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Bombesin protection against FK506 neurotoxicity
Journal of Pediatric Surgery (2007) 42, 750 – 752
www.elsevier.com/locate/jpedsurg
Correspondence Bombesin protection against FK506 neurotoxicity To the Editor, We read with great interest the article by Higuchi et al [1] reporting that administration of bombesin prevents neurotoxicity induced by FK506 (tacrolimus) on transplanted graft enteric ganglia in rats submitted to small bowel transplantation. The authors conclude that bombesin may arise as an attractive therapeutic agent. We feel that some points of the article deserve comment. We have shown that bombesin can prevent impairing effects on behavior induced by application of the 25 to 35 neurotoxic fragment of b-amyloid peptide to rat hippocampal neurons [2]. In the light of this and other findings, we have proposed that bombesin and other bombesin-like peptides (such as the gastrin-releasing peptide) should be investigated as potential neuroprotective agents [2,3]. Consistent with this view, the study by Higuchi et al [1] provides the first direct evidence that bombesin can display neurotrophic and neuroprotective effects. We believe that this finding might have an important impact on research investigating the potential use of bombesin-like peptides as therapeutic agents. In their article, Higuchi et al [1] did not discuss possible cellular mechanisms mediating the protective effect of bombesin against FK506-induced neurotoxicity. We would like to point out that alterations in the release and/or actions of proinflammatory cytokines (eg, tumor necrosis factor a and interleukin b) and nitric oxide might be involved in the actions of bombesin in FK506-treated rats. Animal studies have shown that FK506 affects expression of tumor necrosis factor a, interleukin b, and inducible nitric oxide synthase [4,5]. We have shown that a synthetic analogue of bombesin that displays antagonist activity at bombesin receptors induces alterations in the levels of tumor necrosis factor a and interleukin b in cultured macrophages as well as in a rat model of acute lung injury, and alters the levels of inducible nitric oxide synthase messenger RNA in macrophages [6]. Thus, it is likely that bombesin-induced modulation of inflammatory processes plays a key role in the effects observed by Higuchi et al [1]. In addition, bombesin-induced modulation of the protein kinase C, mitogen-activated protein kinase, and protein kinase A signaling pathways might be involved in the neuroprotective effects of bombesin [2]. Experiments 0022-3468/$ – see front matter D 2007 Elsevier Inc. All rights reserved.
addressing these issues could have important implications for the development of novel therapeutic strategies based on the bombesin family of neuropeptides. Rafael Roesler Gilberto Schwartsmann Department of Pharmacology Federal University of Rio Grande do Sul 90035-003 Porto Alegre, RS, Brazil Department of Internal Medicine Federal University of Rio Grande do Sul 90035-003 Porto Alegre, RS, Brazil Cancer Research Laboratory Federal University of Rio Grande do Sul 90035-003 Porto Alegre, RS, Brazil E-mail addresses: [email protected] [email protected] Felipe Dal Pizzol Experimental Physiopathology Laboratory Department of Medicine University of Southern Santa Catarina 88006-000 Criciu´ma, SC, Brazil [email protected] doi:10.1016/j.jpedsurg.2007.01.018
References [1] Higuchi K, Kimura O, Furukawa T, et al. Bombesin can rescue the enteric ganglia from FK506 neurotoxicity on small bowel transplantation. J Pediatr Surg 2006;41:1957 - 61. [2] Roesler R, Luft T, Oliveira SH, et al. Molecular mechanisms mediating gastrin-releasing peptide receptor modulation of memory consolidation in the hippocampus. Neuropharmacology 2006;51:350 - 7. [3] Roesler R, Henriques JA, Schwartsmann G. Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurological disorders. CNS Neurol Disord Drug Targets 2006;5:197 - 204. [4] Lopez-Vales R, Garcia-Alias G, Fores J, et al. FK 506 reduces tissue damage and prevents functional deficit after spinal cord injury in the rat. J Neurosci Res 2005;81:827 - 36. [5] Zawadzka M, Kaminska B. A novel mechanism of FK506-mediated neuroprotection: downregulation of cytokine expression in glial cells. Glia 2005;49:36 - 51. [6] Dal Pizzol F, Di Leone LP, Ritter C, et al. Gastrin-releasing peptide receptor antagonist effects on an animal model of sepsis. Am J Respir Crit Care Med 2006;173:84 - 90.
www.elsevier.com/locate/jpedsurg
Correspondence Bombesin protection against FK506 neurotoxicity To the Editor, We read with great interest the article by Higuchi et al [1] reporting that administration of bombesin prevents neurotoxicity induced by FK506 (tacrolimus) on transplanted graft enteric ganglia in rats submitted to small bowel transplantation. The authors conclude that bombesin may arise as an attractive therapeutic agent. We feel that some points of the article deserve comment. We have shown that bombesin can prevent impairing effects on behavior induced by application of the 25 to 35 neurotoxic fragment of b-amyloid peptide to rat hippocampal neurons [2]. In the light of this and other findings, we have proposed that bombesin and other bombesin-like peptides (such as the gastrin-releasing peptide) should be investigated as potential neuroprotective agents [2,3]. Consistent with this view, the study by Higuchi et al [1] provides the first direct evidence that bombesin can display neurotrophic and neuroprotective effects. We believe that this finding might have an important impact on research investigating the potential use of bombesin-like peptides as therapeutic agents. In their article, Higuchi et al [1] did not discuss possible cellular mechanisms mediating the protective effect of bombesin against FK506-induced neurotoxicity. We would like to point out that alterations in the release and/or actions of proinflammatory cytokines (eg, tumor necrosis factor a and interleukin b) and nitric oxide might be involved in the actions of bombesin in FK506-treated rats. Animal studies have shown that FK506 affects expression of tumor necrosis factor a, interleukin b, and inducible nitric oxide synthase [4,5]. We have shown that a synthetic analogue of bombesin that displays antagonist activity at bombesin receptors induces alterations in the levels of tumor necrosis factor a and interleukin b in cultured macrophages as well as in a rat model of acute lung injury, and alters the levels of inducible nitric oxide synthase messenger RNA in macrophages [6]. Thus, it is likely that bombesin-induced modulation of inflammatory processes plays a key role in the effects observed by Higuchi et al [1]. In addition, bombesin-induced modulation of the protein kinase C, mitogen-activated protein kinase, and protein kinase A signaling pathways might be involved in the neuroprotective effects of bombesin [2]. Experiments 0022-3468/$ – see front matter D 2007 Elsevier Inc. All rights reserved.
addressing these issues could have important implications for the development of novel therapeutic strategies based on the bombesin family of neuropeptides. Rafael Roesler Gilberto Schwartsmann Department of Pharmacology Federal University of Rio Grande do Sul 90035-003 Porto Alegre, RS, Brazil Department of Internal Medicine Federal University of Rio Grande do Sul 90035-003 Porto Alegre, RS, Brazil Cancer Research Laboratory Federal University of Rio Grande do Sul 90035-003 Porto Alegre, RS, Brazil E-mail addresses: [email protected] [email protected] Felipe Dal Pizzol Experimental Physiopathology Laboratory Department of Medicine University of Southern Santa Catarina 88006-000 Criciu´ma, SC, Brazil [email protected] doi:10.1016/j.jpedsurg.2007.01.018
References [1] Higuchi K, Kimura O, Furukawa T, et al. Bombesin can rescue the enteric ganglia from FK506 neurotoxicity on small bowel transplantation. J Pediatr Surg 2006;41:1957 - 61. [2] Roesler R, Luft T, Oliveira SH, et al. Molecular mechanisms mediating gastrin-releasing peptide receptor modulation of memory consolidation in the hippocampus. Neuropharmacology 2006;51:350 - 7. [3] Roesler R, Henriques JA, Schwartsmann G. Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurological disorders. CNS Neurol Disord Drug Targets 2006;5:197 - 204. [4] Lopez-Vales R, Garcia-Alias G, Fores J, et al. FK 506 reduces tissue damage and prevents functional deficit after spinal cord injury in the rat. J Neurosci Res 2005;81:827 - 36. [5] Zawadzka M, Kaminska B. A novel mechanism of FK506-mediated neuroprotection: downregulation of cytokine expression in glial cells. Glia 2005;49:36 - 51. [6] Dal Pizzol F, Di Leone LP, Ritter C, et al. Gastrin-releasing peptide receptor antagonist effects on an animal model of sepsis. Am J Respir Crit Care Med 2006;173:84 - 90.