An investigation into the neuroprotective properties of acyclovir
- Authors: Müller, Adrienne Carmel
- Date: 2006
- Subjects: Acyclovir -- Therapeutic use , Acyclovir -- Physiological effect , Nervous system -- Degeneration -- Treatment , Memory disorders -- Treatment , Quinolinic acid
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3776 , http://hdl.handle.net/10962/d1003254 , Acyclovir -- Therapeutic use , Acyclovir -- Physiological effect , Nervous system -- Degeneration -- Treatment , Memory disorders -- Treatment , Quinolinic acid
- Description: Accumulating evidence suggests that quinolinic acid has a role to play in disorders involving impairment of learning and memory. In the present study, the effect of the guanosine analogue antiherpetic, acyclovir, on quinolinic acid-induced spatial memory deficits was investigated, as well as some of the mechanisms which underlie this effect. Behavioural studies using a Morris water maze show that post-treatment of rats with acyclovir significantly improves spatial memory deficits induced by intrahippocampal injections of quinolinic acid. Histological analysis of the hippocampi show that the effect of acyclovir is related to its ability to alleviate quinolinic acid-induced necrotic cell death, through interference with some of the mechanisms of neurodegeneration. However, acyclovir is unable to alter a quinolinic acid-induced increase in glutamate release in the rat hippocampus, even though it alleviates quinolinic acid induced oxidative stress by scavenging the superoxide anion in vitro and in vivo in whole rat brain and hippocampus respectively. Due to the inverse relationship which exists between superoxide anion and glutathione levels, acyclovir also curtails the quinolinic acid-induced decrease in hippocampal glutathione levels. Acyclovir suppresses quinolinic acid-induced lipid peroxidation in vitro and in vivo, in whole rat brain and hippocampus respectively, through its alleviation of oxidative stress and possibly through the binding of iron (II) and / or iron (III), preventing the participation and redox recycling of iron (II) in the Fenton reaction, which quinolinic acid is thought to enhance by weak binding of ferrous ions. This argument is further strengthened by the ability of the drug to suppress iron (II)-induced lipid peroxidation in vitro directly. Inorganic studies including ultraviolet and visible spectroscopy, electrochemistry and the ferrozine assay show that acyclovir binds to iron (II) and iron (III) and that quinolinic acid forms an easily oxidisable association with iron (II). Acyclovir inhibits the endogenous biosynthesis of quinolinic acid by inhibiting the activity of liver tryptophan-2,3-dioxygenase, intestinal indoleamine-2,3-dioxygenase and rat liver 3-hydroxyanthranillic acid oxygenase in vitro and in vivo, possibly through competitive inhibition of haeme, scavenging of superoxide anion and binding of iron (II) respectively. An inverse relationship exists between tryptophan-2,3-dioxygenase activity and brain serotonin levels. Acyclovir administration in rats induces a rise in forebrain serotonin and 5-hydroxyindole acetic acid and reduces the turnover of forebrain serotonin to 5-hydroxyindole acetic acid. Furthermore, it shows that acyclovir does not alter forebrain norepinephrine levels. The results of the pineal indole metabolism study show that acyclovir increases 5-hydroxytryptophol, N-acetylserotonin and the neurohormone melatonin, but decreases 5-hydroxyindole acetic acid. The results of this study show that acyclovir has some neuroprotective properties which may make it useful in the alleviation of the anomalous neurobiology in neurodegenerative disorders.
- Full Text:
- Date Issued: 2006
- Authors: Müller, Adrienne Carmel
- Date: 2006
- Subjects: Acyclovir -- Therapeutic use , Acyclovir -- Physiological effect , Nervous system -- Degeneration -- Treatment , Memory disorders -- Treatment , Quinolinic acid
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3776 , http://hdl.handle.net/10962/d1003254 , Acyclovir -- Therapeutic use , Acyclovir -- Physiological effect , Nervous system -- Degeneration -- Treatment , Memory disorders -- Treatment , Quinolinic acid
- Description: Accumulating evidence suggests that quinolinic acid has a role to play in disorders involving impairment of learning and memory. In the present study, the effect of the guanosine analogue antiherpetic, acyclovir, on quinolinic acid-induced spatial memory deficits was investigated, as well as some of the mechanisms which underlie this effect. Behavioural studies using a Morris water maze show that post-treatment of rats with acyclovir significantly improves spatial memory deficits induced by intrahippocampal injections of quinolinic acid. Histological analysis of the hippocampi show that the effect of acyclovir is related to its ability to alleviate quinolinic acid-induced necrotic cell death, through interference with some of the mechanisms of neurodegeneration. However, acyclovir is unable to alter a quinolinic acid-induced increase in glutamate release in the rat hippocampus, even though it alleviates quinolinic acid induced oxidative stress by scavenging the superoxide anion in vitro and in vivo in whole rat brain and hippocampus respectively. Due to the inverse relationship which exists between superoxide anion and glutathione levels, acyclovir also curtails the quinolinic acid-induced decrease in hippocampal glutathione levels. Acyclovir suppresses quinolinic acid-induced lipid peroxidation in vitro and in vivo, in whole rat brain and hippocampus respectively, through its alleviation of oxidative stress and possibly through the binding of iron (II) and / or iron (III), preventing the participation and redox recycling of iron (II) in the Fenton reaction, which quinolinic acid is thought to enhance by weak binding of ferrous ions. This argument is further strengthened by the ability of the drug to suppress iron (II)-induced lipid peroxidation in vitro directly. Inorganic studies including ultraviolet and visible spectroscopy, electrochemistry and the ferrozine assay show that acyclovir binds to iron (II) and iron (III) and that quinolinic acid forms an easily oxidisable association with iron (II). Acyclovir inhibits the endogenous biosynthesis of quinolinic acid by inhibiting the activity of liver tryptophan-2,3-dioxygenase, intestinal indoleamine-2,3-dioxygenase and rat liver 3-hydroxyanthranillic acid oxygenase in vitro and in vivo, possibly through competitive inhibition of haeme, scavenging of superoxide anion and binding of iron (II) respectively. An inverse relationship exists between tryptophan-2,3-dioxygenase activity and brain serotonin levels. Acyclovir administration in rats induces a rise in forebrain serotonin and 5-hydroxyindole acetic acid and reduces the turnover of forebrain serotonin to 5-hydroxyindole acetic acid. Furthermore, it shows that acyclovir does not alter forebrain norepinephrine levels. The results of the pineal indole metabolism study show that acyclovir increases 5-hydroxytryptophol, N-acetylserotonin and the neurohormone melatonin, but decreases 5-hydroxyindole acetic acid. The results of this study show that acyclovir has some neuroprotective properties which may make it useful in the alleviation of the anomalous neurobiology in neurodegenerative disorders.
- Full Text:
- Date Issued: 2006
An investigation of the neuroprotective effects of estrogen in a model of quinolinic acid-induced neurodegeneration
- Authors: Heron, Paula Michelle
- Date: 2002
- Subjects: Estrogen , Quinolinic acid , Nervous system -- Degeneration
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3759 , http://hdl.handle.net/10962/d1003237 , Estrogen , Quinolinic acid , Nervous system -- Degeneration
- Description: The hippocampus, located in the medial temporal lobe, is an important region of the brain responsible for the formation of memory. Thus, any agent that induces stress in this area has detrimental effects and could lead to various types of dementia. Such agents include the neurotoxin, Quinolinic acid. Quinolinic acid (QUIN) is a neurotoxic metabolite of the tryptophan-kynurenine pathway and is an endogenous glutamate agonist that selectively injures and kills vulnerable neurons via the activation of the NMDA class of excitatory amino acid receptors. Estrogen is a female hormone that is responsible for reproduction. However, in the last decade estrogen has been shown to exhibit a wide range of actions on the brain, including neuroprotection. Estrogen has been shown to exhibit intrinsic antioxidant activity and protects cultured neurons against oxidative cell death. This is achieved by estrogen’s ability to scavenge free radicals, which is dependent on the presence of the hydroxyl group at the C3 position on the A ring of the steroid molecule. Numerous studies have shown that estrogen protects neurons against various toxic substances and may play a role in delaying the onset of neurodegenerative diseases, such as Alzheimer’s disease. Neuronal damage due to oxidative stress has been implicated in several neurodegenerative disorders. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. The study aims to elucidate and further characterise the mechanism behind estrogen’s neuroprotection, using QUIN as a model of neurotoxicity. Initial studies confirm estrogen’s ability to scavenge potent free radicals. In addition, the results show that estrogen forms an interaction with iron (II) and also acts at the NMDA receptor as an agonist. Both mechanisms reduce the ability of QUIN to cause damage to neurons, since QUIN-induced toxicity is dependent on the activation of the NMDA receptor and the formation of a complex with iron (II) to induce lipid peroxidation. Heat shock proteins, especially Hsp 70 play a role in cytoprotection by capturing denatured proteins and facilitating the refolding of these proteins once the stress has been relieved. Estrogen has been shown to increase the level of expression of Hsp70, both inducible and cognate forms of the protein. This suggests that estrogen helps to protect against cellular protein damage induced by any form of stress the cell may encounter. The discovery of neuroprotective agents, such as estrogen, is becoming important as accumulating evidence indicates a protective role in vivo. Thus further research may favour the use of these agents in the treatment of several neurodegenerative disorders. Considering how devastating diseases, such as Alzheimer’s disease, are to a patient and the patient’s families, the discovery of new protective agents are a matter of urgency.
- Full Text:
- Date Issued: 2002
- Authors: Heron, Paula Michelle
- Date: 2002
- Subjects: Estrogen , Quinolinic acid , Nervous system -- Degeneration
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3759 , http://hdl.handle.net/10962/d1003237 , Estrogen , Quinolinic acid , Nervous system -- Degeneration
- Description: The hippocampus, located in the medial temporal lobe, is an important region of the brain responsible for the formation of memory. Thus, any agent that induces stress in this area has detrimental effects and could lead to various types of dementia. Such agents include the neurotoxin, Quinolinic acid. Quinolinic acid (QUIN) is a neurotoxic metabolite of the tryptophan-kynurenine pathway and is an endogenous glutamate agonist that selectively injures and kills vulnerable neurons via the activation of the NMDA class of excitatory amino acid receptors. Estrogen is a female hormone that is responsible for reproduction. However, in the last decade estrogen has been shown to exhibit a wide range of actions on the brain, including neuroprotection. Estrogen has been shown to exhibit intrinsic antioxidant activity and protects cultured neurons against oxidative cell death. This is achieved by estrogen’s ability to scavenge free radicals, which is dependent on the presence of the hydroxyl group at the C3 position on the A ring of the steroid molecule. Numerous studies have shown that estrogen protects neurons against various toxic substances and may play a role in delaying the onset of neurodegenerative diseases, such as Alzheimer’s disease. Neuronal damage due to oxidative stress has been implicated in several neurodegenerative disorders. The detection and measurement of lipid peroxidation is the evidence most frequently cited to support the involvement of free radical reactions in toxicology and in human disease. The study aims to elucidate and further characterise the mechanism behind estrogen’s neuroprotection, using QUIN as a model of neurotoxicity. Initial studies confirm estrogen’s ability to scavenge potent free radicals. In addition, the results show that estrogen forms an interaction with iron (II) and also acts at the NMDA receptor as an agonist. Both mechanisms reduce the ability of QUIN to cause damage to neurons, since QUIN-induced toxicity is dependent on the activation of the NMDA receptor and the formation of a complex with iron (II) to induce lipid peroxidation. Heat shock proteins, especially Hsp 70 play a role in cytoprotection by capturing denatured proteins and facilitating the refolding of these proteins once the stress has been relieved. Estrogen has been shown to increase the level of expression of Hsp70, both inducible and cognate forms of the protein. This suggests that estrogen helps to protect against cellular protein damage induced by any form of stress the cell may encounter. The discovery of neuroprotective agents, such as estrogen, is becoming important as accumulating evidence indicates a protective role in vivo. Thus further research may favour the use of these agents in the treatment of several neurodegenerative disorders. Considering how devastating diseases, such as Alzheimer’s disease, are to a patient and the patient’s families, the discovery of new protective agents are a matter of urgency.
- Full Text:
- Date Issued: 2002
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