An investigation into the neuroprotective effects of estrogen and progesterone in a model of homocysteine-induced neurodegeration
- Authors: Wu, Wing Man
- Date: 2006
- Subjects: Homocysteine , Estrogen , Estrogen -- Therapeutic use , Progesterone , Hormone receptors , Methyl aspartate , Oxidative stress , Alzheimer's disease -- Treatment , Nervous system -- Degeneration -- Prevention
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3806 , http://hdl.handle.net/10962/d1003284 , Homocysteine , Estrogen , Estrogen -- Therapeutic use , Progesterone , Hormone receptors , Methyl aspartate , Oxidative stress , Alzheimer's disease -- Treatment , Nervous system -- Degeneration -- Prevention
- Description: Homocysteine (Hcy) is a sulfur containing amino acid and is a potent neurotoxin. It has been shown that elevated levels of Hcy, termed hyperhomocysteinemia, plays a role in the pathologies of Alzheimer’s disease (AD) and age-related cognitive decline. Hcy is a glutamate agonist, which causes in increase in Ca[superscript (2+)] influx via the activation of NMDA class of excitatory amino acid receptors, which results in neuronal cell death and apoptosis. Estrogen and progesterone are female hormones that are responsible for reproduction and maternal behaviour. However, in the last decade, it is evident that both female hormones have neuroprotective properties in many animal models of neurodegeneration. Collectively, both estrogen and progesterone reduce the consequences of the oxidative stress by enhancing the antioxidant defence mechanisms, reducing excitotoxicity by altering glutamate receptor activity and reducing the damage caused by lipid peroxidation. However, the mechanisms by which estrogen and progesterone provide such neuroprotection probably depend on the type and concentration of hormone present. Moreover, numerous studies have shown that hormone replacement therapy (HRT, estrogen and progestins) or estrogen-only replacement therapy (ERT) may prevent or delay the onset of AD and improve cognition for women with AD. Clinical trials have also shown that women taking HRT may modify the effects of Hcy levels on cognitive functioning. Oxidative stress increases in the aging brain and thus has a powerful effect on enhanced susceptibility to neurodegenerative disease. The detection and measurement of lipid peroxidation and superoxide anion radicals in the brain tissue supports the involvement of free radical reactions in neurotoxicity and in neurodegenerative disorders. The hippocampus is an important region of the brain responsible for the formation of memory. However, agents that induce stress in this area have harmful effects and could lead to dementia. This study aims to investigate and clarify the neuroprotective effects of estrogen and progesterone, using Hcy-induced neurodegenerative models. The initial studies demonstrate that estrogen and progesterone have the ability to scavenge potent free radicals. Histological studies undertaken reveal that both estrogen and progesterone protect against Hcy-induced neuronal cell death. In addition, immunohistochemical investigations show that Hcy-induced apoptosis in the hippocampus can be inhibited by both estrogen and progesterone. However, estrogen also acts at the NMDA receptor as an agonist, while progesterone blocks at the NMDA receptor. These mechanisms reduce the ability of Hcy to cause damage to neurons, since Hcy-induced neurotoxicity is dependent on the overstimulation of the NMDA receptor. SOD and GPx are important enzymatic antioxidants which can react with ROS and neutralize them before these inflict damage in the brain. Hcy can increase oxidative stress by inhibiting expression and function of these antioxidants. However, it has been shown that the antioxidant abilities of both estrogen and progesterone can up-regulate the activities of SOD and GPx. These results provide further evidence that estrogen and progesterone act as antioxidants and are free radical scavengers. The discovery of neuroprotective agents is becoming important as accumulating evidence indicates the protective role of both estrogen and progesterone in Hcy-induced neurodegeneration. Thus further work in clinical trials is needed to examine whether reducing Hcy levels with HRT can become the treatment of neurodegenerative disorders, such as Alzheimer’s disease.
- Full Text:
- Date Issued: 2006
- Authors: Wu, Wing Man
- Date: 2006
- Subjects: Homocysteine , Estrogen , Estrogen -- Therapeutic use , Progesterone , Hormone receptors , Methyl aspartate , Oxidative stress , Alzheimer's disease -- Treatment , Nervous system -- Degeneration -- Prevention
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3806 , http://hdl.handle.net/10962/d1003284 , Homocysteine , Estrogen , Estrogen -- Therapeutic use , Progesterone , Hormone receptors , Methyl aspartate , Oxidative stress , Alzheimer's disease -- Treatment , Nervous system -- Degeneration -- Prevention
- Description: Homocysteine (Hcy) is a sulfur containing amino acid and is a potent neurotoxin. It has been shown that elevated levels of Hcy, termed hyperhomocysteinemia, plays a role in the pathologies of Alzheimer’s disease (AD) and age-related cognitive decline. Hcy is a glutamate agonist, which causes in increase in Ca[superscript (2+)] influx via the activation of NMDA class of excitatory amino acid receptors, which results in neuronal cell death and apoptosis. Estrogen and progesterone are female hormones that are responsible for reproduction and maternal behaviour. However, in the last decade, it is evident that both female hormones have neuroprotective properties in many animal models of neurodegeneration. Collectively, both estrogen and progesterone reduce the consequences of the oxidative stress by enhancing the antioxidant defence mechanisms, reducing excitotoxicity by altering glutamate receptor activity and reducing the damage caused by lipid peroxidation. However, the mechanisms by which estrogen and progesterone provide such neuroprotection probably depend on the type and concentration of hormone present. Moreover, numerous studies have shown that hormone replacement therapy (HRT, estrogen and progestins) or estrogen-only replacement therapy (ERT) may prevent or delay the onset of AD and improve cognition for women with AD. Clinical trials have also shown that women taking HRT may modify the effects of Hcy levels on cognitive functioning. Oxidative stress increases in the aging brain and thus has a powerful effect on enhanced susceptibility to neurodegenerative disease. The detection and measurement of lipid peroxidation and superoxide anion radicals in the brain tissue supports the involvement of free radical reactions in neurotoxicity and in neurodegenerative disorders. The hippocampus is an important region of the brain responsible for the formation of memory. However, agents that induce stress in this area have harmful effects and could lead to dementia. This study aims to investigate and clarify the neuroprotective effects of estrogen and progesterone, using Hcy-induced neurodegenerative models. The initial studies demonstrate that estrogen and progesterone have the ability to scavenge potent free radicals. Histological studies undertaken reveal that both estrogen and progesterone protect against Hcy-induced neuronal cell death. In addition, immunohistochemical investigations show that Hcy-induced apoptosis in the hippocampus can be inhibited by both estrogen and progesterone. However, estrogen also acts at the NMDA receptor as an agonist, while progesterone blocks at the NMDA receptor. These mechanisms reduce the ability of Hcy to cause damage to neurons, since Hcy-induced neurotoxicity is dependent on the overstimulation of the NMDA receptor. SOD and GPx are important enzymatic antioxidants which can react with ROS and neutralize them before these inflict damage in the brain. Hcy can increase oxidative stress by inhibiting expression and function of these antioxidants. However, it has been shown that the antioxidant abilities of both estrogen and progesterone can up-regulate the activities of SOD and GPx. These results provide further evidence that estrogen and progesterone act as antioxidants and are free radical scavengers. The discovery of neuroprotective agents is becoming important as accumulating evidence indicates the protective role of both estrogen and progesterone in Hcy-induced neurodegeneration. Thus further work in clinical trials is needed to examine whether reducing Hcy levels with HRT can become the treatment of neurodegenerative disorders, such as Alzheimer’s disease.
- Full Text:
- Date Issued: 2006
An investigation into the neuroprotective properties of curcumin
- Authors: Daniel, Sheril
- Date: 2003
- Subjects: Turmeric -- Therapeutic use , Nervous system -- Degeneration -- Prevention
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3753 , http://hdl.handle.net/10962/d1003231 , Turmeric -- Therapeutic use , Nervous system -- Degeneration -- Prevention
- Description: An increasing number of studies show that nutritional antioxidants such as vitamin E and polyphenols are capable of blocking neuronal death in vitro and may have therapeutic properties in animal models of neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. In the present study, the neuroprotective ability of one such polyphenolic antioxidant, curcumin, was investigated. Curcumin is the yellow curry spice derived from turmeric, and is widely used as a dietary component and herbal medicine in India. Most neurological disorders are postulated to have an oxidative or excitototoxic basis. Thus the effects of curcumin on oxidative stress in the rat brain were investigated. Curcumin, administered to the rat in vivo and in vitro, was able to exert protective effects on oxidative damage in the brain, induced by cyanide, a mitochondrial inhibitor. Curcumin also offered protection against quinolinic acid induced lipid peroxidation, and this protection was extended to lipid peroxidation induced by metals such as lead and cadmium in the rat brain. Experiments conducted on the pineal gland revealed an increased production of the neuroprotective hormone melatonin in presence of curcumin in vivo. The hippocampus is functionally related to vital behaviour and intellectual activities and is known to be a primary target for neuronal degeneration in the brains of patients with Alzheimer’s disease. Histological studies were undertaken to assess the effects of curcumin on lead induced toxicity on the rat hippocampus, the results of which show that curcumin affords significant protection to the hippocampus of the lead treated rats. This study also sought to elucidate possible mechanisms by which curcumin exerts its neuroprotective capabilities. Curcumin was found to inhibit the action of cyanide on the mitochondrial electron transport chain, one of the most common sources of free radicals. Electrochemical, UV/VIS and Infrared spectroscopy were used to characterise interactions between curcumin and the metals lead, cadmium, iron (II) and iron (III). Curcumin was shown to directly chelate these metals with the formation and isolation of two new curcumin complexes with lead, and one complex each with cadmium and iron (III). These results suggest chelation of toxic metals as a mechanism of neuroprotection afforded by curcumin. The need for neuroprotective agents is urgent considering the rapid rise in the elderly population and the proportionate increase in neurological disorders. The findings of this study indicate that curcumin, a well-established dietary antioxidant, is capable of playing a bigger role in neuroprotection, which needs to be further explored and exploited.
- Full Text:
- Date Issued: 2003
- Authors: Daniel, Sheril
- Date: 2003
- Subjects: Turmeric -- Therapeutic use , Nervous system -- Degeneration -- Prevention
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3753 , http://hdl.handle.net/10962/d1003231 , Turmeric -- Therapeutic use , Nervous system -- Degeneration -- Prevention
- Description: An increasing number of studies show that nutritional antioxidants such as vitamin E and polyphenols are capable of blocking neuronal death in vitro and may have therapeutic properties in animal models of neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. In the present study, the neuroprotective ability of one such polyphenolic antioxidant, curcumin, was investigated. Curcumin is the yellow curry spice derived from turmeric, and is widely used as a dietary component and herbal medicine in India. Most neurological disorders are postulated to have an oxidative or excitototoxic basis. Thus the effects of curcumin on oxidative stress in the rat brain were investigated. Curcumin, administered to the rat in vivo and in vitro, was able to exert protective effects on oxidative damage in the brain, induced by cyanide, a mitochondrial inhibitor. Curcumin also offered protection against quinolinic acid induced lipid peroxidation, and this protection was extended to lipid peroxidation induced by metals such as lead and cadmium in the rat brain. Experiments conducted on the pineal gland revealed an increased production of the neuroprotective hormone melatonin in presence of curcumin in vivo. The hippocampus is functionally related to vital behaviour and intellectual activities and is known to be a primary target for neuronal degeneration in the brains of patients with Alzheimer’s disease. Histological studies were undertaken to assess the effects of curcumin on lead induced toxicity on the rat hippocampus, the results of which show that curcumin affords significant protection to the hippocampus of the lead treated rats. This study also sought to elucidate possible mechanisms by which curcumin exerts its neuroprotective capabilities. Curcumin was found to inhibit the action of cyanide on the mitochondrial electron transport chain, one of the most common sources of free radicals. Electrochemical, UV/VIS and Infrared spectroscopy were used to characterise interactions between curcumin and the metals lead, cadmium, iron (II) and iron (III). Curcumin was shown to directly chelate these metals with the formation and isolation of two new curcumin complexes with lead, and one complex each with cadmium and iron (III). These results suggest chelation of toxic metals as a mechanism of neuroprotection afforded by curcumin. The need for neuroprotective agents is urgent considering the rapid rise in the elderly population and the proportionate increase in neurological disorders. The findings of this study indicate that curcumin, a well-established dietary antioxidant, is capable of playing a bigger role in neuroprotection, which needs to be further explored and exploited.
- Full Text:
- Date Issued: 2003
An investigation into the possible neuroprotective properties of phenytoin
- Authors: Naga, Nishal
- Date: 2002
- Subjects: Phenytoin -- Therapeutic use , Phenytoin -- Physiological effect , Nervous system -- Degeneration -- Prevention
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3780 , http://hdl.handle.net/10962/d1003258 , Phenytoin -- Therapeutic use , Phenytoin -- Physiological effect , Nervous system -- Degeneration -- Prevention
- Description: Cerebral ischaemia, traumatic injury to the brain, inflammatory neurological disorders and HIV infections are amongst the most prevalent causes of neurodegeneration. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Sodium channel blockers have been often used for this matter as they prevent the cascade of events culminating in free radical generation and eventually neuronal apoptosis. Newer compounds, such as antiperoxidants and free radical scavengers, show encouraging experimental results, but their clinical use is still very limited. Phenytoin being a popular drug in the treatment of epilepsy has also been used as a neuroprotectant during certain neurological emergencies and in pharmacological prophylaxis of post-traumatic epilepsy. Furthermore this agent functions by prolonging inactivation of voltage gated sodium channels. In these sets of experiment the neuroprotective properties of phenytoin were examined. The histological study revealed that phenytoin confers protection to the CA1 and CA3 regions of the hippocampus under the insult of QUIN. Cells maintain their characteristic shape and minimal tissue necrosis occurs in the presence of this agent. The in vitro effect of this antiepileptic drug on free radicals generation shows that phenytoin does not reduce or prevent the formation of these reactive species. Lipid peroxidation was induced using QUIN and iron (II), two known neurotoxins. The study reveals that only lipid peroxidation induced using iron (II) is reduced by phenytoin. These experiments were carried out in whole rat brain homogenate. These studies show that phenytoin possesses poor free radical scavenging properties. However, the dose-related reduction of iron-induced lipid peroxidation allows for speculation that phenytoin interacts with iron in order to reduce neuronal damage. Metal binding studies were performed using UV, IR and electrochemical analysis to examine the interaction of phenytoin with iron (II) and iron (III). Phenytoin, when added to iron (II) in solution, first oxidises the latter to iron (III) and maintains it in that form. A shift in the peak was observed in the UV spectrum when iron was added to phenytoin. Moreover, electrochemical studies indicate that the interaction between the metal and the ligand is very weak. The IR analysis it shows that phenytoin may be coordinating with iron through the Nitrogen atom on the phenytoin molecule. These studies show that phenytoin maintains iron in its oxidised form, which is a good property to possess as a neuroprotectants. Pineal organ culture showed that phenytoin does not increase melatonin production but slightly and non-significantly reduces the levels of this pineal hormone. However there is a significant rise in precursor NAS levels. As melatonin is known to possess antioxidant and free radical scavenging properties, this could mean that this drug can cause the CNS to become more susceptible to attacks by reactive oxygen species.
- Full Text:
- Date Issued: 2002
- Authors: Naga, Nishal
- Date: 2002
- Subjects: Phenytoin -- Therapeutic use , Phenytoin -- Physiological effect , Nervous system -- Degeneration -- Prevention
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3780 , http://hdl.handle.net/10962/d1003258 , Phenytoin -- Therapeutic use , Phenytoin -- Physiological effect , Nervous system -- Degeneration -- Prevention
- Description: Cerebral ischaemia, traumatic injury to the brain, inflammatory neurological disorders and HIV infections are amongst the most prevalent causes of neurodegeneration. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Neuroprotective strategies are usually to limit the progressive secondary injury that generally occurs, thus limiting overall tissue damage. Sodium channel blockers have been often used for this matter as they prevent the cascade of events culminating in free radical generation and eventually neuronal apoptosis. Newer compounds, such as antiperoxidants and free radical scavengers, show encouraging experimental results, but their clinical use is still very limited. Phenytoin being a popular drug in the treatment of epilepsy has also been used as a neuroprotectant during certain neurological emergencies and in pharmacological prophylaxis of post-traumatic epilepsy. Furthermore this agent functions by prolonging inactivation of voltage gated sodium channels. In these sets of experiment the neuroprotective properties of phenytoin were examined. The histological study revealed that phenytoin confers protection to the CA1 and CA3 regions of the hippocampus under the insult of QUIN. Cells maintain their characteristic shape and minimal tissue necrosis occurs in the presence of this agent. The in vitro effect of this antiepileptic drug on free radicals generation shows that phenytoin does not reduce or prevent the formation of these reactive species. Lipid peroxidation was induced using QUIN and iron (II), two known neurotoxins. The study reveals that only lipid peroxidation induced using iron (II) is reduced by phenytoin. These experiments were carried out in whole rat brain homogenate. These studies show that phenytoin possesses poor free radical scavenging properties. However, the dose-related reduction of iron-induced lipid peroxidation allows for speculation that phenytoin interacts with iron in order to reduce neuronal damage. Metal binding studies were performed using UV, IR and electrochemical analysis to examine the interaction of phenytoin with iron (II) and iron (III). Phenytoin, when added to iron (II) in solution, first oxidises the latter to iron (III) and maintains it in that form. A shift in the peak was observed in the UV spectrum when iron was added to phenytoin. Moreover, electrochemical studies indicate that the interaction between the metal and the ligand is very weak. The IR analysis it shows that phenytoin may be coordinating with iron through the Nitrogen atom on the phenytoin molecule. These studies show that phenytoin maintains iron in its oxidised form, which is a good property to possess as a neuroprotectants. Pineal organ culture showed that phenytoin does not increase melatonin production but slightly and non-significantly reduces the levels of this pineal hormone. However there is a significant rise in precursor NAS levels. As melatonin is known to possess antioxidant and free radical scavenging properties, this could mean that this drug can cause the CNS to become more susceptible to attacks by reactive oxygen species.
- Full Text:
- Date Issued: 2002
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