24 ng/mL respectively). Bupropion administration resulted in significantly lower TNF-alpha (0.09 0.06 ng/mL) and IL-1 (0.2 0.11 ng/mL) levels (P < .05; Fig 1). MDA
There was no difference among the groups in MDA serum levels (Fig 1). Survival
There was a high mortality rate, with most deaths occuring within 72 hours after I/R. Survival rate for bupropion and control groups were 40% and 20%, respectively (Fig 3).
Fig 3. Effect of bupropion on survival after intestinal Ischemiareperfusion. Survival rates were recorded for 3 days. Although there was a trend toward improved survival in bupropion group, it did not reach statistical significance.
Although there was a trend toward improved survival in the bupropion group, it did not reach statistical significance (P ¼ .1). DISCUSSION
I/R injury is a potentially devastating condition associated with many surgical pathologies. In our model, bupropion was effective to reduce intestinal I/R injury and TNF-alpha elevations. The effects on AST and ALT suggested protection against remote organ injury. However, bupropion did not provide significant protection against mortality after severe intestinal I/R (70 minutes of ischemia). Agents that inhibit TNF-alpha have shown effectiveness to reduce I/R injury in various experimental models. Considering the evidence that bupropion inhibits TNFalpha production,6e8 our results were expected. In fact, Brustolim et al had shown a wide immunomodulatory action of bupropion, reducing not only TNF-alpha, but also IL-1 and interferon-gamma, as well as increasing the antiinflammatory cytokine interleukin-10.8 Those authors had speculate that bupropion inhibited TNF-production via a dopaminergic-mediated increase in cAMP in inflammatory cells. In our study we observed reductions in IL-1, but no effects on lipid peroxidation or IL-6. The potential of bupropion to reduce intestinal inflammatory responses had been evaluated previously. Bupropion use has been associated with remission of Crohn’s disease, whose physiopathologic mechanisms involve TNF-alpha, and wherein anti-TNF-alpha agents have been effective treatments.10,11 Bupropion also reduced stresseinduced ulcerations in the rodent gastrointestinal system.12 Finally, bupropion reduced the severity of irritable bowel syndrome.13 In conclusion, we have shown that bupropion reduced intestinal I/R injury, probably through inhibition of the inflammatory cytokine TNF-alpha. ACKNOWLEDGMENTS We would like to thank the staff at our laboratories for invaluable assistance.
BUPROPION REDUCES INFLAMMATORY RESPONSE
REFERENCES 1. Mallick IH, Yang W, Winslet MC, Seifalian AM. Ischemiareperfusion injury of the intestine and protective strategies against injury. Dig Dis Sci. 2004;49:1359e1377. 2. Kong SE, Blennerhassett LR, Heel KA, et al. Ischemiareperfusion injury to the intestine. Aust N Z J Surg. 1998;68:554e561. 3. Pascher A, Klupp J. Biologics in the treatment of transplant rejection and ischemia/reperfusion injury: new applications for TNFalpha inhibitors? BioDrugs. 2005;19:211e231. 4. Zhang C, Xu X, Potter BJ, et al. TNF-alpha contributes to endothelial dysfunction in ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol. 2006;26:475e480. 5. Esposito E, Cuzzocrea S. TNF-alpha as a therapeutic target in inflammatory diseases, ischemia-reperfusion injury and trauma. Curr Med Chem. 2009;16:3152e3167. 6. Kast RE. Anti- and pro-inflammatory considerations in antidepressant use during medical illness: bupropion lowers and mirtazapine increases circulating tumor necrosis factor-alpha levels. Gen Hosp Psychiatry. 2003;25:495e496.
2505 7. Foley KF, DeSanty KP, Kast RE. Bupropion: pharmacology and therapeutic applications. Expert Rev Neurother. 2006;6: 1249e1265. 8. Brustolim D, Ribeiro-dos-Santos R, Kast RE, et al. A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice. Int Immunopharmacol. 2006;6: 903e907. 9. Cámara CR, Guzmán FJ, Barrera EA, et al. Ketamine anesthesia reduces intestinal ischemia/reperfusion injury in rats. World J Gastroenterol. 2008;14:5192e5196. 10. Kane S, Altschuler EL, Kast RE. Crohn’s disease remission on bupropion. Gastroenterology. 2003;125:1290. 11. Kast RE, Altschuler EL. Remission of Crohn’s disease on bupropion. Gastroenterology. 2001;121:1260e1261. 12. Gabry KE, Chrousos GP, Rice KC, et al. Marked suppression of gastric ulcerogenesis and intestinal responses to stress by a novel class of drugs. Mol Psychiatry. 2002;7:474e483. 13. Cheng KJ, Chou YH, Liou YJ. Efficacy of bupropion for irritable bowel syndrome. Psychosomatics. 2010;51:536e537.
I
NTESTINAL ISCHEMIA occurs when the intestinal blood supply is interrupted, or when there is inadequate perfusion due to shock or hypovolemia.1 This condition is ubiquitous during transplantation and other surgical procedures. The initial damage caused by ischemia is worsened by reperfusion, the ischemia-reperfusion (I/R) injury. I/R adversely affects transplant outcomes, and induces a systemic life-threatening inflammatory response. Multiple mechanisms are involved in I/R injury, such as production of reactive oxygen species, intravascular thrombosis, inflammatory cell infiltration, and cytokine production.2 Novel protective strategies, such as pharmacologic preconditioning, are active fields of research.l One of the main orchestrators of I/R injury as well as graft rejection is the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha). TNF-alpha participates in all levels of the physiopathology of I/R injury; it promotes leukocyte infiltration, induced cell death and endothelial dysfunction, as well as activates an inflammatory cascade that results in further production of cytokines and chemokines, mediating remote organ injury.3,4 Pharmacologic modulation of TNF-alpha production is a promising strategy to prevent I/R injury.5
Bupropion is an antidepressant whose main mechanism of action is believed to be inhibition of dopamine and noradrenalin reuptake. Recent evidence suggests bupropion can act as an anti-TNF-alpha agent.6,7 In a recent study, Brustolim et al showed that bupropion dose-dependently reduced TNF-alpha production in a mouse lipopolysaccharideinduced inflammation model.8 Our aim was to investigate whether bupropion could reduce intestinal I/R injury as well. From the Departamento de Fisiología, (C.R.C.-L., F.J-G.-G., J.M.I.-H., N.E.F.-G.) and Unidad de Hígado, Departamento de Medicina Interna (P.C.-P., L.E.M.-E.), Universidad Autónoma de Nuevo León, School of Medicine and Servicio de Anatomía Patológica y Citopatología (G.A.-G.) and Departamento de Medicina Interna (C.R.C.-L.), Hospital Universitario “José Eleuterio González”, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, México. Address reprint requests to Carlos Rodrigo Cámara Lemarroy, Departamento de Medicina Interna, Hospital Universitario “José Eleuterio González,” U.A.N.L., Av Francisco I. Madero y Dr. Eduardo Aguirre Pequeño S/No, Col Mitras Centro, 64460, Monterrey, Nuevo León, México. E-mail: crcamara83@hotmail. com
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.04.010
ª 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
2502
Transplantation Proceedings, 45, 2502e2505 (2013)
BUPROPION REDUCES INFLAMMATORY RESPONSE
MATERIALS AND METHODS Animal procedures were performed in accordance with the proper use and care of laboratory animals and approved by our ethics committee. Experiments were performed on 15 male Sprague-Dawley rats weighing 200 to 250 g. Animals were maintained under standard conditions, of stable room temperature (24 C 3 C) 12 hour light/12 hour dark cycles, and access to commercial rat pellets and water ad libitum. Briefly, after ketamine/xylazine anesthesia (Anesket, Pfizer Inc, Mexico; 50/10 mg/kg, intraperitoneally) we performed a midline laparotomy. Animals were placed under heating lamp to preserve core body temperature at 37 C. Ischemia was induced by crossclamping the superior mesenteric artery for 45 minutes (ischemia), followed by its removal to allow 180 minutes of reperfusion. Rats were randomly divided into 5 groups (n ¼ 5): (1) shamoperated that underwent laparotomy with intestines manipulated but not rendered ischemic; (2), controls subjected to I/R; (3), bupropion group, (100 mg/kg; Wellbutrin, GlaxoSmithKline) as described by Brustolim et al8 and administered orally via gavage, at 60 minutes before the I/R procedure.
Tissue Examination Immediately after concluding the reperfusion period, rats were sacrificed by exsanguination from the aorta to obtaine intestinal tissue samples. The samples fixed in 10% neutral buffered formalin overnight were embedded in paraffin to obiaim 4-mm-thick sections that were stained with hematoxylin and eosin for light microscopy examination by a blinded pathologist. The Chiu score of mucosa injury to evaluate the degree of histologic damage9 consists of values from 0 to 5: 0, normal mucosa; 1, subepithelial (Gruenhagen’s) spaces; 2, extension of the subepithelial spaces with moderate epithelial lifting from the lamina propria; 3, extensive epithelial lifting with occasional denuded villi tips; 4, denuded villi with exposed lamina propria and dilated capillaries; and 5, disintegration of the lamina propria with hemorrhage and ulceration.
Serum Analysis Blood samples were used to determine serum levels of AST (aspartate aminotransferase) and ALT (alanine aminotransferase) by standard biochemical automated methods, using commercially available kits on DT6011 and DTSC11 analyzers (System Vitros Chemical, Johnson and Johnson, USA). AST serum levels serve as indirect markers of intestinal injury, while ALT is more specific for hepatic injury. Serum concentrations of TNF-alpha, interleukin-1
2503 (IL-1) and interleukin-6 (IL-6) were determined using a rat enzymelinked immunosorbent assay kit (PeproTech, Mexico). Lipid peroxidation, expressed as malonaldehyde (MDA) levels, was assessed by the TBARS method using a commercially available colorimetric assay kit (Cayman chemicals, USA).
Survival To assess survival, additional groups of rats (n ¼ 10 per group) underwent the study protocol (control and bupropion). Since a period of 45 minutes of mesenteric ischemia resulted in neglible mortality, we used an ischemia time of 70 minutes. The animals were observed for 3 days to record mortality rates.
Statistical Analysis SPSS 11.0 statistical software (SPSS Inc, Software, Chicago, Ill, USA) was employed to analyze data by one-way analysis of variance, and LSD post hoc test (when data were normally distributed), or Kruskal-Wallis (when data were not normally distributed). Survival curves were determined using the Kaplan-Meier method with the log-rank test to compare the curves. All results are expressed as mean values standard deviations with P < .05 considered to be statistically significant.
RESULTS ALT and AST
In both the control and bupropion groups AST values were significantly elevated after I/R, with no difference between them. ALT levels elevated after I/R (88.4 21 IU/L), were reduced by bupropion (52.6 23.3 IU/L, P < .05; Fig 1). Morphologic Examination
The sham group revealed a Chiu score of mucosal injury of 0.6 0.53, indicating a negligible effects. Severe mucosal injury was evident the control group after I/R (Fig 2), a Chiu score of 3.6 1.2. The bupropion group displayed some injury, as significantly less than the controls (Chiu score: 2.6 0.53; P < .05). Serum Cytokine Levels
There was no difference among the groups in IL-6 levels (data not shown). Both TNF-alpha and IL-1 serum levels
Fig 1. Serum levels of interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malonaldehyde (MDA). Both cytokines and ALT elevations after ischemia-reperfusion (l/R) were attenuated by bupropion pretreatment. (*P < .05 vs sham ** P < .05 vs control). There were no significant differences in MDA levels between groups.
2504
CÁMARA-LEMARROY, GUZMÁN-DE LA GARZA, CORDERO-PÉREZ ET AL
Fig 2. Hematoxylin and eosinestained images of intestinal mucosa (100). Tissue injury (ulceration, hemorrhage, and epithelial loss) after ischemia-reperfusion was evident in control group (C) compared with sham operated animals (A). In bupropion group (B), morphologic alterations were less severe.
were elevated significantly after I/R injury in the control group (0.96 1.1 and 0.53 0.24 ng/mL respectively). Bupropion administration resulted in significantly lower TNF-alpha (0.09 0.06 ng/mL) and IL-1 (0.2 0.11 ng/mL) levels (P < .05; Fig 1). MDA
There was no difference among the groups in MDA serum levels (Fig 1). Survival
There was a high mortality rate, with most deaths occuring within 72 hours after I/R. Survival rate for bupropion and control groups were 40% and 20%, respectively (Fig 3).
Fig 3. Effect of bupropion on survival after intestinal Ischemiareperfusion. Survival rates were recorded for 3 days. Although there was a trend toward improved survival in bupropion group, it did not reach statistical significance.
Although there was a trend toward improved survival in the bupropion group, it did not reach statistical significance (P ¼ .1). DISCUSSION
I/R injury is a potentially devastating condition associated with many surgical pathologies. In our model, bupropion was effective to reduce intestinal I/R injury and TNF-alpha elevations. The effects on AST and ALT suggested protection against remote organ injury. However, bupropion did not provide significant protection against mortality after severe intestinal I/R (70 minutes of ischemia). Agents that inhibit TNF-alpha have shown effectiveness to reduce I/R injury in various experimental models. Considering the evidence that bupropion inhibits TNFalpha production,6e8 our results were expected. In fact, Brustolim et al had shown a wide immunomodulatory action of bupropion, reducing not only TNF-alpha, but also IL-1 and interferon-gamma, as well as increasing the antiinflammatory cytokine interleukin-10.8 Those authors had speculate that bupropion inhibited TNF-production via a dopaminergic-mediated increase in cAMP in inflammatory cells. In our study we observed reductions in IL-1, but no effects on lipid peroxidation or IL-6. The potential of bupropion to reduce intestinal inflammatory responses had been evaluated previously. Bupropion use has been associated with remission of Crohn’s disease, whose physiopathologic mechanisms involve TNF-alpha, and wherein anti-TNF-alpha agents have been effective treatments.10,11 Bupropion also reduced stresseinduced ulcerations in the rodent gastrointestinal system.12 Finally, bupropion reduced the severity of irritable bowel syndrome.13 In conclusion, we have shown that bupropion reduced intestinal I/R injury, probably through inhibition of the inflammatory cytokine TNF-alpha. ACKNOWLEDGMENTS We would like to thank the staff at our laboratories for invaluable assistance.
BUPROPION REDUCES INFLAMMATORY RESPONSE
REFERENCES 1. Mallick IH, Yang W, Winslet MC, Seifalian AM. Ischemiareperfusion injury of the intestine and protective strategies against injury. Dig Dis Sci. 2004;49:1359e1377. 2. Kong SE, Blennerhassett LR, Heel KA, et al. Ischemiareperfusion injury to the intestine. Aust N Z J Surg. 1998;68:554e561. 3. Pascher A, Klupp J. Biologics in the treatment of transplant rejection and ischemia/reperfusion injury: new applications for TNFalpha inhibitors? BioDrugs. 2005;19:211e231. 4. Zhang C, Xu X, Potter BJ, et al. TNF-alpha contributes to endothelial dysfunction in ischemia/reperfusion injury. Arterioscler Thromb Vasc Biol. 2006;26:475e480. 5. Esposito E, Cuzzocrea S. TNF-alpha as a therapeutic target in inflammatory diseases, ischemia-reperfusion injury and trauma. Curr Med Chem. 2009;16:3152e3167. 6. Kast RE. Anti- and pro-inflammatory considerations in antidepressant use during medical illness: bupropion lowers and mirtazapine increases circulating tumor necrosis factor-alpha levels. Gen Hosp Psychiatry. 2003;25:495e496.
2505 7. Foley KF, DeSanty KP, Kast RE. Bupropion: pharmacology and therapeutic applications. Expert Rev Neurother. 2006;6: 1249e1265. 8. Brustolim D, Ribeiro-dos-Santos R, Kast RE, et al. A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice. Int Immunopharmacol. 2006;6: 903e907. 9. Cámara CR, Guzmán FJ, Barrera EA, et al. Ketamine anesthesia reduces intestinal ischemia/reperfusion injury in rats. World J Gastroenterol. 2008;14:5192e5196. 10. Kane S, Altschuler EL, Kast RE. Crohn’s disease remission on bupropion. Gastroenterology. 2003;125:1290. 11. Kast RE, Altschuler EL. Remission of Crohn’s disease on bupropion. Gastroenterology. 2001;121:1260e1261. 12. Gabry KE, Chrousos GP, Rice KC, et al. Marked suppression of gastric ulcerogenesis and intestinal responses to stress by a novel class of drugs. Mol Psychiatry. 2002;7:474e483. 13. Cheng KJ, Chou YH, Liou YJ. Efficacy of bupropion for irritable bowel syndrome. Psychosomatics. 2010;51:536e537.