Andy13
Community Veteran, The Chemist
I think this is the first time anyone has posted anything regarding DNP and positive effects on health. First, let me make clear, this is for informational purposes only. Since the 1930’s, there have been no clinical trials using DNP. The information I am presenting is based on a rat model, the closest we can get to simulating effects in humans.
DNP Reduces the production of damaging free radicals
Free radicals are generated from electron transport during aerobic respiration. When electrons are passed down the electron transport chain, protons are pumped into the inner membrane space, creating a proton gradient. The potential energy of this gradient is used to synthesize ATP from ADP and PO4. Occasionally, electrons are diverted to molecular oxygen at points during electron transport rather than proceeding through subsequent electron carriers. This one-electron reduction of oxygen generates superoxide (O2*-). This is a reactive oxygen species (ROS, a free radical) that is wreaks havoc on cellular components such as lipids, proteins, and DNA. Generation of ROS is undesirable. ROS cause oxidative damage. Oxidative damage is associated with onset of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease as well as cancer and aging.
DNP works by uncoupling oxidative phosphorylation. Specifically, DNP decreases the proton motive force by transporting protons back into the matrix. In essence, the cell has to work harder to make the same amount of ATP. What is interesting is that a decreased proton motive force and electro chemical gradient is associated with a REDUCED production of reactive oxygen species. Even though more substrates are metabolized and more electrons are passed through the electron transport chain (respiration is increase) to make the same amount of ATP, LESS damaging reactive oxygen species are generated. Oxidative damage from ROS is linked to onset of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases as well as cancer and the process of aging. Mild uncoupling of oxidative phosphorylation (by DNP) has been shown to provide a protective effect against oxidative damage-mediated neurodegeneration in rats.
DNP, which causes mild uncoupling, may in fact be beneficial for one’s health. The dosage and administration frequency of DNP to provide these benefits remains unclear. It is quite possible that a dose of DNP too low to cause significant weight loss could still be have positive effects against undesirable ROS production.
J Neurotrauma. 2005 Oct;22(10):1142-9.
The uncoupling agent 2,4-dinitrophenol improves mitochondrial homeostasis following striatal quinolinic acid injections.
Korde AS, Sullivan PG, Maragos WF.
It is now generally accepted that excitotoxic cell death involves bioenergetic failure resulting from the cycling of Ca2+ and the generation of reactive oxygen species (ROS) by mitochondria. Both Ca2+ cycling and ROS formation by mitochondria are dependent on the mitochondrial membrane potential (Deltapsi(m)) that results from the proton gradient that is generated across the inner membrane. Mitochondrial uncoupling refers to a condition in which protons cross the inner membrane back into the matrix while bypassing the ATP synthase. As a consequence of this "short-circuit," there is a reduction in Deltapsi(m). We have previously demonstrated that animals treated with the classic uncoupling agent 2,4-dinitrophenol (DNP) show significant protection against brain damage following striatal injections of the NMDA agonist quinolinic acid (QA). In an effort to elucidate the mechanism of neuroprotection, we have assessed the effects of DNP on several parameters of mitochondrial function caused by QA. The results presented herein demonstrate that treatment with DNP attenuates QA-induced increases in mitochondrial Ca2+ levels and ROS formation and also improves mitochondrial respiration. Our findings indicate that DNP may confer protection against acute brain injury involving excitotoxic pathways by mechanisms that maintain mitochondrial function.
J Neurochem. 2005 Sep;94(6):1676-84. Epub 2005 Jul 25.
The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia.
Korde AS, Pettigrew LC, Craddock SD, Maragos WF.
Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable 'upstream' targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia-reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function.
J Neurotrauma. 2004 Oct;21(10):1396-404.
The mitochondrial uncoupling agent 2,4-dinitrophenol improves mitochondrial function, attenuates oxidative damage, and increases white matter sparing in the contused spinal cord.
Jin Y, McEwen ML, Nottingham SA, Maragos WF, Dragicevic NB, Sullivan PG, Springer JE.
The purpose of this study was to investigate the potential neuroprotective efficacy of the mitochondrial uncoupler 2,4-dinitrophenol (DNP) in rats following a mild to moderate spinal cord contusion injury. Animals received intraperitoneal injections of vehicle (DMSO) or 5 mg/mL of DNP prior to injury. Twenty-four hours following surgery, mitochondrial function was assessed in mitochondria isolated from spinal cord synaptosomes. In addition, synaptosomes were used to measure indicators of reactive oxygen species formation, lipid peroxidation, and protein oxidation. Relative to vehicle-treated animals, pretreatment with DNP maintained mitochondrial bioenergetics and significantly decreased reactive oxygen species levels, lipid peroxidation, and protein carbonyl content following spinal cord injury. Furthermore, pretreatment with DNP significantly increased the amount of remaining white matter at the injury epicenter 6 weeks after injury. These results indicate that treatment with mitochondrial uncoupling agents may provide a novel approach for the treatment of secondary injury following spinal cord contusion.
DNP Reduces the production of damaging free radicals
Free radicals are generated from electron transport during aerobic respiration. When electrons are passed down the electron transport chain, protons are pumped into the inner membrane space, creating a proton gradient. The potential energy of this gradient is used to synthesize ATP from ADP and PO4. Occasionally, electrons are diverted to molecular oxygen at points during electron transport rather than proceeding through subsequent electron carriers. This one-electron reduction of oxygen generates superoxide (O2*-). This is a reactive oxygen species (ROS, a free radical) that is wreaks havoc on cellular components such as lipids, proteins, and DNA. Generation of ROS is undesirable. ROS cause oxidative damage. Oxidative damage is associated with onset of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease as well as cancer and aging.
DNP works by uncoupling oxidative phosphorylation. Specifically, DNP decreases the proton motive force by transporting protons back into the matrix. In essence, the cell has to work harder to make the same amount of ATP. What is interesting is that a decreased proton motive force and electro chemical gradient is associated with a REDUCED production of reactive oxygen species. Even though more substrates are metabolized and more electrons are passed through the electron transport chain (respiration is increase) to make the same amount of ATP, LESS damaging reactive oxygen species are generated. Oxidative damage from ROS is linked to onset of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases as well as cancer and the process of aging. Mild uncoupling of oxidative phosphorylation (by DNP) has been shown to provide a protective effect against oxidative damage-mediated neurodegeneration in rats.
DNP, which causes mild uncoupling, may in fact be beneficial for one’s health. The dosage and administration frequency of DNP to provide these benefits remains unclear. It is quite possible that a dose of DNP too low to cause significant weight loss could still be have positive effects against undesirable ROS production.
J Neurotrauma. 2005 Oct;22(10):1142-9.
The uncoupling agent 2,4-dinitrophenol improves mitochondrial homeostasis following striatal quinolinic acid injections.
Korde AS, Sullivan PG, Maragos WF.
It is now generally accepted that excitotoxic cell death involves bioenergetic failure resulting from the cycling of Ca2+ and the generation of reactive oxygen species (ROS) by mitochondria. Both Ca2+ cycling and ROS formation by mitochondria are dependent on the mitochondrial membrane potential (Deltapsi(m)) that results from the proton gradient that is generated across the inner membrane. Mitochondrial uncoupling refers to a condition in which protons cross the inner membrane back into the matrix while bypassing the ATP synthase. As a consequence of this "short-circuit," there is a reduction in Deltapsi(m). We have previously demonstrated that animals treated with the classic uncoupling agent 2,4-dinitrophenol (DNP) show significant protection against brain damage following striatal injections of the NMDA agonist quinolinic acid (QA). In an effort to elucidate the mechanism of neuroprotection, we have assessed the effects of DNP on several parameters of mitochondrial function caused by QA. The results presented herein demonstrate that treatment with DNP attenuates QA-induced increases in mitochondrial Ca2+ levels and ROS formation and also improves mitochondrial respiration. Our findings indicate that DNP may confer protection against acute brain injury involving excitotoxic pathways by mechanisms that maintain mitochondrial function.
J Neurochem. 2005 Sep;94(6):1676-84. Epub 2005 Jul 25.
The mitochondrial uncoupler 2,4-dinitrophenol attenuates tissue damage and improves mitochondrial homeostasis following transient focal cerebral ischemia.
Korde AS, Pettigrew LC, Craddock SD, Maragos WF.
Ischemic stroke is caused by acute neuronal degeneration provoked by interruption of cerebral blood flow. Although the mechanisms contributing to ischemic neuronal degeneration are myriad, mitochondrial dysfunction is now recognized as a pivotal event that can lead to either necrotic or apoptotic neuronal death. Lack of suitable 'upstream' targets to prevent loss of mitochondrial homeostasis has, so far, restricted the development of mechanistically based interventions to promote neuronal survival. Here, we show that the uncoupling agent 2,4 dinitrophenol (DNP) reduces infarct volume approximately 40% in a model of focal ischemia-reperfusion injury in the rat brain. The mechanism of protection involves an early decrease in mitochondrial reactive oxygen species formation and calcium uptake leading to improved mitochondrial function and a reduction in the release of cytochrome c into the cytoplasm. The observed effects of DNP were not associated with enhanced cerebral perfusion. These findings indicate that compounds with uncoupling properties may confer neuroprotection through a mechanism involving stabilization of mitochondrial function.
J Neurotrauma. 2004 Oct;21(10):1396-404.
The mitochondrial uncoupling agent 2,4-dinitrophenol improves mitochondrial function, attenuates oxidative damage, and increases white matter sparing in the contused spinal cord.
Jin Y, McEwen ML, Nottingham SA, Maragos WF, Dragicevic NB, Sullivan PG, Springer JE.
The purpose of this study was to investigate the potential neuroprotective efficacy of the mitochondrial uncoupler 2,4-dinitrophenol (DNP) in rats following a mild to moderate spinal cord contusion injury. Animals received intraperitoneal injections of vehicle (DMSO) or 5 mg/mL of DNP prior to injury. Twenty-four hours following surgery, mitochondrial function was assessed in mitochondria isolated from spinal cord synaptosomes. In addition, synaptosomes were used to measure indicators of reactive oxygen species formation, lipid peroxidation, and protein oxidation. Relative to vehicle-treated animals, pretreatment with DNP maintained mitochondrial bioenergetics and significantly decreased reactive oxygen species levels, lipid peroxidation, and protein carbonyl content following spinal cord injury. Furthermore, pretreatment with DNP significantly increased the amount of remaining white matter at the injury epicenter 6 weeks after injury. These results indicate that treatment with mitochondrial uncoupling agents may provide a novel approach for the treatment of secondary injury following spinal cord contusion.
