Neuroprotective actions of 2,4-dinitrophenol: Friend or foe?

Ferreira, Sérgio Teixeira; Felice, Fernanda Guarino De

doi:10.1590/S1980-57642008DN10400002

Abstract

2,4-dinitrophenol (DNP) has long been known to be toxic at high concentrations, an effect related to uncoupling of mitochondrial oxidative phosphorylation. Five years ago, however, we reported that low concentrations of DNP protect neurons against the toxicity of the amyloid-b peptide. Since then, a number of other studies have provided evidence of beneficial actions of DNP (at low concentrations), including neuroprotection against different types of insult, blockade of amyloid aggregation, stimulation of neurite outgrowth and neuronal differentiation, and even extension of lifespan in certain organisms. Some of these effects appear due to mild mitochondrial uncoupling and prevention of oxidative stress, whereas other actions are related to activation of additional intracellular signaling pathways. This study discusses the evidence supporting beneficial neuroprotective actions of DNP. DNP and other compounds with similar biological activities may be of interest in the development of novel therapeutic approaches for neurodegenerative diseases and other neurological disorders.

Key words:
2,4-dinitrophenol; amyloid-b peptide; neurodegenerative diseases; neuroprotection; oxidative stress; therapy

Resumo

O 2,4-dinitrofenol (DNP) tem sido conhecido há bastante tempo como tóxico em altas concentrações, um efeito relacionado a desacoplamento da fosforilação oxidativa nas mitocôndrias. Há cinco anos, entretanto, nós relatamos que baixas concentrações do DNF protegem neurônios da toxicidade do peptídeo b-amilóide. Desde então, outros estudos trouxeram evidência adicional dos efeitos benéficos do DNP (em baixas concentrações), incluindo neuroproteção contra diferentes tipos de agressão, bloqueio da agregação do amilóide, estimulação de crescimento neurítico e diferenciação neuronal, e mesmo extensão da sobrevida em alguns organismos. Alguns desses efeitos parecem ser devidos a leve desacoplamento mitocondrial e prevenção do estresse oxidativo, enquanto outras ações são relacionadas à ativação de sistemas adicionais de sinalização intracelular. Este estudo discute a as evidências que dão suporte a ações neuroprotetoras benéficas do DNP. DNP e outros compostos com atividades biológicas similares podem ser de interesse no desenvolvimento de novas abordagens terapêuticas para doenças neurodegenerativas e outros transtornos neurológicos.

Palavras-chave:
2,4-dinitrofenol; peptídeo b-amilóide; doenças neurodegenerativas; neuroproteção; estresse oxidativo; terapia

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References

¹
Parascandola J. Dinitrophenol and bioenergetics: an historical perspective, Mol Cell Biochem 1974;5:69-77.
²
Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994;330:613-622.
³
Mattson M. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Med 2003;3:65-94.
⁴
Brand MD. Uncoupling to survive? The role of mitochondrial inefficiency in ageing, Exp Gerontol 2000;35:811-820.
⁵
Maragos WF, Rockich KT, Dean JJ, Young KL. Pre- or post-treatment with the mitochondrial uncoupler 2,4-dinitrophenol attenuates striatal quinolinate lesions. Brain Res 2003;966:312-316.
⁶
Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov 2006;20:1-11.
⁷
Korde AS, Sullivan PG, Maragos WF. The uncoupling agent 2,4-dinitrophenol improves mitochondrial homeostasis following striatal quinolinic acid injections. J Neurotrauma 2005;22:1142-1149.
⁸
Korde AS, Pettigrew LC, Craddock SD, Maragos WF. The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia. J Neurochem 2005;94:1676-1684.
⁹
Mattiasson G, Shamloo M, Gido G, et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 2003;9:1062-1068.
¹⁰
Jin Y, McEwen ML, Nottingham SA, et al. The mitochondrial uncoupling agent 2,4-dinitrophenol improves mitochondrial function, attenuates oxidative damage, and increases white matter sparing in the contused spinal cord. J Neurotrauma 2004;21:1396-1404.
¹¹
Bordone L, Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 2005;6:298-305.
¹²
Barros MH, Bandy B, Tahara EB, Kowaltowski AJ. Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae. J Biol Chem 2004;279:49883-49888.
¹³
Padalko VI. Uncoupler of oxidative phosphorylation prolongs the lifespan of Drosophila. Biochemistry (Mosc). 2005;70:986-989.
¹⁴
Ferreira. ST, De Felice FG, Chapeaurouge A. Metastable, partially folded states in the productive folding and in the misfolding and amyloid aggregation of proteins, Cell Biochem Biophys. 2006(in press).
¹⁵
Czech. C, Tremp G, Pradier L. Presenilins and Alzheimer's disease: biological functions and pathogenic mechanisms. Prog Neurobiol 2000;60:363-384.
¹⁶
Ernst RL, Hay JW, Fenn C, Tinklenberg J, Yesavage JA. Cognitive function and the costs of Alzheimer's disease. An exploratory study. Arch Neurol 1997;54:687-693.
¹⁷
De Felice FG, Ferreira ST. Beta-amyloid production, aggregation, and clearance as targets for therapy in Alzheimer's disease. Cell Mol Neurobiol 2002;22:545-563.
¹⁸
Klein WL, Stine WB Jr, Teplow DB. Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer's disease Neurobiol Aging 2004;25:569-80.
¹⁹
Ferreira ST, Vieira MNN, De Felice FG. Soluble protein oligomers as emerging toxins in amyloid diseases. IUBMB Life 2007;59:332-345
²⁰
De Felice FG, Houzel JC, Garcia-Abreu J, et al. Inhibition of Alzheimer's disease beta-amyloid aggregation, neurotoxicity, and in vivo deposition by nitrophenols: implications for Alzheimer's therapy. FASEB J 2001;15:1297-1299.
²¹
De Felice FG, Vieira MN, Saraiva LM, et al. Targeting the neurotoxic species in Alzheimer's disease: inhibitors of Abeta oligomerization. FASEB J 2004;18:1366-1372.
²²
Vieira MNN, Figueroa-Villar JD, Meirelles MNL, Ferreira ST, De Felice FG. Small molecule inhibitors of lysozyme amyloid aggregation. Cell Biochem Biophys 2006;44:549-553
²³
Raghu P, Reddy GB, Sivakumar B. Inhibition of transthyretin amyloid fibril formation by 2,4-dinitrophenol through tetramer stabilization, Arch Biochem Biophys 2002;400:43-47.
²⁴
Cardoso I, Merlini G, Saraiva MJ. 4-Iodo-4-deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters. FASEB J 2003;17:803-809.
²⁵
Benitez-King G, Ramirez-Rodriguez G, Ortiz L, Meza I. The neuronal cytoskeleton as a potential therapeutic target in neurodegenerative diseases and schizophrenia. Curr Drug Targets CNS Neurol Disord 2004;3:515-533.
²⁶
Iqbal K, Alonso Adel C, Chen S, et al. Tau pathology in Alzheimer's disease and other tauopathies. Biochim Biophys Acta 2005;1739:198-210.
²⁷
Scheff SW, Price DA. Synaptic pathology in Alzheimer's disease: a review of ultrastructural studies. Neurobiol Aging 2003;24:1029-1046.
²⁸
Wasilewska-Sampaio AP, Silveira MS, Holub O, et al. Neuritogenesis and neuronal differentiation promoted by 2,4-dinitrophenol, a novel anti-amyloidogenic compound, FASEB J 2005;19:1627-1636.
²⁹
Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 1975;72:1858-1862.
³⁰
Drubin DG, Kirschner MW. Tau protein function in living cells, J Cell Biol 1986;103:2739-2746.
³¹
Avila J, Lucas JJ, Perez M, Hernandez F. Role of tau protein in both physiological and pathological conditions. Physiol Rev 2004;84:361-384.
³²
De Felice FG, Wu D, Lambert MP, et al. Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Abeta oligomers. Neurobiol Aging 2007 (in press).
³³
Jacobs WB, Fehlings MG. The molecular basis of neural regeneration. Neurosurgery 2003;53:943-948.
³⁴
Song HJ, Ming GL, Poo MM. cAMP-induced switching in turning direction of nerve growth cones. Nature 1997;388: 275-179.
³⁵
Song H, Ming G, He Z, et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 1998;281:1515-1518.
³⁶
Cai D, Qiu J, Cao Z, McAtee M, Bregman BS, Filbin MT. Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. J Neurosci 2001;21: 4731-4739.
³⁷
De Felice FG, Wasilewska-Sampaio AP, Barbosa ACAP, Gomes FCA, Klein WL and Ferreira ST. Cyclic AMP enhancers and Ab oligomerization blockers as potential therapeutic agents in Alzheimer's disease. Curr Alzheimer Res 2007;4:265-274.

Publication Dates

Publication in this collection
Oct-Dec 2007

History

Received
10 July 2007
Reviewed
11 Aug 2007
Accepted
29 Oct 2007

This is an open-access article distributed under the terms of the Creative Commons Attribution License

[1] ¹
Parascandola J. Dinitrophenol and bioenergetics: an historical perspective, Mol Cell Biochem 1974;5:69-77.

[2] ²
Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994;330:613-622.

[3] ³
Mattson M. Excitotoxic and excitoprotective mechanisms: abundant targets for the prevention and treatment of neurodegenerative disorders. Neuromolecular Med 2003;3:65-94.

[4] ⁴
Brand MD. Uncoupling to survive? The role of mitochondrial inefficiency in ageing, Exp Gerontol 2000;35:811-820.

[5] ⁵
Maragos WF, Rockich KT, Dean JJ, Young KL. Pre- or post-treatment with the mitochondrial uncoupler 2,4-dinitrophenol attenuates striatal quinolinate lesions. Brain Res 2003;966:312-316.

[6] ⁶
Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov 2006;20:1-11.

[7] ⁷
Korde AS, Sullivan PG, Maragos WF. The uncoupling agent 2,4-dinitrophenol improves mitochondrial homeostasis following striatal quinolinic acid injections. J Neurotrauma 2005;22:1142-1149.

[8] ⁸
Korde AS, Pettigrew LC, Craddock SD, Maragos WF. The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia. J Neurochem 2005;94:1676-1684.

[9] ⁹
Mattiasson G, Shamloo M, Gido G, et al. Uncoupling protein-2 prevents neuronal death and diminishes brain dysfunction after stroke and brain trauma. Nat Med 2003;9:1062-1068.

[10] ¹⁰
Jin Y, McEwen ML, Nottingham SA, et al. The mitochondrial uncoupling agent 2,4-dinitrophenol improves mitochondrial function, attenuates oxidative damage, and increases white matter sparing in the contused spinal cord. J Neurotrauma 2004;21:1396-1404.

[11] ¹¹
Bordone L, Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 2005;6:298-305.

[12] ¹²
Barros MH, Bandy B, Tahara EB, Kowaltowski AJ. Higher respiratory activity decreases mitochondrial reactive oxygen release and increases life span in Saccharomyces cerevisiae. J Biol Chem 2004;279:49883-49888.

[13] ¹³
Padalko VI. Uncoupler of oxidative phosphorylation prolongs the lifespan of Drosophila. Biochemistry (Mosc). 2005;70:986-989.

[14] ¹⁴
Ferreira. ST, De Felice FG, Chapeaurouge A. Metastable, partially folded states in the productive folding and in the misfolding and amyloid aggregation of proteins, Cell Biochem Biophys. 2006(in press).

[15] ¹⁵
Czech. C, Tremp G, Pradier L. Presenilins and Alzheimer's disease: biological functions and pathogenic mechanisms. Prog Neurobiol 2000;60:363-384.

[16] ¹⁶
Ernst RL, Hay JW, Fenn C, Tinklenberg J, Yesavage JA. Cognitive function and the costs of Alzheimer's disease. An exploratory study. Arch Neurol 1997;54:687-693.

[17] ¹⁷
De Felice FG, Ferreira ST. Beta-amyloid production, aggregation, and clearance as targets for therapy in Alzheimer's disease. Cell Mol Neurobiol 2002;22:545-563.

[18] ¹⁸
Klein WL, Stine WB Jr, Teplow DB. Small assemblies of unmodified amyloid beta-protein are the proximate neurotoxin in Alzheimer's disease Neurobiol Aging 2004;25:569-80.

[19] ¹⁹
Ferreira ST, Vieira MNN, De Felice FG. Soluble protein oligomers as emerging toxins in amyloid diseases. IUBMB Life 2007;59:332-345

[20] ²⁰
De Felice FG, Houzel JC, Garcia-Abreu J, et al. Inhibition of Alzheimer's disease beta-amyloid aggregation, neurotoxicity, and in vivo deposition by nitrophenols: implications for Alzheimer's therapy. FASEB J 2001;15:1297-1299.

[21] ²¹
De Felice FG, Vieira MN, Saraiva LM, et al. Targeting the neurotoxic species in Alzheimer's disease: inhibitors of Abeta oligomerization. FASEB J 2004;18:1366-1372.

[22] ²²
Vieira MNN, Figueroa-Villar JD, Meirelles MNL, Ferreira ST, De Felice FG. Small molecule inhibitors of lysozyme amyloid aggregation. Cell Biochem Biophys 2006;44:549-553

[23] ²³
Raghu P, Reddy GB, Sivakumar B. Inhibition of transthyretin amyloid fibril formation by 2,4-dinitrophenol through tetramer stabilization, Arch Biochem Biophys 2002;400:43-47.

[24] ²⁴
Cardoso I, Merlini G, Saraiva MJ. 4-Iodo-4-deoxydoxorubicin and tetracyclines disrupt transthyretin amyloid fibrils in vitro producing noncytotoxic species: screening for TTR fibril disrupters. FASEB J 2003;17:803-809.

[25] ²⁵
Benitez-King G, Ramirez-Rodriguez G, Ortiz L, Meza I. The neuronal cytoskeleton as a potential therapeutic target in neurodegenerative diseases and schizophrenia. Curr Drug Targets CNS Neurol Disord 2004;3:515-533.

[26] ²⁶
Iqbal K, Alonso Adel C, Chen S, et al. Tau pathology in Alzheimer's disease and other tauopathies. Biochim Biophys Acta 2005;1739:198-210.

[27] ²⁷
Scheff SW, Price DA. Synaptic pathology in Alzheimer's disease: a review of ultrastructural studies. Neurobiol Aging 2003;24:1029-1046.

[28] ²⁸
Wasilewska-Sampaio AP, Silveira MS, Holub O, et al. Neuritogenesis and neuronal differentiation promoted by 2,4-dinitrophenol, a novel anti-amyloidogenic compound, FASEB J 2005;19:1627-1636.

[29] ²⁹
Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA 1975;72:1858-1862.

[30] ³⁰
Drubin DG, Kirschner MW. Tau protein function in living cells, J Cell Biol 1986;103:2739-2746.

[31] ³¹
Avila J, Lucas JJ, Perez M, Hernandez F. Role of tau protein in both physiological and pathological conditions. Physiol Rev 2004;84:361-384.

[32] ³²
De Felice FG, Wu D, Lambert MP, et al. Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Abeta oligomers. Neurobiol Aging 2007 (in press).

[33] ³³
Jacobs WB, Fehlings MG. The molecular basis of neural regeneration. Neurosurgery 2003;53:943-948.

[34] ³⁴
Song HJ, Ming GL, Poo MM. cAMP-induced switching in turning direction of nerve growth cones. Nature 1997;388: 275-179.

[35] ³⁵
Song H, Ming G, He Z, et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 1998;281:1515-1518.

[36] ³⁶
Cai D, Qiu J, Cao Z, McAtee M, Bregman BS, Filbin MT. Neuronal cyclic AMP controls the developmental loss in ability of axons to regenerate. J Neurosci 2001;21: 4731-4739.

[37] ³⁷
De Felice FG, Wasilewska-Sampaio AP, Barbosa ACAP, Gomes FCA, Klein WL and Ferreira ST. Cyclic AMP enhancers and Ab oligomerization blockers as potential therapeutic agents in Alzheimer's disease. Curr Alzheimer Res 2007;4:265-274.

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