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Tempol – an ocular neuroprotectant?
New drug VEGF Trap-Eye – Eylea in the treatment of age-related macular degeneration, and macular edema in central retinal vein occlusion and diabetic retinopathy Robert Rejdak1,2 Department
of General Ophthalmology, Medical University in Lublin, Chmielna 1, PL 20-079 Lublin, Poland; Mossakowski Medical Research Center, PAS, Pawiñskiego 5, PL 02-106 Warszawa, Poland
Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of choroidal and retinal neovascularization. Anti-VEGF therapy changed the standard-of-care for ocular disease with neovascularisation. VEGF Trap-Eye (Eylea) is a new, promising drug from this group. Clinical trials evaluating the efficacy of VEGF Trap-Eye in the treatment of wet Age-related Macular Degeneration (VIEW1, VIEW2),
Central Retinal Vain Occlusion (GALILEO, COPERNICUS) and Diabetic Macular Edema (DA VINCI) are conducted. Results from all of these trials are promising and demonstrate the wide-range of applications for VEGF Trap-Eye in ophthalmology. The aim of the presentation is to report results of clinical trials on VEGF Trap-Eye in major maculopathies carried out so far.
Tempol – an ocular neuroprotectant? Sebastian Thaler Centre for Ophthalmology, University of Tübingen, Röntgenweg 11, D-72076, Tübingen, Germany
Neuroprotective therapeutic approaches aim at the late stages of chronic neuronal damage, which share common characteristics in many different neurodegenerative diseases in the brain, e.g. Parkinson’s, Alzheimer’s, or Huntington’s disease, but also in the retina, e.g. glaucoma, hereditary photoreceptor degeneration, or retinal ischemia. Several important factors are known to contribute to apoptotic cell death in neurodegenerative diseases. One of them is oxidative stress, which leads to oxidative damage of cellular macromolecules. Production of reactive oxygen species (ROS) and the formation of reactive nitrogen species (RNS) has been shown to play a role in retinal ganglion cell (RGC) death in different glaucoma models, and increased oxidative stress levels have also been demonstrated in glaucoma patients. One candidate for a therapeutic antioxidant approach in treating neuronal degeneration is the stable nitroxide tempol (4-hydroxy-2,2,6,6-tetramethylpiperidinyl-1-oxyl), a low weight antioxidant that acts as 26
Pharmacological Reports, 2013, 65, suppl.
a superoxide dismutase (SOD) mimetic. Tempol is highly cell-permeable and easily crosses the bloodbrain barrier. It has been shown to protect neuronal cells in models of brain trauma, ischemic stroke, and Parkinson’s disease in vitro and in vivo. Tempol significantly improved RGC survival in an in vitro model of TNF-a and hypoxia-induced RGC damage. In vivo, our group could show that systemic Tempol can rescue RGC in a rat partial optic nerve crush (PONC) model. However, the required tempol doses bear the risk of serious systemic side effects. We therefore made an attempt to develop more effective derivatives of tempol. In contrast to some other ROS or RNS, the superoxide radical is short lived and cannot easily diffuse through biological membranes. Neutralizing it at the site of its generation could be crucial for preventing generation of other diffusible ROS and RNS (e.g. peroxynitrite). We hypothesized, that modifying the hydrophilic tempol molecule with attached lipophilic acyl chains could direct tempol to
XVIIIJD International Congress of the Polish Pharmacological Society Symposia
sites of free radical generation and may then allow a better efficacy. We tested four different tempol acyl esters in the PONC model and found one of them, tempol-C8, to be more effective than tempol itself.
Antioxidants like tempol may offer important opportunities for future neuroprotective treatment concepts in retinal ganglion cell degeneration.
Ketone therapy in central nervous system disorders Tomasz ¯arnowski Chair of Ophthalmology, Medical University of Lublin, Chmielna 1, PL 20-079 Lublin, Poland
Ketogenic diet has been used in treating epilepsy for more than 80 years. It is based on a drastic change of proportions in the consumption of carbohydrates, proteins and fats. In everyday diet we consume approximately 34% of fats, 50% of carbohydrates and 14% of proteins. While ketogenic diet consists of 80–90% of fats and in 10–20% of carbohydrates and proteins together. Despite its indisputable effectiveness, the functioning of the ketogenic diet has not been explained. It seems that its functioning mechanism is unique and results from a number of chronic metabolic changes as well as the adaptation in the central nervous system that occurs during its long-term appli-
cation. Ketone bodies (acetone, acetoacetate and bhydroxybutyrate) which blood levels are elevated during application of the ketogenic diet could be responsible for the effects. The most recent clinical and experimental data suggest that the ketogenic diet also has neuroprotective properties, which makes it a useful alternative therapeutic method in the modification of the natural history of the diseases related with neurodegeneration processes. The paper is to present some aspects of anticonvulsant and antiepileptic properties of ketogenic diet and ketone bodies in some experimental rodent models of epilepsy and neurodegeneration.
Pharmacological Reports, 2013, 65, suppl.
27
of General Ophthalmology, Medical University in Lublin, Chmielna 1, PL 20-079 Lublin, Poland; Mossakowski Medical Research Center, PAS, Pawiñskiego 5, PL 02-106 Warszawa, Poland
Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of choroidal and retinal neovascularization. Anti-VEGF therapy changed the standard-of-care for ocular disease with neovascularisation. VEGF Trap-Eye (Eylea) is a new, promising drug from this group. Clinical trials evaluating the efficacy of VEGF Trap-Eye in the treatment of wet Age-related Macular Degeneration (VIEW1, VIEW2),
Central Retinal Vain Occlusion (GALILEO, COPERNICUS) and Diabetic Macular Edema (DA VINCI) are conducted. Results from all of these trials are promising and demonstrate the wide-range of applications for VEGF Trap-Eye in ophthalmology. The aim of the presentation is to report results of clinical trials on VEGF Trap-Eye in major maculopathies carried out so far.
Tempol – an ocular neuroprotectant? Sebastian Thaler Centre for Ophthalmology, University of Tübingen, Röntgenweg 11, D-72076, Tübingen, Germany
Neuroprotective therapeutic approaches aim at the late stages of chronic neuronal damage, which share common characteristics in many different neurodegenerative diseases in the brain, e.g. Parkinson’s, Alzheimer’s, or Huntington’s disease, but also in the retina, e.g. glaucoma, hereditary photoreceptor degeneration, or retinal ischemia. Several important factors are known to contribute to apoptotic cell death in neurodegenerative diseases. One of them is oxidative stress, which leads to oxidative damage of cellular macromolecules. Production of reactive oxygen species (ROS) and the formation of reactive nitrogen species (RNS) has been shown to play a role in retinal ganglion cell (RGC) death in different glaucoma models, and increased oxidative stress levels have also been demonstrated in glaucoma patients. One candidate for a therapeutic antioxidant approach in treating neuronal degeneration is the stable nitroxide tempol (4-hydroxy-2,2,6,6-tetramethylpiperidinyl-1-oxyl), a low weight antioxidant that acts as 26
Pharmacological Reports, 2013, 65, suppl.
a superoxide dismutase (SOD) mimetic. Tempol is highly cell-permeable and easily crosses the bloodbrain barrier. It has been shown to protect neuronal cells in models of brain trauma, ischemic stroke, and Parkinson’s disease in vitro and in vivo. Tempol significantly improved RGC survival in an in vitro model of TNF-a and hypoxia-induced RGC damage. In vivo, our group could show that systemic Tempol can rescue RGC in a rat partial optic nerve crush (PONC) model. However, the required tempol doses bear the risk of serious systemic side effects. We therefore made an attempt to develop more effective derivatives of tempol. In contrast to some other ROS or RNS, the superoxide radical is short lived and cannot easily diffuse through biological membranes. Neutralizing it at the site of its generation could be crucial for preventing generation of other diffusible ROS and RNS (e.g. peroxynitrite). We hypothesized, that modifying the hydrophilic tempol molecule with attached lipophilic acyl chains could direct tempol to
XVIIIJD International Congress of the Polish Pharmacological Society Symposia
sites of free radical generation and may then allow a better efficacy. We tested four different tempol acyl esters in the PONC model and found one of them, tempol-C8, to be more effective than tempol itself.
Antioxidants like tempol may offer important opportunities for future neuroprotective treatment concepts in retinal ganglion cell degeneration.
Ketone therapy in central nervous system disorders Tomasz ¯arnowski Chair of Ophthalmology, Medical University of Lublin, Chmielna 1, PL 20-079 Lublin, Poland
Ketogenic diet has been used in treating epilepsy for more than 80 years. It is based on a drastic change of proportions in the consumption of carbohydrates, proteins and fats. In everyday diet we consume approximately 34% of fats, 50% of carbohydrates and 14% of proteins. While ketogenic diet consists of 80–90% of fats and in 10–20% of carbohydrates and proteins together. Despite its indisputable effectiveness, the functioning of the ketogenic diet has not been explained. It seems that its functioning mechanism is unique and results from a number of chronic metabolic changes as well as the adaptation in the central nervous system that occurs during its long-term appli-
cation. Ketone bodies (acetone, acetoacetate and bhydroxybutyrate) which blood levels are elevated during application of the ketogenic diet could be responsible for the effects. The most recent clinical and experimental data suggest that the ketogenic diet also has neuroprotective properties, which makes it a useful alternative therapeutic method in the modification of the natural history of the diseases related with neurodegeneration processes. The paper is to present some aspects of anticonvulsant and antiepileptic properties of ketogenic diet and ketone bodies in some experimental rodent models of epilepsy and neurodegeneration.
Pharmacological Reports, 2013, 65, suppl.
27