Indomethacin reduces lipid peroxidation in rat brain homogenate by binding Fe2+
- Anoopkumar-Dukie, Shailendra, Lack, Barbara, McPhail, Kerry L, Nyokong, Tebello, Lambat, Zaynab, Maharaj, Deepat, Daya, Santy
- Authors: Anoopkumar-Dukie, Shailendra , Lack, Barbara , McPhail, Kerry L , Nyokong, Tebello , Lambat, Zaynab , Maharaj, Deepat , Daya, Santy
- Date: 2003
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/304763 , vital:58487 , xlink:href="https://doi.org/10.1023/A:1021958016928"
- Description: One of the hallmarks of Alzheimer's disease (AD) is the progressive degeneration of cholinergic neurons in the cerebral cortex and hippocampus. It is generally accepted that this neuronal degeneration is due to free-radical-induced damage. These free radicals attack vital structural components of the neurons. This implies that agents that reduce free radical generation could potentially delay the progression of AD. Free radical generation in the brain is assisted by the presence of iron, required by the Fenton reaction. Thus, agents that reduce iron availability for this reaction could potentially reduce free radical formation. Since non steroidal anti-inflammatory drugs (NSAIDS) have been shown to reduce the severity of AD, we investigated the possible mechanism by which indomethacin could afford neuroprotection. Our results show that indomethacin (1 mM) is able to reduce the iron-induced rise in lipid peroxidation in rat brain homogenates. In addition, our NMR data indicate that indomethacin binds the Fe2+/Fe3+ ion. This was confirmed by a study using UV/Vis spectrophotometry. The results imply that indomethacin provides a neuroprotective effect by binding to iron and thus making it unavailable for free radical production.
- Full Text:
- Date Issued: 2003
- Authors: Anoopkumar-Dukie, Shailendra , Lack, Barbara , McPhail, Kerry L , Nyokong, Tebello , Lambat, Zaynab , Maharaj, Deepat , Daya, Santy
- Date: 2003
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/304763 , vital:58487 , xlink:href="https://doi.org/10.1023/A:1021958016928"
- Description: One of the hallmarks of Alzheimer's disease (AD) is the progressive degeneration of cholinergic neurons in the cerebral cortex and hippocampus. It is generally accepted that this neuronal degeneration is due to free-radical-induced damage. These free radicals attack vital structural components of the neurons. This implies that agents that reduce free radical generation could potentially delay the progression of AD. Free radical generation in the brain is assisted by the presence of iron, required by the Fenton reaction. Thus, agents that reduce iron availability for this reaction could potentially reduce free radical formation. Since non steroidal anti-inflammatory drugs (NSAIDS) have been shown to reduce the severity of AD, we investigated the possible mechanism by which indomethacin could afford neuroprotection. Our results show that indomethacin (1 mM) is able to reduce the iron-induced rise in lipid peroxidation in rat brain homogenates. In addition, our NMR data indicate that indomethacin binds the Fe2+/Fe3+ ion. This was confirmed by a study using UV/Vis spectrophotometry. The results imply that indomethacin provides a neuroprotective effect by binding to iron and thus making it unavailable for free radical production.
- Full Text:
- Date Issued: 2003
The identification of the UV degradants of melatonin and their ability to scavenge free radicals
- Maharaj, Deepa S, Anoopkumar-Dukie, Shailendra, Glass, Beverley D, Antunes, Edith M, Lack, Barbara A, Walker, Roderick B, Daya, Santylal
- Authors: Maharaj, Deepa S , Anoopkumar-Dukie, Shailendra , Glass, Beverley D , Antunes, Edith M , Lack, Barbara A , Walker, Roderick B , Daya, Santylal
- Date: 2002
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184303 , vital:44198 , xlink:href="https://doi.org/10.1034/j.1600-079X.2002.01866.x"
- Description: Ultraviolet (UV) light is known to induce the generation of free radicals in biological tissues such as skin. Of these free radicals, the O2–· and particularly the ·OH radical can induce cellular damage including lipid peroxidation. Thus, the use of antioxidants to prevent such damage induced by UV irradiation has received much attention recently. One such antioxidant, which has the potential to be incorporated into sunscreens, is the pineal secretory product melatonin. One of the concerns of using melatonin in sunscreens is its photostability. In the present study, we investigated the photostability of melatonin subjected to UV irradiation. In addition, we used liquid chromatography mass spectrometry (LC-MS) to identify the degradants and we also assessed the ability of the degradants to inhibit O2–· generation as well as lipid peroxidation in rat brain homogenate. The results show that UV irradiation of melatonin (0.1 mg/mL) using a 400-W lamp for 2 hr caused a significant decline of melatonin to 18% of its original concentration after 20 min, with the decline continuing until the melatonin concentration reaches zero at 120 min. The LC-MS results show that the degradants of melatonin are 6-hydroxymelatonin and N1-acetyl-N2-formyl-5-methoxykynurenamine (AFMK). These degradants were able to provide equipotent activity against potassium cyanide (KCN)-induced superoxide generation compared to non-irradiated melatonin. Thus, the study shows that although melatonin is rapidly degraded by UV irradiation, the degradants retain antioxidant activity, making melatonin a likely candidate for inclusion in sunscreens.
- Full Text:
- Date Issued: 2002
- Authors: Maharaj, Deepa S , Anoopkumar-Dukie, Shailendra , Glass, Beverley D , Antunes, Edith M , Lack, Barbara A , Walker, Roderick B , Daya, Santylal
- Date: 2002
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184303 , vital:44198 , xlink:href="https://doi.org/10.1034/j.1600-079X.2002.01866.x"
- Description: Ultraviolet (UV) light is known to induce the generation of free radicals in biological tissues such as skin. Of these free radicals, the O2–· and particularly the ·OH radical can induce cellular damage including lipid peroxidation. Thus, the use of antioxidants to prevent such damage induced by UV irradiation has received much attention recently. One such antioxidant, which has the potential to be incorporated into sunscreens, is the pineal secretory product melatonin. One of the concerns of using melatonin in sunscreens is its photostability. In the present study, we investigated the photostability of melatonin subjected to UV irradiation. In addition, we used liquid chromatography mass spectrometry (LC-MS) to identify the degradants and we also assessed the ability of the degradants to inhibit O2–· generation as well as lipid peroxidation in rat brain homogenate. The results show that UV irradiation of melatonin (0.1 mg/mL) using a 400-W lamp for 2 hr caused a significant decline of melatonin to 18% of its original concentration after 20 min, with the decline continuing until the melatonin concentration reaches zero at 120 min. The LC-MS results show that the degradants of melatonin are 6-hydroxymelatonin and N1-acetyl-N2-formyl-5-methoxykynurenamine (AFMK). These degradants were able to provide equipotent activity against potassium cyanide (KCN)-induced superoxide generation compared to non-irradiated melatonin. Thus, the study shows that although melatonin is rapidly degraded by UV irradiation, the degradants retain antioxidant activity, making melatonin a likely candidate for inclusion in sunscreens.
- Full Text:
- Date Issued: 2002
A sensitive and reliable method for the detection of lipid peroxidation in biological tissues
- Anoopkumar-Dukie, Shailendra, Walker, Roderick B, Daya, Santylal
- Authors: Anoopkumar-Dukie, Shailendra , Walker, Roderick B , Daya, Santylal
- Date: 2001
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184325 , vital:44208 , xlink:href="https://doi.org/10.1211/0022357011775299"
- Description: A simple, accurate and cost effective method has been designed for the determination of lipid peroxidation in biological tissue samples. The method was a modification and improvement on existing methods available for lipid peroxidation determination. Solid-phase extraction was used to separate the thiobarbituric acid–malondialdehyde complex from thiobarbituric acidreactive substances and HPLC was performed using a C18 (Waters Spherisorb, 5 µm, 250¬4.6 mm i.d.) column to achieve isolation of the complex. The procedure was validated with respect to linearity of calibration (0.998), precision, sensitivity and limits of quantitation (1 nmol mL−1) and detection (0.5 nmol mL−1). Resorcinol was used as an external standard. The method was tested by inducing free radical generation with a known free radical generator, quinolinic acid, in rat brain homogenate. The results showed that the method presented allowed detection of lipid peroxidation products at concentrations in the nanomolar (nM) range compared with the micromolar (µM) range detected by other methods, thus rendering it suitable for use with biological samples. In addition, the modified method allowed for detection of the purified lipid peroxidation products, thus eliminating the possibility of simultaneous detection of impurities that absorb at the same wavelength.
- Full Text:
- Date Issued: 2001
- Authors: Anoopkumar-Dukie, Shailendra , Walker, Roderick B , Daya, Santylal
- Date: 2001
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184325 , vital:44208 , xlink:href="https://doi.org/10.1211/0022357011775299"
- Description: A simple, accurate and cost effective method has been designed for the determination of lipid peroxidation in biological tissue samples. The method was a modification and improvement on existing methods available for lipid peroxidation determination. Solid-phase extraction was used to separate the thiobarbituric acid–malondialdehyde complex from thiobarbituric acidreactive substances and HPLC was performed using a C18 (Waters Spherisorb, 5 µm, 250¬4.6 mm i.d.) column to achieve isolation of the complex. The procedure was validated with respect to linearity of calibration (0.998), precision, sensitivity and limits of quantitation (1 nmol mL−1) and detection (0.5 nmol mL−1). Resorcinol was used as an external standard. The method was tested by inducing free radical generation with a known free radical generator, quinolinic acid, in rat brain homogenate. The results showed that the method presented allowed detection of lipid peroxidation products at concentrations in the nanomolar (nM) range compared with the micromolar (µM) range detected by other methods, thus rendering it suitable for use with biological samples. In addition, the modified method allowed for detection of the purified lipid peroxidation products, thus eliminating the possibility of simultaneous detection of impurities that absorb at the same wavelength.
- Full Text:
- Date Issued: 2001
The effect of variations in pH and temperature on stability of melatonin in aqueous solution
- Daya, Santylal, Walker, Roderick B, Glass, Beverley D, Anoopkumar-Dukie, Shailendra
- Authors: Daya, Santylal , Walker, Roderick B , Glass, Beverley D , Anoopkumar-Dukie, Shailendra
- Date: 2001
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184314 , vital:44207 , xlink:href="https://doi.org/10.1034/j.1600-079x.2001.310209.x"
- Description: Melatonin (N-acetyl-5-methoxytryptamine) has a diverse range of functions, including the control of neuroendocrine events. A number of studies have shown that melatonin may be of potential benefit for the treatment of insomnia, as well as neurodegenerative disorders. At present, there are numerous dosage forms of melatonin, with the oral route of administration being most popular. Presently, there is little information on the stability of melatonin over a pH range. With the changes in pH in the gastro-intestinal tract, as well as in different experimental conditions, information on the stability of melatonin would be important. We used a high-performance liquid chromatography method to determine the stability of melatonin solutions over a pH range (1.2–12) at room temperature and at 37°C over a period of 21 days. The results show that no melatonin degradation occurred in the first 2 days. From days 3 to 21, there was a gradual decline in melatonin at all pHs, with the decline not exceeding 30%. No decline in melatonin levels occurred in the first 2 days at 37°C. From days 3 to 21, melatonin levels declined gradually, with the decline not exceeding 29%.
- Full Text:
- Date Issued: 2001
- Authors: Daya, Santylal , Walker, Roderick B , Glass, Beverley D , Anoopkumar-Dukie, Shailendra
- Date: 2001
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184314 , vital:44207 , xlink:href="https://doi.org/10.1034/j.1600-079x.2001.310209.x"
- Description: Melatonin (N-acetyl-5-methoxytryptamine) has a diverse range of functions, including the control of neuroendocrine events. A number of studies have shown that melatonin may be of potential benefit for the treatment of insomnia, as well as neurodegenerative disorders. At present, there are numerous dosage forms of melatonin, with the oral route of administration being most popular. Presently, there is little information on the stability of melatonin over a pH range. With the changes in pH in the gastro-intestinal tract, as well as in different experimental conditions, information on the stability of melatonin would be important. We used a high-performance liquid chromatography method to determine the stability of melatonin solutions over a pH range (1.2–12) at room temperature and at 37°C over a period of 21 days. The results show that no melatonin degradation occurred in the first 2 days. From days 3 to 21, there was a gradual decline in melatonin at all pHs, with the decline not exceeding 30%. No decline in melatonin levels occurred in the first 2 days at 37°C. From days 3 to 21, melatonin levels declined gradually, with the decline not exceeding 29%.
- Full Text:
- Date Issued: 2001
An investigation into the neuroprotective properties of ibuprofen
- Lambat, Zaynab Y, Conrad, Natasha, Anoopkumar-Dukie, Shailendra, Walker, Roderick B, Daya, Santylal
- Authors: Lambat, Zaynab Y , Conrad, Natasha , Anoopkumar-Dukie, Shailendra , Walker, Roderick B , Daya, Santylal
- Date: 2000
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184335 , vital:44209 , xlink:href="https://doi.org/10.1023/A:1011115006856"
- Description: There is increasing evidence suggesting a protective role for anti-inflammatory medications in neurological disorders such as Alzheimer's disease (AD). While there has not been any direct evidence for this, a number of clinical studies indicate that those patients who have had a history of nonsteroidal anti-inflammatory use, have a lower incidence of AD. Since there is currently no evidence on the mechanism by which these agents offer possible neuroprotection, we investigated the potential neuroprotective properties of the nonsteroidal anti-inflammatory drug, ibuprofen, by examining whether this agent could reduce lipid peroxidation and superoxide radical generation. Quinolinic acid and cyanide, known neurotoxins, were used to induce lipid peroxidation and superoxide anion formation respectively, in rat brain homogenate. The results show that ibuprofen significantly (p more than 0.05) reduced quinolinic acid-induced lipid peroxidation and cyanide-induced superoxide production. The results of the present report therefore suggest a possible mechanism for the neuroprotective effect of ibuprofen.
- Full Text: false
- Date Issued: 2000
- Authors: Lambat, Zaynab Y , Conrad, Natasha , Anoopkumar-Dukie, Shailendra , Walker, Roderick B , Daya, Santylal
- Date: 2000
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184335 , vital:44209 , xlink:href="https://doi.org/10.1023/A:1011115006856"
- Description: There is increasing evidence suggesting a protective role for anti-inflammatory medications in neurological disorders such as Alzheimer's disease (AD). While there has not been any direct evidence for this, a number of clinical studies indicate that those patients who have had a history of nonsteroidal anti-inflammatory use, have a lower incidence of AD. Since there is currently no evidence on the mechanism by which these agents offer possible neuroprotection, we investigated the potential neuroprotective properties of the nonsteroidal anti-inflammatory drug, ibuprofen, by examining whether this agent could reduce lipid peroxidation and superoxide radical generation. Quinolinic acid and cyanide, known neurotoxins, were used to induce lipid peroxidation and superoxide anion formation respectively, in rat brain homogenate. The results show that ibuprofen significantly (p more than 0.05) reduced quinolinic acid-induced lipid peroxidation and cyanide-induced superoxide production. The results of the present report therefore suggest a possible mechanism for the neuroprotective effect of ibuprofen.
- Full Text: false
- Date Issued: 2000
Cyanide-induced free radical production and lipid peroxidation in rat brain homogenate is reduced by aspirin
- Daya, Santylal, Walker, Roderick B, Anoopkumar-Dukie, Shailendra
- Authors: Daya, Santylal , Walker, Roderick B , Anoopkumar-Dukie, Shailendra
- Date: 2000
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184346 , vital:44210 , xlink:href="https://doi.org/10.1007/BF02674529"
- Description: The neuroprotective properties of aspirin were investigated using cyanide-induced neurotoxicity as model. Cyanide, a known neurotoxic agent significantly increased lipid peroxidation and superoxide anion levels in rat brain homogenate in a concentration-dependent manner (0.25–1.0 mM). When homogenate, containing 1.0 mM KCN was cotreated with aspirin (1.0 mM) there was a significant decrease in lipid peroxidation. Aspirin (0.5 mM and 1.0 mM) also significantly reduced KCN-induced superoxide anion generation. The results of the present report therefore indicate a neuroprotective role for aspirin.
- Full Text:
- Date Issued: 2000
- Authors: Daya, Santylal , Walker, Roderick B , Anoopkumar-Dukie, Shailendra
- Date: 2000
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184346 , vital:44210 , xlink:href="https://doi.org/10.1007/BF02674529"
- Description: The neuroprotective properties of aspirin were investigated using cyanide-induced neurotoxicity as model. Cyanide, a known neurotoxic agent significantly increased lipid peroxidation and superoxide anion levels in rat brain homogenate in a concentration-dependent manner (0.25–1.0 mM). When homogenate, containing 1.0 mM KCN was cotreated with aspirin (1.0 mM) there was a significant decrease in lipid peroxidation. Aspirin (0.5 mM and 1.0 mM) also significantly reduced KCN-induced superoxide anion generation. The results of the present report therefore indicate a neuroprotective role for aspirin.
- Full Text:
- Date Issued: 2000
Melatonin alters the photodegradation of paracetamol
- Anoopkumar-Dukie, Shailendra, Glass, Beverley D, Walker, Roderick B, Daya, Santylal
- Authors: Anoopkumar-Dukie, Shailendra , Glass, Beverley D , Walker, Roderick B , Daya, Santylal
- Date: 2000
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184357 , vital:44211 , xlink:href="https://doi.org/10.1211/146080800128735755"
- Description: The effects of melatonin, a known free-radical scavenger, on paracetamol in the presence of UV irradiation was studied by use of HPLC. The experiments were performed in air and nitrogen. The results show that the rate of photodegradation of melatonin is faster in air than in nitrogen whereas that of paracetamol is similar in air and nitrogen. When the two drugs were combined, melatonin retarded the degradation of paracetamol for up to 6h in the presence of nitrogen. However, in the presence of air melatonin rapidly enhances the photodegradation of paracetamol. This study shows that a combination of melatonin and paracetamol in the presence of air and UV irradiation can lead to rapid inactivation of both agents, thus raising important concerns about the possible use of melatonin as sunscreen
- Full Text:
- Date Issued: 2000
- Authors: Anoopkumar-Dukie, Shailendra , Glass, Beverley D , Walker, Roderick B , Daya, Santylal
- Date: 2000
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/184357 , vital:44211 , xlink:href="https://doi.org/10.1211/146080800128735755"
- Description: The effects of melatonin, a known free-radical scavenger, on paracetamol in the presence of UV irradiation was studied by use of HPLC. The experiments were performed in air and nitrogen. The results show that the rate of photodegradation of melatonin is faster in air than in nitrogen whereas that of paracetamol is similar in air and nitrogen. When the two drugs were combined, melatonin retarded the degradation of paracetamol for up to 6h in the presence of nitrogen. However, in the presence of air melatonin rapidly enhances the photodegradation of paracetamol. This study shows that a combination of melatonin and paracetamol in the presence of air and UV irradiation can lead to rapid inactivation of both agents, thus raising important concerns about the possible use of melatonin as sunscreen
- Full Text:
- Date Issued: 2000
Serotonin-melatonin interactions in acetaminophen and N,N-dimethylformamide toxicity
- Anoopkumar-Dukie, Shailendra
- Authors: Anoopkumar-Dukie, Shailendra
- Date: 2000
- Subjects: Serotonin , Acetaminophen , Melatonin
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3898 , http://hdl.handle.net/10962/d1003957 , Serotonin , Acetaminophen , Melatonin
- Description: Acetaminophen and N,N-dimethylformamide (DMF) are compounds which are extremely toxic to the liver. Acetaminophen is a drug which is well known for its analgesic and antipyretic properties. However, the abuse potential of this agent as a non-narcotic analgesic in alcoholics is well known. It is also the leading cause of overdose in England. DMF toxicity results mainly from occupational exposure. At present there are no known reports of an antidote for DMF poisoning, while N-acetylcysteine, the antidote for acetaminophen poisoning, is known to produce adverse effects. The present study evaluates the potential of melatonin as an antidote for acetaminophen and DMF poisoning. This study also investigates the mechanism underlying acetaminophen addiction and abuse. Initial studies involved in vitro techniques in an attempt to remove the complexities of organ interactions. The photodegradation studies, using ultraviolet (UV) light, revealed that melatonin accelerates the rate of acetaminophen degradation in the presence of air, and reduces the rate of degradation in the presence of nitrogen. This study also revealed that melatonin is rapidly degraded in the presence of air, following UV irradiation. The effect of DMF on hydroxyl radical generation was also determined. DMF was shown to act as a free radical scavenger, rather that a generator of free radicals. The in vitro studies were followed by lipid peroxidation determination. DMF (0.4ml/kg and 0.8ml/kg) did not produce any significant increases in lipid peroxidation in the liver. Three different doses of acetaminophen (30mg/kg, 100mg/kg, and 500mg/kg) were administered to rats for seven days. Acetaminophen (500mg/kg) was shown to significantly increase (p<0.05) lipid peroxidation in the liver. Melatonin (2.5mg/kg) was not able to significantly reduce the damage. The lower doses of acetaminophen (30mg/kg and 100mg/kg) did not increase lipid peroxidation. Electron microscopy studies showed that DMF adversely affects the liver, and in particular, the endoplasmic reticulum. Co administration of melatonin (2.5mg/kg) was able to reduce the damage. Further experiments need to be performed before an accurate assessment can be made on the ability of melatonin as an antidote for DMF and acetaminophen poisoning. Several experiments were done in an attempt to uncover the biochemical mechanism underlying acetaminophen addiction and abuse. The first experiment targeted the liver enzyme tryptophan-2,3-dioxygenase (TDO). This enzyme is the major determinant of tryptophan levels in vivo. Acetaminophen administration (100mg/kg for three hours) was shown to significantly inhibit (p<0.05) the activity of TDO, indicating increased peripheral levels of tryptophan. This experiment was followed up with determination of brain serotonin and pineal melatonin. Brain serotonin was determined using the ELISA technique. Melatonin was estimated using this technique as well as with pineal organ culture. Acetaminophen administration (100mg/kg for three hours) significantly increased (p<0.05) brain serotonin levels. Using organ culture where exogenous (3H) tryptophan is metabolised to (3H) melatonin, acetaminophen (100mg/kg for three hours) was shown to significantly increase (p<0.05) pineal melatonin concentrations. However, the ELISA technique did not reveal any changes in endogenous pineal melatonin levels. The final experiment was the determination of urinary 5-hydroxyindole acetic acid (5- HIAA), the major metabolite of serotonin, following acetaminophen administration (100mg/kg for three hours). Acetaminophen was shown to significantly reduce 5-HIAA levels (p<0.05) suggesting reduced catabolism of serotonin. The findings of this study indicate that acetaminophen mimics the actions of an antidepressant. This compelling finding has important clinical implications, and needs to be examined further.
- Full Text:
- Date Issued: 2000
- Authors: Anoopkumar-Dukie, Shailendra
- Date: 2000
- Subjects: Serotonin , Acetaminophen , Melatonin
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3898 , http://hdl.handle.net/10962/d1003957 , Serotonin , Acetaminophen , Melatonin
- Description: Acetaminophen and N,N-dimethylformamide (DMF) are compounds which are extremely toxic to the liver. Acetaminophen is a drug which is well known for its analgesic and antipyretic properties. However, the abuse potential of this agent as a non-narcotic analgesic in alcoholics is well known. It is also the leading cause of overdose in England. DMF toxicity results mainly from occupational exposure. At present there are no known reports of an antidote for DMF poisoning, while N-acetylcysteine, the antidote for acetaminophen poisoning, is known to produce adverse effects. The present study evaluates the potential of melatonin as an antidote for acetaminophen and DMF poisoning. This study also investigates the mechanism underlying acetaminophen addiction and abuse. Initial studies involved in vitro techniques in an attempt to remove the complexities of organ interactions. The photodegradation studies, using ultraviolet (UV) light, revealed that melatonin accelerates the rate of acetaminophen degradation in the presence of air, and reduces the rate of degradation in the presence of nitrogen. This study also revealed that melatonin is rapidly degraded in the presence of air, following UV irradiation. The effect of DMF on hydroxyl radical generation was also determined. DMF was shown to act as a free radical scavenger, rather that a generator of free radicals. The in vitro studies were followed by lipid peroxidation determination. DMF (0.4ml/kg and 0.8ml/kg) did not produce any significant increases in lipid peroxidation in the liver. Three different doses of acetaminophen (30mg/kg, 100mg/kg, and 500mg/kg) were administered to rats for seven days. Acetaminophen (500mg/kg) was shown to significantly increase (p<0.05) lipid peroxidation in the liver. Melatonin (2.5mg/kg) was not able to significantly reduce the damage. The lower doses of acetaminophen (30mg/kg and 100mg/kg) did not increase lipid peroxidation. Electron microscopy studies showed that DMF adversely affects the liver, and in particular, the endoplasmic reticulum. Co administration of melatonin (2.5mg/kg) was able to reduce the damage. Further experiments need to be performed before an accurate assessment can be made on the ability of melatonin as an antidote for DMF and acetaminophen poisoning. Several experiments were done in an attempt to uncover the biochemical mechanism underlying acetaminophen addiction and abuse. The first experiment targeted the liver enzyme tryptophan-2,3-dioxygenase (TDO). This enzyme is the major determinant of tryptophan levels in vivo. Acetaminophen administration (100mg/kg for three hours) was shown to significantly inhibit (p<0.05) the activity of TDO, indicating increased peripheral levels of tryptophan. This experiment was followed up with determination of brain serotonin and pineal melatonin. Brain serotonin was determined using the ELISA technique. Melatonin was estimated using this technique as well as with pineal organ culture. Acetaminophen administration (100mg/kg for three hours) significantly increased (p<0.05) brain serotonin levels. Using organ culture where exogenous (3H) tryptophan is metabolised to (3H) melatonin, acetaminophen (100mg/kg for three hours) was shown to significantly increase (p<0.05) pineal melatonin concentrations. However, the ELISA technique did not reveal any changes in endogenous pineal melatonin levels. The final experiment was the determination of urinary 5-hydroxyindole acetic acid (5- HIAA), the major metabolite of serotonin, following acetaminophen administration (100mg/kg for three hours). Acetaminophen was shown to significantly reduce 5-HIAA levels (p<0.05) suggesting reduced catabolism of serotonin. The findings of this study indicate that acetaminophen mimics the actions of an antidepressant. This compelling finding has important clinical implications, and needs to be examined further.
- Full Text:
- Date Issued: 2000
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