Melatonin and anticancer therapy interactions with 5-Fluorouracil
- Authors: Cassim, Layla
- Date: 2008
- Subjects: Melatonin Melatonin -- Therapeutic use Antineoplastic agents Fluorouracil Fluorouracil -- Toxicology Cancer -- Treatment
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3746 , http://hdl.handle.net/10962/d1003224
- Description: On the basis of clinical studies, some researchers have advocated that the neurohormone and antioxidant melatonin, shown to possess intrinsic anticancer properties, be used as co-therapy in cancer patients being treated with the antineoplastic agent 5-fluorouracil, as increased patient survival times and enhanced quality of life have been observed. The focus of this research was thus to investigate the mechanisms of this seemingly beneficial drug interaction between 5-fluorouracil and melatonin. Metabolism studies were undertaken, in which it was established that there is no hepatic metabolic drug interaction between these agents by cytochrome P450, and that neither agent alters the activity of this enzyme system. Co-therapy with melatonin is thus unlikely to alter plasma levels of 5-fluorouracil by this mechanism. Novel mechanisms by which 5-fluorouracil is toxic were elucidated, such as the induction of lipid peroxidation, due to the formation of reactive oxygen species; decreases in brain serotonin, dopamine and norepinephrine levels, possibly leading to depression; hippocampal shrinkage and morphological alterations and lysis of hippocampal cells, which may underlie cognitive impairment; and a reduction in the nociceptive threshold when administered acutely. All these deleterious effects are attenuated by the co-administration of melatonin, suggesting that the agent exhibits antidepressive and analgesic properties, in addition to its known antioxidative and free radical-scavenging abilities. This suggests that melatonin cotherapy can significantly decrease 5-fluorouracil-induced toxicity, but this may also exert a protective effect on cancer cells and thus compromise the anticancer efficacy of 5-fluorouracil. It was, furthermore, found that stimulation of indoleamine 2,3-dioxygenase activity, mediated by increases in superoxide anion and interferon-γ levels, may underlie resistance to 5-fluorouracil therapy. Melatonin was shown to increase superoxide anion levels in vivo, and this is believed to be by conversion to the metabolite and known oxidant 6- hydroxymelatonin. This highlights that the possible deleterious effects of melatonin metabolites should be studied further. Serum corticosterone levels and cytokine profiles are unaltered by both 5-FU and melatonin, suggesting that these agents may be used by HIV infected individuals without promoting the progression to AIDS. It can thus be concluded that melatonin co-therapy is potentially useful in countering 5-fluorouracil toxicity.
- Full Text:
- Date Issued: 2008
- Authors: Cassim, Layla
- Date: 2008
- Subjects: Melatonin Melatonin -- Therapeutic use Antineoplastic agents Fluorouracil Fluorouracil -- Toxicology Cancer -- Treatment
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3746 , http://hdl.handle.net/10962/d1003224
- Description: On the basis of clinical studies, some researchers have advocated that the neurohormone and antioxidant melatonin, shown to possess intrinsic anticancer properties, be used as co-therapy in cancer patients being treated with the antineoplastic agent 5-fluorouracil, as increased patient survival times and enhanced quality of life have been observed. The focus of this research was thus to investigate the mechanisms of this seemingly beneficial drug interaction between 5-fluorouracil and melatonin. Metabolism studies were undertaken, in which it was established that there is no hepatic metabolic drug interaction between these agents by cytochrome P450, and that neither agent alters the activity of this enzyme system. Co-therapy with melatonin is thus unlikely to alter plasma levels of 5-fluorouracil by this mechanism. Novel mechanisms by which 5-fluorouracil is toxic were elucidated, such as the induction of lipid peroxidation, due to the formation of reactive oxygen species; decreases in brain serotonin, dopamine and norepinephrine levels, possibly leading to depression; hippocampal shrinkage and morphological alterations and lysis of hippocampal cells, which may underlie cognitive impairment; and a reduction in the nociceptive threshold when administered acutely. All these deleterious effects are attenuated by the co-administration of melatonin, suggesting that the agent exhibits antidepressive and analgesic properties, in addition to its known antioxidative and free radical-scavenging abilities. This suggests that melatonin cotherapy can significantly decrease 5-fluorouracil-induced toxicity, but this may also exert a protective effect on cancer cells and thus compromise the anticancer efficacy of 5-fluorouracil. It was, furthermore, found that stimulation of indoleamine 2,3-dioxygenase activity, mediated by increases in superoxide anion and interferon-γ levels, may underlie resistance to 5-fluorouracil therapy. Melatonin was shown to increase superoxide anion levels in vivo, and this is believed to be by conversion to the metabolite and known oxidant 6- hydroxymelatonin. This highlights that the possible deleterious effects of melatonin metabolites should be studied further. Serum corticosterone levels and cytokine profiles are unaltered by both 5-FU and melatonin, suggesting that these agents may be used by HIV infected individuals without promoting the progression to AIDS. It can thus be concluded that melatonin co-therapy is potentially useful in countering 5-fluorouracil toxicity.
- Full Text:
- Date Issued: 2008
Neuroprotective mechanisms of nevirapine and efavirenz in a model of neurodegeneration
- Authors: Zheve, Georgina Teurai
- Date: 2008
- Subjects: HIV infections -- Treatment AIDS (Disease) -- Treatment AIDS dementia complex -- Treatment Nervous system -- Degeneration -- Treatment Melatonin Neurotoxic agents Quinolinic acid
- Language: English
- Type: Thesis , Masters , MPharm
- Identifier: vital:3807 , http://hdl.handle.net/10962/d1003285
- Description: AIDS Dementia Complex (ADC) is a neurodegenerative disorder implicated in HIV-1 infection that is associated with elevated levels of the neurotoxin, quinolinic acid (QA) which causes a cascade of events to occur, leading to the production of reactive oxygen species (ROS), these being ultimately responsible for oxidative neurotoxicity. In clinical studies, Non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV) and nevirapine (NVP) have been shown to potentially delay the progressive degeneration of neurons, thus reducing the frequency and neurological deficits associated with ADC. Despite these neuroprotective implications, there is still no biochemical data to demonstrate the mechanisms through which these agents offer neuroprotection. The present study aims to elucidate and further characterize the possible antioxidant and neuroprotective mechanisms of NVP and EFV in vitro and in vivo, using QA-induced neurotoxicity as a model. Research has demonstrated that antioxidants and metal chelators have the ability to offer neuroprotection against free radical induced injury and may be beneficial in the prevention or treatment of neurodegeneration. Hence the antioxidant and metal binding properties of these agents were investigated respectively. Inorganic studies, including the 1, 1-diphenyl-2 picrylhydrazyl (DPPH) assay, show that these agents readily scavenge free radicals in vitro, thus postulating the antioxidant property of these agents. The enhancement of superoxide radical generation and iron mediated Fenton reaction by QA is related to lipid peroxidation in biological systems, the extent of which was assayed using the nitroblue tetrazolium and thiobarbituric acid method respectively. Both agents significantly curtail QA-induced lipid peroxidation and potentially scavenge superoxide anions generated by cyanide in vitro. Furthermore, in vivo results demonstrate the ability of NVP and EFV to protect hippocampal neurons against lipid peroxidation induced by QA and superoxide radicals generated as a consequence thereof. The alleviation of QA-induced oxidative stress in vitro possibly occurs through the binding of iron (II) and / or iron (III), and this argument is further strengthened by the ability of EFV and not NVP to reduce iron (II)-induced lipid peroxidation in vitro directly. In addition the ferrozine and electrochemistry assay were used to measure the extent of iron (II) Fe[superscript 2+] and iron (III) Fe[superscript 3+] chelation activity. Both assays demonstrate that these agents bind iron (II) and iron (III), and prevent redox recycling of iron and subsequent complexation of Fe[superscript 2+] with QA which enhances neuronal damage. Both NNRTIs inhibit the endogenous biosynthesis of QA by inhibiting liver tryptophan 2, 3-dioxygenase activity in vivo and subsequently increasing hippocampal serotonin levels. Furthermore, these agents reduce the turnover of hippocampal serotonin to 5-hydroxyindole acetic acid. NVP and not EFV increase 5-hydroxyindole acetic acid and norepinephrine levels in the hippocampus. The results of the pineal indole metabolism study show that NVP increases the synthesis of melatonin, but decreases N-acetylserotonin, 5-hydroxyindole acetic acid and 5-hydroxytryptophol levels. Furthermore, it shows that EFV decreases 5-hydroxyindole acetic acid and melatonin synthesis. Behavioural studies using a Morris water maze show that the post-treatment of rats with NVP and EFV significantly improves QA-induced spatial memory deficits in the hippocampus. This study therefore provides novel information regarding the neuroprotective mechanisms of NVP and EFV. These findings strengthen the argument that these NNRTIs not only have antiviral effects but possess potential neuroprotective properties, which may contribute to the effectiveness of these drugs in the treatment of ADC.
- Full Text:
- Date Issued: 2008
- Authors: Zheve, Georgina Teurai
- Date: 2008
- Subjects: HIV infections -- Treatment AIDS (Disease) -- Treatment AIDS dementia complex -- Treatment Nervous system -- Degeneration -- Treatment Melatonin Neurotoxic agents Quinolinic acid
- Language: English
- Type: Thesis , Masters , MPharm
- Identifier: vital:3807 , http://hdl.handle.net/10962/d1003285
- Description: AIDS Dementia Complex (ADC) is a neurodegenerative disorder implicated in HIV-1 infection that is associated with elevated levels of the neurotoxin, quinolinic acid (QA) which causes a cascade of events to occur, leading to the production of reactive oxygen species (ROS), these being ultimately responsible for oxidative neurotoxicity. In clinical studies, Non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV) and nevirapine (NVP) have been shown to potentially delay the progressive degeneration of neurons, thus reducing the frequency and neurological deficits associated with ADC. Despite these neuroprotective implications, there is still no biochemical data to demonstrate the mechanisms through which these agents offer neuroprotection. The present study aims to elucidate and further characterize the possible antioxidant and neuroprotective mechanisms of NVP and EFV in vitro and in vivo, using QA-induced neurotoxicity as a model. Research has demonstrated that antioxidants and metal chelators have the ability to offer neuroprotection against free radical induced injury and may be beneficial in the prevention or treatment of neurodegeneration. Hence the antioxidant and metal binding properties of these agents were investigated respectively. Inorganic studies, including the 1, 1-diphenyl-2 picrylhydrazyl (DPPH) assay, show that these agents readily scavenge free radicals in vitro, thus postulating the antioxidant property of these agents. The enhancement of superoxide radical generation and iron mediated Fenton reaction by QA is related to lipid peroxidation in biological systems, the extent of which was assayed using the nitroblue tetrazolium and thiobarbituric acid method respectively. Both agents significantly curtail QA-induced lipid peroxidation and potentially scavenge superoxide anions generated by cyanide in vitro. Furthermore, in vivo results demonstrate the ability of NVP and EFV to protect hippocampal neurons against lipid peroxidation induced by QA and superoxide radicals generated as a consequence thereof. The alleviation of QA-induced oxidative stress in vitro possibly occurs through the binding of iron (II) and / or iron (III), and this argument is further strengthened by the ability of EFV and not NVP to reduce iron (II)-induced lipid peroxidation in vitro directly. In addition the ferrozine and electrochemistry assay were used to measure the extent of iron (II) Fe[superscript 2+] and iron (III) Fe[superscript 3+] chelation activity. Both assays demonstrate that these agents bind iron (II) and iron (III), and prevent redox recycling of iron and subsequent complexation of Fe[superscript 2+] with QA which enhances neuronal damage. Both NNRTIs inhibit the endogenous biosynthesis of QA by inhibiting liver tryptophan 2, 3-dioxygenase activity in vivo and subsequently increasing hippocampal serotonin levels. Furthermore, these agents reduce the turnover of hippocampal serotonin to 5-hydroxyindole acetic acid. NVP and not EFV increase 5-hydroxyindole acetic acid and norepinephrine levels in the hippocampus. The results of the pineal indole metabolism study show that NVP increases the synthesis of melatonin, but decreases N-acetylserotonin, 5-hydroxyindole acetic acid and 5-hydroxytryptophol levels. Furthermore, it shows that EFV decreases 5-hydroxyindole acetic acid and melatonin synthesis. Behavioural studies using a Morris water maze show that the post-treatment of rats with NVP and EFV significantly improves QA-induced spatial memory deficits in the hippocampus. This study therefore provides novel information regarding the neuroprotective mechanisms of NVP and EFV. These findings strengthen the argument that these NNRTIs not only have antiviral effects but possess potential neuroprotective properties, which may contribute to the effectiveness of these drugs in the treatment of ADC.
- Full Text:
- Date Issued: 2008
An investigation into the neuroprotective properties of the non-steroidal anti-inflammatory agents tolmetin, sulindac and turmeric
- Authors: Dairam, Amichand
- Date: 2006
- Subjects: Nonsteroidal anti-inflammatory agents Antioxidants Tolmetin -- Therapeutic use Sulindac -- Therapeutic use Turmeric -- Therapeutic use Nervous system -- Degeneration -- Prevention Alzheimer's disease
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3752 , http://hdl.handle.net/10962/d1003230
- Description: Accumulating evidence suggests that anti-inflammatory agents and antioxidants have neuroprotective properties and may be beneficial in the treatment of neurodegenerative disorders. In the present study, the possible neuroprotective properties of tolmetin, sulindac and turmeric were investigated. The antioxidant effects of tolmetin and sulindac were determined by inducing free radical generation with quinolinic acid (QA), cyanide or iron (II) in rat brain homogenates or primary hippocampal neurons. Tolmetin and sulindac significantly reduce lipid peroxidation and scavenge the superoxide anion. Metal binding studies were conducted to determine whether metal chelation is a possible mechanism through which these agents reduce QA and iron (II)-induced lipid peroxidation. UV/VIS, infrared spectroscopy as well as electrochemical studies show that both agents bind to iron (II) and/or iron (III). Histological examination of the hippocampus showed that pre-treatment of animals with tolmetin or sulindac offers protection against intrahippocampal injections of QA. These agents also attenuate QA-induced apoptosis and reduce the loss of neurons in the hippocampus. The co-incubation of primary hippocampal neurons with the NSAIDS also enhanced cell viability which is significantly reduced by QA. Behavioural studies using a water maze showed that the treatment of animals after QA-induced neurotoxicity reduces QA-induced spatial memory loss. Tolmetin and sulindac also reduced glutathione depletion and protein oxidation in rat hippocampus. Both NSAIDS inhibit liver tryptophan 2,3-dioxygenase activity in vitro and in vivo and subsequently increased hippocampal serotonin levels. However, both NSAIDS also reduce dopamine levels in rat striatum. Tolmetin but not sulindac increased the synthesis of melatonin by the pineal gland. The active components of turmeric known as the curcuminoids were separated using preparative thin layer chromatography (TLC). The purity was confirmed by TLC, NMR and mass spectrometry. The environmental toxin lead, induces lipid peroxidation and reduces primary hippocampal neuronal viability. The co-incubation of the neurons with the curcuminoids significantly reduces lead-induced lipid peroxidation and enhances neuronal cell viability in the presence of lead. Lead-induced spatial memory deficit is also attenuated with curcumin, demethoxycurcumin but not bisdemethoxycurcumin. The curcuminoids also reduce lead-induced hippocampal glutathione depletion and protein oxidation. Metal binding studies show that the curcuminoids bind to lead and is another possible mechanism through which the curcuminoids reduce lead-induced neurotoxicity. The findings of this study indicate a possible role of tolmetin, sulindac and turmeric in neurodegenerative disorders such as Alzheimer’s disease. However, tolmetin and sulindac reduce dopamine levels.
- Full Text:
- Date Issued: 2006
- Authors: Dairam, Amichand
- Date: 2006
- Subjects: Nonsteroidal anti-inflammatory agents Antioxidants Tolmetin -- Therapeutic use Sulindac -- Therapeutic use Turmeric -- Therapeutic use Nervous system -- Degeneration -- Prevention Alzheimer's disease
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:3752 , http://hdl.handle.net/10962/d1003230
- Description: Accumulating evidence suggests that anti-inflammatory agents and antioxidants have neuroprotective properties and may be beneficial in the treatment of neurodegenerative disorders. In the present study, the possible neuroprotective properties of tolmetin, sulindac and turmeric were investigated. The antioxidant effects of tolmetin and sulindac were determined by inducing free radical generation with quinolinic acid (QA), cyanide or iron (II) in rat brain homogenates or primary hippocampal neurons. Tolmetin and sulindac significantly reduce lipid peroxidation and scavenge the superoxide anion. Metal binding studies were conducted to determine whether metal chelation is a possible mechanism through which these agents reduce QA and iron (II)-induced lipid peroxidation. UV/VIS, infrared spectroscopy as well as electrochemical studies show that both agents bind to iron (II) and/or iron (III). Histological examination of the hippocampus showed that pre-treatment of animals with tolmetin or sulindac offers protection against intrahippocampal injections of QA. These agents also attenuate QA-induced apoptosis and reduce the loss of neurons in the hippocampus. The co-incubation of primary hippocampal neurons with the NSAIDS also enhanced cell viability which is significantly reduced by QA. Behavioural studies using a water maze showed that the treatment of animals after QA-induced neurotoxicity reduces QA-induced spatial memory loss. Tolmetin and sulindac also reduced glutathione depletion and protein oxidation in rat hippocampus. Both NSAIDS inhibit liver tryptophan 2,3-dioxygenase activity in vitro and in vivo and subsequently increased hippocampal serotonin levels. However, both NSAIDS also reduce dopamine levels in rat striatum. Tolmetin but not sulindac increased the synthesis of melatonin by the pineal gland. The active components of turmeric known as the curcuminoids were separated using preparative thin layer chromatography (TLC). The purity was confirmed by TLC, NMR and mass spectrometry. The environmental toxin lead, induces lipid peroxidation and reduces primary hippocampal neuronal viability. The co-incubation of the neurons with the curcuminoids significantly reduces lead-induced lipid peroxidation and enhances neuronal cell viability in the presence of lead. Lead-induced spatial memory deficit is also attenuated with curcumin, demethoxycurcumin but not bisdemethoxycurcumin. The curcuminoids also reduce lead-induced hippocampal glutathione depletion and protein oxidation. Metal binding studies show that the curcuminoids bind to lead and is another possible mechanism through which the curcuminoids reduce lead-induced neurotoxicity. The findings of this study indicate a possible role of tolmetin, sulindac and turmeric in neurodegenerative disorders such as Alzheimer’s disease. However, tolmetin and sulindac reduce dopamine levels.
- Full Text:
- Date Issued: 2006
An investigation into the antioxidative potential and regulatory aspects of liver tryptophan 2,3-dioxygenase by tryptophan and related analogues
- Authors: Antunes, Ana Paula Martins
- Date: 1998
- Subjects: Tryptophan -- Physiological effect , Antioxidants , Liver
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4010 , http://hdl.handle.net/10962/d1004070 , Tryptophan -- Physiological effect , Antioxidants , Liver
- Description: The amino acid, tryptophan, obtained through dietary means, is metabolised by the enzymes tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and tryptophan hydroxylase. All the enzymes have an effect on circulating tryptophan levels, especially TDO, since it is the major site of tryptophan catabolism in the liver and results in the production of kynurenine metabolites, viz. kynurenine, kynurenic acid, 3-hydroxyanthranilic acid and quinolinic acid. Extrahepatically, IDO is responsible for the synthesis of the kynurenine metabolites. Tryptophan 2,3-dioxygenase and IDO activity is increased by hormones or substrates such as tryptophan, and inflammation, in the case of IDO. Tryptophan availability for serotonin (5-HT) synthesis by the enzyme tryptophan hydroxylase is primarily dependent on TDO activity. A study was attempted in order to ascertain whether any of the endogenous metabolites of the kynurenine and serotonergic pathways would be able to inhibit TDO activity. Results showed that although the kynurenines had no effect, the indoleamines, except for the indoleacetic acids, were able to reduce TDO activity. 6-Methoxy-2-benzoxazolinone (6-MBOA), a structural analogue to melatonin, was the most potent inhibitor with a reduction in activity of 55 % compared with the control. The pineal gland in the rat brain has been shown to have the highest IDO activity. With induction, the kynurenine metabolite concentrations of kynurenic acid and quinolinic acid are increased. The effects of both compounds were determined on the serotonergic pathway. Although kynurenic acid produced no significant effect, quinolinic acid significantly reduced N-acetylserotonin and melatonin synthesis at concentrations of lOJLM and 100 JLM respectively. Many authors have implicated oxygen derived species as causative agents in the important neurodegenerative disorders such as Parkinson's and Huntington's disease. Increased radical generation and lipid peroxidation have been suggested to be responsible for the toxic destruction of neurons, especially in the brain because of its high lipid content and oxygen demand. The brain is therefore vulnerable to oxidative attack. During inflammatory diseases, IDO is induced with a resultant increase in kynurenines. This study was also an attempt at determining the effect of kynurenines on lipid peroxidation. All metabolites of the kynurenine pathway were able to induce lipid peroxidation significantly. The antioxidative potential of various tryptophan analogues, viz. serotonin, melatonin and 6-methoxy-2-benzoxazolinone, was determined using quinolinic acid-induced lipid peroxidation. Serotonin, melatonin and 6-MBOA were able to significantly reduce quinolinic acid-induced lipid peroxidation.
- Full Text:
- Date Issued: 1998
- Authors: Antunes, Ana Paula Martins
- Date: 1998
- Subjects: Tryptophan -- Physiological effect , Antioxidants , Liver
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4010 , http://hdl.handle.net/10962/d1004070 , Tryptophan -- Physiological effect , Antioxidants , Liver
- Description: The amino acid, tryptophan, obtained through dietary means, is metabolised by the enzymes tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO) and tryptophan hydroxylase. All the enzymes have an effect on circulating tryptophan levels, especially TDO, since it is the major site of tryptophan catabolism in the liver and results in the production of kynurenine metabolites, viz. kynurenine, kynurenic acid, 3-hydroxyanthranilic acid and quinolinic acid. Extrahepatically, IDO is responsible for the synthesis of the kynurenine metabolites. Tryptophan 2,3-dioxygenase and IDO activity is increased by hormones or substrates such as tryptophan, and inflammation, in the case of IDO. Tryptophan availability for serotonin (5-HT) synthesis by the enzyme tryptophan hydroxylase is primarily dependent on TDO activity. A study was attempted in order to ascertain whether any of the endogenous metabolites of the kynurenine and serotonergic pathways would be able to inhibit TDO activity. Results showed that although the kynurenines had no effect, the indoleamines, except for the indoleacetic acids, were able to reduce TDO activity. 6-Methoxy-2-benzoxazolinone (6-MBOA), a structural analogue to melatonin, was the most potent inhibitor with a reduction in activity of 55 % compared with the control. The pineal gland in the rat brain has been shown to have the highest IDO activity. With induction, the kynurenine metabolite concentrations of kynurenic acid and quinolinic acid are increased. The effects of both compounds were determined on the serotonergic pathway. Although kynurenic acid produced no significant effect, quinolinic acid significantly reduced N-acetylserotonin and melatonin synthesis at concentrations of lOJLM and 100 JLM respectively. Many authors have implicated oxygen derived species as causative agents in the important neurodegenerative disorders such as Parkinson's and Huntington's disease. Increased radical generation and lipid peroxidation have been suggested to be responsible for the toxic destruction of neurons, especially in the brain because of its high lipid content and oxygen demand. The brain is therefore vulnerable to oxidative attack. During inflammatory diseases, IDO is induced with a resultant increase in kynurenines. This study was also an attempt at determining the effect of kynurenines on lipid peroxidation. All metabolites of the kynurenine pathway were able to induce lipid peroxidation significantly. The antioxidative potential of various tryptophan analogues, viz. serotonin, melatonin and 6-methoxy-2-benzoxazolinone, was determined using quinolinic acid-induced lipid peroxidation. Serotonin, melatonin and 6-MBOA were able to significantly reduce quinolinic acid-induced lipid peroxidation.
- Full Text:
- Date Issued: 1998
The pineal gland as a model to elucidate the primary mode of action of sympathoactive agents
- Authors: Welman, Alan David
- Date: 1991
- Subjects: Pineal gland , Cythochemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3876 , http://hdl.handle.net/10962/d1001610
- Description: An attempt was made to use the pineal gland as a model for the study of the primary mode of action of sympathoactive agents. Two drugs were investigated, viz. alpha-methyldopa and ephedrine whose mode of action is not entirely clear. Organ cultures of pineal glands from rats treated chronically with alpha-methyldopa showed enhanced conversion of radioactive serotonin to melatonin (aMT) , as well as its precursor Nacetylserotonin (aHT). This treatment was also found to raise Nacetyltransferase (NAT) activity. These increases associated with alpha-methyldopa treatment were further enhanced by the beta-adrenergic agonist, isoproterenol, suggesting a supersensitivity-type effect occurring at the level of the beta-receptor. A subsequent binding study, however, showed a decrease in beta-receptor binding with exposure to alpha-methyldopa, providing mitigating evidence against the occurrence of a supersensitivity phenomenon. It is possible that a metabolite of alpha-methyldopa acts as an alpha 1 and beta-adrenergic agonist, resulting in greater melatonin (aMT) and N-acetylserotonin (aHT) synthesis than by a beta-adrenergic agonist, isoproterenol. Combined treatment of pineals with alpha-methyldopa and an alphareceptor blocker, phentolamine, resulted in melatonin (aMT) , Nacetylserotonin (aHT) , and N-acetyltransferase (NAT) activity levels which were lower than those obtained with alpha-methyldopa treatment alone, thus confirming the alpha-adrenergic activity of the metabolite of alpha-methyldopa. Additional pineal metabolites were isolated and measured simultaneously in the organ culture experiments. Organ cultures of rat pineal glands treated with ephedrine showed raised levels of melatonin (aMT) and N-acetylserotonin (aHT). Treatment with ephedrine also produced raised N-acetyltransferase activity. A further enhancement of these parameters was induced by norepinephrine, suggesting a supersensitivity-type effect occurring at the level of the beta-adrenergic receptor. Rats were treated with reserpine (a norepinephrine depleter) and the pineals exposed to ephedrine. Endogenous norepinephrine normally released by the action of ephedrine was thus absent, and under these conditions, levels of melatonin (aMT) and N-acetylserotonin (aHT) were reduced. N-acetyltransferase (NAT) activity was also reduced, but maintained levels pointing to substantial adrenergic activity of ephedrine as well as norepinephrine released by virtue of the drug's action. A subsequent binding study showed a decrease in beta-adrenergic receptor binding with exposure to ephedrine and a further decrease in ephedrine treated pineals from reserpine treated rats, thus ruling out the occurrence of a supersensitivity phenomenon. It is possible that both ephedrine and released norepinephrine have alpha- and beta-receptor activity. Additional pineal metabolites were isolated and measured in the organ culture experiments. A 16-hour time profile of the production of melatonin (aMT) and N-acetylserotonin (aHT) with norepinephrine and ephedrine treatment provided useful information regarding the course of action of the two agents. A pineal cell-culture system was developed and exposed to ephedrine and norepinephrine. N-acetyltransferase (NAT) activity levels measured after exposure to these agents were raised, confirming the adrenergic activity of both in the model. Finally, an HPLC system coupled to a UV detector was used in an attempt to measure melatonin (aMT) extracted from pineal organ culture media. The results showed that melatonin could be measured by this method, however, a more sensitive detection system was recommended for future work.
- Full Text:
- Date Issued: 1991
- Authors: Welman, Alan David
- Date: 1991
- Subjects: Pineal gland , Cythochemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3876 , http://hdl.handle.net/10962/d1001610
- Description: An attempt was made to use the pineal gland as a model for the study of the primary mode of action of sympathoactive agents. Two drugs were investigated, viz. alpha-methyldopa and ephedrine whose mode of action is not entirely clear. Organ cultures of pineal glands from rats treated chronically with alpha-methyldopa showed enhanced conversion of radioactive serotonin to melatonin (aMT) , as well as its precursor Nacetylserotonin (aHT). This treatment was also found to raise Nacetyltransferase (NAT) activity. These increases associated with alpha-methyldopa treatment were further enhanced by the beta-adrenergic agonist, isoproterenol, suggesting a supersensitivity-type effect occurring at the level of the beta-receptor. A subsequent binding study, however, showed a decrease in beta-receptor binding with exposure to alpha-methyldopa, providing mitigating evidence against the occurrence of a supersensitivity phenomenon. It is possible that a metabolite of alpha-methyldopa acts as an alpha 1 and beta-adrenergic agonist, resulting in greater melatonin (aMT) and N-acetylserotonin (aHT) synthesis than by a beta-adrenergic agonist, isoproterenol. Combined treatment of pineals with alpha-methyldopa and an alphareceptor blocker, phentolamine, resulted in melatonin (aMT) , Nacetylserotonin (aHT) , and N-acetyltransferase (NAT) activity levels which were lower than those obtained with alpha-methyldopa treatment alone, thus confirming the alpha-adrenergic activity of the metabolite of alpha-methyldopa. Additional pineal metabolites were isolated and measured simultaneously in the organ culture experiments. Organ cultures of rat pineal glands treated with ephedrine showed raised levels of melatonin (aMT) and N-acetylserotonin (aHT). Treatment with ephedrine also produced raised N-acetyltransferase activity. A further enhancement of these parameters was induced by norepinephrine, suggesting a supersensitivity-type effect occurring at the level of the beta-adrenergic receptor. Rats were treated with reserpine (a norepinephrine depleter) and the pineals exposed to ephedrine. Endogenous norepinephrine normally released by the action of ephedrine was thus absent, and under these conditions, levels of melatonin (aMT) and N-acetylserotonin (aHT) were reduced. N-acetyltransferase (NAT) activity was also reduced, but maintained levels pointing to substantial adrenergic activity of ephedrine as well as norepinephrine released by virtue of the drug's action. A subsequent binding study showed a decrease in beta-adrenergic receptor binding with exposure to ephedrine and a further decrease in ephedrine treated pineals from reserpine treated rats, thus ruling out the occurrence of a supersensitivity phenomenon. It is possible that both ephedrine and released norepinephrine have alpha- and beta-receptor activity. Additional pineal metabolites were isolated and measured in the organ culture experiments. A 16-hour time profile of the production of melatonin (aMT) and N-acetylserotonin (aHT) with norepinephrine and ephedrine treatment provided useful information regarding the course of action of the two agents. A pineal cell-culture system was developed and exposed to ephedrine and norepinephrine. N-acetyltransferase (NAT) activity levels measured after exposure to these agents were raised, confirming the adrenergic activity of both in the model. Finally, an HPLC system coupled to a UV detector was used in an attempt to measure melatonin (aMT) extracted from pineal organ culture media. The results showed that melatonin could be measured by this method, however, a more sensitive detection system was recommended for future work.
- Full Text:
- Date Issued: 1991
The pineal gland as a model to elucidate the primary mode of action of sympathoactive agents
- Authors: Welman, Alan David
- Date: 1991
- Subjects: Pineal gland , Cythochemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4279 , http://hdl.handle.net/10962/d1002005 , Pineal gland
- Description: An attempt was made to use the pineal gland as a model for the study of the primary mode of action of sympathoactive agents. Two drugs were investigated, viz. alpha-methyldopa and ephedrine whose mode of action is not entirely clear. Organ cultures of pineal glands from rats treated chronically with alpha-methyldopa showed enhanced conversion of radioactive serotonin to melatonin (aMT) , as well as its precursor Nacetylserotonin (aHT). This treatment was also found to raise Nacetyltransferase (NAT) activity. These increases associated with alpha-methyldopa treatment were further enhanced by the beta-adrenergic agonist, isoproterenol, suggesting a supersensitivity-type effect occurring at the level of the beta-receptor. A subsequent binding study, however, showed a decrease in beta-receptor binding with exposure to alpha-methyldopa, providing mitigating evidence against the occurrence of a supersensitivity phenomenon. It is possible that a metabolite of alpha-methyldopa acts as an alpha 1 and beta-adrenergic agonist, resulting in greater melatonin (aMT) and N-acetylserotonin (aHT) synthesis than by a beta-adrenergic agonist, isoproterenol. Combined treatment of pineals with alpha-methyldopa and an alphareceptor blocker, phentolamine, resulted in melatonin (aMT) , Nacetylserotonin (aHT) , and N-acetyltransferase (NAT) activity levels which were lower than those obtained with alpha-methyldopa treatment alone, thus confirming the alpha-adrenergic activity of the metabolite of alpha-methyldopa. Additional pineal metabolites were isolated and measured simultaneously in the organ culture experiments. Organ cultures of rat pineal glands treated with ephedrine showed raised levels of melatonin (aMT) and N-acetylserotonin (aHT). Treatment with ephedrine also produced raised N-acetyltransferase activity. A further enhancement of these parameters was induced by norepinephrine, suggesting a supersensitivity-type effect occurring at the level of the beta-adrenergic receptor. Rats were treated with reserpine (a norepinephrine depleter) and the pineals exposed to ephedrine. Endogenous norepinephrine normally released by the action of ephedrine was thus absent, and under these conditions, levels of melatonin (aMT) and N-acetylserotonin (aHT) were reduced. N-acetyltransferase (NAT) activity was also reduced, but maintained levels pointing to substantial adrenergic activity of ephedrine as well as norepinephrine released by virtue of the drug's action. A subsequent binding study showed a decrease in beta-adrenergic receptor binding with exposure to ephedrine and a further decrease in ephedrine treated pineals from reserpine treated rats, thus ruling out the occurrence of a supersensitivity phenomenon. It is possible that both ephedrine and released norepinephrine have alpha- and beta-receptor activity. Additional pineal metabolites were isolated and measured in the organ culture experiments. A 16-hour time profile of the production of melatonin (aMT) and N-acetylserotonin (aHT) with norepinephrine and ephedrine treatment provided useful information regarding the course of action of the two agents. A pineal cell-culture system was developed and exposed to ephedrine and norepinephrine. N-acetyltransferase (NAT) activity levels measured after exposure to these agents were raised, confirming the adrenergic activity of both in the model. Finally, an HPLC system coupled to a UV detector was used in an attempt to measure melatonin (aMT) extracted from pineal organ culture media. The results showed that melatonin could be measured by this method, however, a more sensitive detection system was recommended for future work
- Full Text:
- Date Issued: 1991
- Authors: Welman, Alan David
- Date: 1991
- Subjects: Pineal gland , Cythochemistry
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:4279 , http://hdl.handle.net/10962/d1002005 , Pineal gland
- Description: An attempt was made to use the pineal gland as a model for the study of the primary mode of action of sympathoactive agents. Two drugs were investigated, viz. alpha-methyldopa and ephedrine whose mode of action is not entirely clear. Organ cultures of pineal glands from rats treated chronically with alpha-methyldopa showed enhanced conversion of radioactive serotonin to melatonin (aMT) , as well as its precursor Nacetylserotonin (aHT). This treatment was also found to raise Nacetyltransferase (NAT) activity. These increases associated with alpha-methyldopa treatment were further enhanced by the beta-adrenergic agonist, isoproterenol, suggesting a supersensitivity-type effect occurring at the level of the beta-receptor. A subsequent binding study, however, showed a decrease in beta-receptor binding with exposure to alpha-methyldopa, providing mitigating evidence against the occurrence of a supersensitivity phenomenon. It is possible that a metabolite of alpha-methyldopa acts as an alpha 1 and beta-adrenergic agonist, resulting in greater melatonin (aMT) and N-acetylserotonin (aHT) synthesis than by a beta-adrenergic agonist, isoproterenol. Combined treatment of pineals with alpha-methyldopa and an alphareceptor blocker, phentolamine, resulted in melatonin (aMT) , Nacetylserotonin (aHT) , and N-acetyltransferase (NAT) activity levels which were lower than those obtained with alpha-methyldopa treatment alone, thus confirming the alpha-adrenergic activity of the metabolite of alpha-methyldopa. Additional pineal metabolites were isolated and measured simultaneously in the organ culture experiments. Organ cultures of rat pineal glands treated with ephedrine showed raised levels of melatonin (aMT) and N-acetylserotonin (aHT). Treatment with ephedrine also produced raised N-acetyltransferase activity. A further enhancement of these parameters was induced by norepinephrine, suggesting a supersensitivity-type effect occurring at the level of the beta-adrenergic receptor. Rats were treated with reserpine (a norepinephrine depleter) and the pineals exposed to ephedrine. Endogenous norepinephrine normally released by the action of ephedrine was thus absent, and under these conditions, levels of melatonin (aMT) and N-acetylserotonin (aHT) were reduced. N-acetyltransferase (NAT) activity was also reduced, but maintained levels pointing to substantial adrenergic activity of ephedrine as well as norepinephrine released by virtue of the drug's action. A subsequent binding study showed a decrease in beta-adrenergic receptor binding with exposure to ephedrine and a further decrease in ephedrine treated pineals from reserpine treated rats, thus ruling out the occurrence of a supersensitivity phenomenon. It is possible that both ephedrine and released norepinephrine have alpha- and beta-receptor activity. Additional pineal metabolites were isolated and measured in the organ culture experiments. A 16-hour time profile of the production of melatonin (aMT) and N-acetylserotonin (aHT) with norepinephrine and ephedrine treatment provided useful information regarding the course of action of the two agents. A pineal cell-culture system was developed and exposed to ephedrine and norepinephrine. N-acetyltransferase (NAT) activity levels measured after exposure to these agents were raised, confirming the adrenergic activity of both in the model. Finally, an HPLC system coupled to a UV detector was used in an attempt to measure melatonin (aMT) extracted from pineal organ culture media. The results showed that melatonin could be measured by this method, however, a more sensitive detection system was recommended for future work
- Full Text:
- Date Issued: 1991
A study of possible interactions between the pineal gland and the opioidergic system
- Authors: Khan, Razeeya B
- Date: 1990
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3729 , http://hdl.handle.net/10962/d1001468
- Description: Recent observations suggest a link between the pineal gland and the opioid system. Possible areas of interaction between the pineal gland and the opioidergic system in Wistar rats were investigated. The effect of opioids on the pineal gland in organ culture was monitored. Neither morphine, methadone nor the opioid antagonist naloxone was found to affect [¹⁴C]-serotonin metabolism by the pineal gland in vitro. Both the pineal gland and the opioid system are influenced by exposure to stressful stimuli. Morphine and melatonin had protective effects on stress-induced gastric lesions. The ability of melatonin to inhibit lesion formation was found not to be exerted via an opioidergic mechanism. Evidence has been obtained for a possible modulation of the stress response by the pineal gland . The opioid drugs are the most potent analgesic agents available. A possible interaction between the opioid system and the pineal gland in the modulation of the response to noxious stimuli was investigated. An intact pineal gland was found to be necessary for the manifestation of the nocturnally increased response of rats to noxious stimuli
- Full Text:
- Date Issued: 1990
- Authors: Khan, Razeeya B
- Date: 1990
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3729 , http://hdl.handle.net/10962/d1001468
- Description: Recent observations suggest a link between the pineal gland and the opioid system. Possible areas of interaction between the pineal gland and the opioidergic system in Wistar rats were investigated. The effect of opioids on the pineal gland in organ culture was monitored. Neither morphine, methadone nor the opioid antagonist naloxone was found to affect [¹⁴C]-serotonin metabolism by the pineal gland in vitro. Both the pineal gland and the opioid system are influenced by exposure to stressful stimuli. Morphine and melatonin had protective effects on stress-induced gastric lesions. The ability of melatonin to inhibit lesion formation was found not to be exerted via an opioidergic mechanism. Evidence has been obtained for a possible modulation of the stress response by the pineal gland . The opioid drugs are the most potent analgesic agents available. A possible interaction between the opioid system and the pineal gland in the modulation of the response to noxious stimuli was investigated. An intact pineal gland was found to be necessary for the manifestation of the nocturnally increased response of rats to noxious stimuli
- Full Text:
- Date Issued: 1990
A study of the effects of the pineal hormone, melatonin, on dopaminergic transmission in the central nervous system of rats
- Authors: Burton, Susan Frances
- Date: 1990
- Subjects: Dopaminergic mechanisms Melatonin Pineal gland -- Secretions Neural transmission Pineal gland Nervous system
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3726 , http://hdl.handle.net/10962/d1001463
- Description: Dopamine mechanisms in the central nervous system are important in the control of both normal and abnormal motor function. The recent observations in both animal and human studies, that melatonin, the principal hormone of the pineal gland, may have a role in the control of movement and the pathophysiology of movement disorders, have given rise to the concept that melatonin may have a modulatory influence on central dopaminergic neurotransmission. This study makes use of three animal behavioural models as well as a biochemical model of central dopaminergic function to further investigate the concept. Results from studies using the biochemical model, which investigated the effect of melatonin on dopamine and apomorphine stimulation of dopamine-sensitive adenylate cylase, suggest that melatonin is neither a competitive antagonist nor agonist at the D₁ receptor level, although the possibility of physiological stimulation or antagonism is not excluded. In behavioural studies, prior melatonin mg/kg administration (1 and 10 (8M) ip) inhibited apomorphine induced stereotypy and locomotor activity in normal rats, and apomorphine-induced rotational behaviour in 6-hydroxydopamine and quinolinic acid lesioned rats. The possibility that these results may have physiological significance is borne out by the observation that, under enviromental lighting conditions that are associated with raised endogeous melatonin levels, apomorphine- induced stereotypy and locomotor activity is attenuated. The general conclusion is that melatonin has an inhibitory influence on central nervous system dopaminergic function, suggesting therefore, that the pineal gland and melatonin may have a role in the pathophysiology and treatment of movement and behavioural disorders associated with dopaminergic dysfunction
- Full Text:
- Date Issued: 1990
- Authors: Burton, Susan Frances
- Date: 1990
- Subjects: Dopaminergic mechanisms Melatonin Pineal gland -- Secretions Neural transmission Pineal gland Nervous system
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3726 , http://hdl.handle.net/10962/d1001463
- Description: Dopamine mechanisms in the central nervous system are important in the control of both normal and abnormal motor function. The recent observations in both animal and human studies, that melatonin, the principal hormone of the pineal gland, may have a role in the control of movement and the pathophysiology of movement disorders, have given rise to the concept that melatonin may have a modulatory influence on central dopaminergic neurotransmission. This study makes use of three animal behavioural models as well as a biochemical model of central dopaminergic function to further investigate the concept. Results from studies using the biochemical model, which investigated the effect of melatonin on dopamine and apomorphine stimulation of dopamine-sensitive adenylate cylase, suggest that melatonin is neither a competitive antagonist nor agonist at the D₁ receptor level, although the possibility of physiological stimulation or antagonism is not excluded. In behavioural studies, prior melatonin mg/kg administration (1 and 10 (8M) ip) inhibited apomorphine induced stereotypy and locomotor activity in normal rats, and apomorphine-induced rotational behaviour in 6-hydroxydopamine and quinolinic acid lesioned rats. The possibility that these results may have physiological significance is borne out by the observation that, under enviromental lighting conditions that are associated with raised endogeous melatonin levels, apomorphine- induced stereotypy and locomotor activity is attenuated. The general conclusion is that melatonin has an inhibitory influence on central nervous system dopaminergic function, suggesting therefore, that the pineal gland and melatonin may have a role in the pathophysiology and treatment of movement and behavioural disorders associated with dopaminergic dysfunction
- Full Text:
- Date Issued: 1990
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