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Rudolf J Wiesner - One of the best experts on this subject based on the ideXlab platform.
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Catecholamine Metabolism induces mitochondrial dna deletions and leads to severe adrenal degeneration during aging
Neuroendocrinology, 2017Co-Authors: Johannes F G Neuhaus, Olivier R Baris, Anne Kittelmann, Katrin Becker, Markus A Rothschild, Rudolf J WiesnerAbstract:Background: Aging is a multifactorial process characterized by organ loss of function and degeneration, but the mechanisms involved remain elusive. We have shown recently that Catecholamine Metabolism drives the accumulation of mitochondrial DNA (mtDNA) deletions in dopaminergic cells, which likely contribute to their degeneration during aging. Here we investigated whether the well-documented degeneration and altered function of adrenals during aging is linked to Catecholamine production in the medulla followed by accumulation of mtDNA deletions. Material and Methods: We analyzed adrenal medullary and cortical samples of both murine and human origin covering a wide range of ages for mtDNA deletion content, mtDNA copy number, mitochondrial and cellular integrity as well as aging-related tissue changes such as fibrosis. Results: Indeed, we demonstrate in mice and humans that the adrenal medulla accumulates a strikingly high amount of mtDNA deletions with age, causing mitochondrial dysfunction in the adrenal medulla, but also in the cortex, accompanied by apoptosis and, more importantly, by severe inflammation and remarkable fibrosis. Additionally, a concomitant and dramatic loss of medullary and cortical cells is observed in old animals. Conclusion: Our results show that accumulation of mtDNA deletions, and the ensuing mitochondrial dysfunction, is a hallmark of adrenal aging, further strengthening the hypothesis that Catecholamine Metabolism is detrimental to mtDNA integrity, mitochondrial function and cell survival. Moreover, the cell loss potentially induced by mitochondrial dysfunction could explain the decline in adrenal hormonal and steroidal secretion during aging.
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Catecholamine Metabolism drives generation of mitochondrial dna deletions in dopaminergic neurons
Brain, 2014Co-Authors: Johannes F G Neuhaus, Olivier R Baris, Simon Hess, Natasha Moser, Hannsjorg Schroder, Shankar J Chinta, Julie K Andersen, Peter Kloppenburg, Rudolf J WiesnerAbstract:Accumulation of mitochondrial DNA deletions is observed especially in dopaminergic neurons of the substantia nigra during ageing and even more in Parkinson's disease. The resulting mitochondrial dysfunction is suspected to play an important role in neurodegeneration. However, the molecular mechanisms involved in the preferential generation of mitochondrial DNA deletions in dopaminergic neurons are still unknown. To study this phenomenon, we developed novel polymerase chain reaction strategies to detect distinct mitochondrial DNA deletions and monitor their accumulation patterns. Applying these approaches in in vitro and in vivo models, we show that Catecholamine Metabolism drives the generation and accumulation of these mitochondrial DNA mutations. As in humans, age-related accumulation of mitochondrial DNA deletions is most prominent in dopaminergic areas of mouse brain and even higher in the Catecholaminergic adrenal medulla. Dopamine treatment of terminally differentiated neuroblastoma cells, as well as stimulation of dopamine turnover in mice over-expressing monoamine oxidase B both induce multiple mitochondrial DNA deletions. Our results thus identify Catecholamine Metabolism as the driving force behind mitochondrial DNA deletions, probably being an important factor in the ageing-associated degeneration of dopaminergic neurons.
Fumihiko Horio - One of the best experts on this subject based on the ideXlab platform.
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Changes in Catecholamine Metabolism by ascorbic acid deficiency in spontaneously hypertensive rats unable to synthesize ascorbic acid
Life sciences, 2003Co-Authors: Kaori Kawai, Susumu Makino, Hiroyuki Ito, Hiroko Kubota, Kumiko Takemori, Fumihiko HorioAbstract:We have previously reported the establishment of a novel rat strain, SHR-od, with both spontaneous hypertension and a defect of ascorbic acid biosynthesis. Blood pressure in mature SHR-od fed an ascorbic acid-supplemented diet is over 190-200 mmHg, while it decreased to around 120 mmHg at 4-5 weeks after the cessation of ascorbic acid supplementation. With regard to possible mechanisms of blood pressure lowering, we focused on Catecholamine synthesis in adrenal glands, since Catecholamine is a major factor for blood pressure regulation and ascorbic acid is a co-factor of dopamine beta-hydroxylase (DBH) in Catecholamine biosynthesis. Male SHR-od (25-week-old) and normotensive ODS rats with a defect in ascorbic acid biosynthesis (25-week-old) were fed a Funabashi-SP diet with or without ascorbic acid (300 mg/kg diet) for 28 days or 35 days. In SHR-od, systolic blood pressure (191 +/- 6 mmHg) began to decrease from day 21 in the ascorbic acid-deficient group, whereas no significant difference was found in ODS rats. In spite of significant lowering of blood pressure, no significant differences were found in Catecholamine levels in serum, adrenal glands and brain on day 28. On day 35, however, urinary excretion of norepinephrine and epinephrine in the ascorbic acid-deficient SHR-od were higher at 490% (P < 0.05) and 460% (P < 0.05) of the respective control. Serum Catecholamine concentrations and the adrenal Catecholamine content tended to be higher in the ascorbic acid-deficient SHR-od than the control of SHR-od and reached to similar level in ODS rats. The administration of ascorbic acid (intraperitoneal injection, 60 mg ascorbic acid/kg body weight, once a day) to the ascorbic acid-deficient SHR-od restored blood pressure to the range 180-190 mmHg within two days. These findings indicate that ascorbic acid deficiency affects Catecholamine Metabolism in the adrenal glands of SHR-od in response to blood pressure lowering, suggesting Catecholamines are not involved in the mechanism for the remarkable reduction in blood pressure in response to ascorbic acid deficiency.
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changes in Catecholamine Metabolism by ascorbic acid deficiency in spontaneously hypertensive rats unable to synthesize ascorbic acid
Life Sciences, 2003Co-Authors: Kaori Kawai, Susumu Makino, Hiroyuki Ito, Hiroko Kubota, Kumiko Takemori, Fumihiko HorioAbstract:Abstract We have previously reported the establishment of a novel rat strain, SHR-od, with both spontaneous hypertension and a defect of ascorbic acid biosynthesis. Blood pressure in mature SHR-od fed an ascorbic acid-supplemented diet is over 190–200 mmHg, while it decreased to around 120 mmHg at 4–5 weeks after the cessation of ascorbic acid supplementation. With regard to possible mechanisms of blood pressure lowering, we focused on Catecholamine synthesis in adrenal glands, since Catecholamine is a major factor for blood pressure regulation and ascorbic acid is a co-factor of dopamine β-hydroxylase (DBH) in Catecholamine biosynthesis. Male SHR-od (25-week-old) and normotensive ODS rats with a defect in ascorbic acid biosynthesis (25-week-old) were fed a Funabashi-SP diet with or without ascorbic acid (300 mg/kg diet) for 28 days or 35 days. In SHR-od, systolic blood pressure (191 ± 6 mmHg) began to decrease from day 21 in the ascorbic acid-deficient group, whereas no significant difference was found in ODS rats. In spite of significant lowering of blood pressure, no significant differences were found in Catecholamine levels in serum, adrenal glands and brain on day 28. On day 35, however, urinary excretion of norepinephrine and epinephrine in the ascorbic acid-deficient SHR-od were higher at 490% (P
Ariel Gordin - One of the best experts on this subject based on the ideXlab platform.
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simultaneous inhibition of catechol o methyltransferase and monoamine oxidase a effects on hemodynamics and Catecholamine Metabolism in healthy volunteers
Clinical Pharmacology & Therapeutics, 1996Co-Authors: Ari Illi, Stig Sundberg, Pirjo Ojalakarlsson, Mika Scheinin, Ariel GordinAbstract:Objective To evaluate the effects of simultaneous pharmacologic inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase type A (MAO-A) on hemodynamics and Catecholamine Metabolism in healthy volunteers at rest and during exercise. Background Entacapone, a COMT inhibitor, is studied as an adjunct to levodopa treatment in patients with Parkinson's disease. Moclobemide, an MAO-A inhibitor, is already in clinical use as an antidepressant. It is likely that entacapone and moclobemide will be used concomitantly in the future in patients who have both Parkinson's disease and depression. It was therefore considered to be important to investigate the tolerability of combined COMT and MAO-A inhibition with entacapone and moclobemide. Design and methods This was a randomized, single-dose, double-blind crossover study of 12 healthy male volunteers. The treatments were either placebo, 200 mg entacapone, 150 mg moclobemide, or the combination of entacapone and moclobemide in single doses. Heart rate, blood pressure, impedance cardiography, and plasma concentrations of Catecholamines and their metabolites were measured both at rest and during submaximal standardized bicycle exercise. Results Entacapone and moclobemide (either alone or in combination) did not change heart rate, blood pressure, or any hemodynamic parameter at rest or during exercise compared with placebo. Neither were the concentrations of norepinephrine and epinephrine in plasma influenced. Both drugs had the expected effects on Catecholamine metabolite concentrations in plasma. The decrease in the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG) induced by moclobemide was not potentiated by entacapone. Conclusion The combined use of therapeutic single doses of entacapone and moclobemide in healthy volunteers did not affect the hemodynamics or concentrations of unconjugated norepinephrine and epinephrine in plasma. Other mechanisms are capable of regulating the concentrations of norepinephrine and epinephrine in circulating blood (and apparently also at their receptors in the heart and vascular tissue) when both COMT and MAO-A activity are inhibited to a significant extent. This was also the case during marked sympathetic stimulation. The changes in the Catecholamine metabolite concentrations provide evidence of effective COMT and MAO inhibition. Concentrations of MHPG in plasma are determined mainly by MAO-A activity because COMT inhibition did not have an additional effect on the moclobemide-induced decrease in plasma MHPG. Clinical Pharmacology & Therapeutics (1996) 59, 450–457; doi:
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comt inhibition by high dose entacapone does not affect hemodynamics but changes Catecholamine Metabolism in healthy volunteers at rest and during exercise
International Journal of Clinical Pharmacology and Therapeutics, 1994Co-Authors: Ari Illi, Stig Sundberg, Mika Scheinin, M Koulu, S Heinavaara, Ariel GordinAbstract:We studied the effects of catechol-O-methyltransferase (COMT) inhibition with entacapone on hemodynamics and Catecholamine Metabolism in healthy volunteers at rest and during a bicycle exercise test. Entacapone was given orally during two periods of seven days each to eleven healthy male volunteers; on the first period 400 mg t.i.d. and on the second 800 mg t.i.d. A submaximal exercise test giving a heart rate of about 163-167 beats/min with the highest predetermined work load was performed on a bicycle ergometer, and blood pressure, heart rate and ECG were recorded. The concentrations of adrenaline, noradrenaline, 3,4-dihydroxyphenylglycol (DHPG), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) in plasma were determined. Blood pressure, heart rate, ECG, and plasma concentrations of unconjugated adrenaline and noradrenaline were not influenced after single and repeated dosing of entacapone. The plasma concentrations of DHPG (a monoamine oxidase (MAO)-dependent metabolite) increased maximally by 245% compared to the control day. DOPAC (a MAO-dependent metabolite) increased maximally by 144% and MHPG (a COMT-dependent metabolite) decreased by 54%. The increase in DHPG and DOPAC was significantly greater with the 800 mg dose than with the 400 mg dose. The decrease in MHPG was significantly greater with the repeated dosing than with the single dose of entacapone. COMT inhibition by entacapone seems not to affect hemodynamics or plasma concentrations of unconjugated adrenaline and noradrenaline in healthy volunteers either at rest or during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
Ari Illi - One of the best experts on this subject based on the ideXlab platform.
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simultaneous inhibition of catechol o methyltransferase and monoamine oxidase a effects on hemodynamics and Catecholamine Metabolism in healthy volunteers
Clinical Pharmacology & Therapeutics, 1996Co-Authors: Ari Illi, Stig Sundberg, Pirjo Ojalakarlsson, Mika Scheinin, Ariel GordinAbstract:Objective To evaluate the effects of simultaneous pharmacologic inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase type A (MAO-A) on hemodynamics and Catecholamine Metabolism in healthy volunteers at rest and during exercise. Background Entacapone, a COMT inhibitor, is studied as an adjunct to levodopa treatment in patients with Parkinson's disease. Moclobemide, an MAO-A inhibitor, is already in clinical use as an antidepressant. It is likely that entacapone and moclobemide will be used concomitantly in the future in patients who have both Parkinson's disease and depression. It was therefore considered to be important to investigate the tolerability of combined COMT and MAO-A inhibition with entacapone and moclobemide. Design and methods This was a randomized, single-dose, double-blind crossover study of 12 healthy male volunteers. The treatments were either placebo, 200 mg entacapone, 150 mg moclobemide, or the combination of entacapone and moclobemide in single doses. Heart rate, blood pressure, impedance cardiography, and plasma concentrations of Catecholamines and their metabolites were measured both at rest and during submaximal standardized bicycle exercise. Results Entacapone and moclobemide (either alone or in combination) did not change heart rate, blood pressure, or any hemodynamic parameter at rest or during exercise compared with placebo. Neither were the concentrations of norepinephrine and epinephrine in plasma influenced. Both drugs had the expected effects on Catecholamine metabolite concentrations in plasma. The decrease in the concentration of 3-methoxy-4-hydroxyphenylglycol (MHPG) induced by moclobemide was not potentiated by entacapone. Conclusion The combined use of therapeutic single doses of entacapone and moclobemide in healthy volunteers did not affect the hemodynamics or concentrations of unconjugated norepinephrine and epinephrine in plasma. Other mechanisms are capable of regulating the concentrations of norepinephrine and epinephrine in circulating blood (and apparently also at their receptors in the heart and vascular tissue) when both COMT and MAO-A activity are inhibited to a significant extent. This was also the case during marked sympathetic stimulation. The changes in the Catecholamine metabolite concentrations provide evidence of effective COMT and MAO inhibition. Concentrations of MHPG in plasma are determined mainly by MAO-A activity because COMT inhibition did not have an additional effect on the moclobemide-induced decrease in plasma MHPG. Clinical Pharmacology & Therapeutics (1996) 59, 450–457; doi:
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comt inhibition by high dose entacapone does not affect hemodynamics but changes Catecholamine Metabolism in healthy volunteers at rest and during exercise
International Journal of Clinical Pharmacology and Therapeutics, 1994Co-Authors: Ari Illi, Stig Sundberg, Mika Scheinin, M Koulu, S Heinavaara, Ariel GordinAbstract:We studied the effects of catechol-O-methyltransferase (COMT) inhibition with entacapone on hemodynamics and Catecholamine Metabolism in healthy volunteers at rest and during a bicycle exercise test. Entacapone was given orally during two periods of seven days each to eleven healthy male volunteers; on the first period 400 mg t.i.d. and on the second 800 mg t.i.d. A submaximal exercise test giving a heart rate of about 163-167 beats/min with the highest predetermined work load was performed on a bicycle ergometer, and blood pressure, heart rate and ECG were recorded. The concentrations of adrenaline, noradrenaline, 3,4-dihydroxyphenylglycol (DHPG), 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) in plasma were determined. Blood pressure, heart rate, ECG, and plasma concentrations of unconjugated adrenaline and noradrenaline were not influenced after single and repeated dosing of entacapone. The plasma concentrations of DHPG (a monoamine oxidase (MAO)-dependent metabolite) increased maximally by 245% compared to the control day. DOPAC (a MAO-dependent metabolite) increased maximally by 144% and MHPG (a COMT-dependent metabolite) decreased by 54%. The increase in DHPG and DOPAC was significantly greater with the 800 mg dose than with the 400 mg dose. The decrease in MHPG was significantly greater with the repeated dosing than with the single dose of entacapone. COMT inhibition by entacapone seems not to affect hemodynamics or plasma concentrations of unconjugated adrenaline and noradrenaline in healthy volunteers either at rest or during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)
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The effects of the COMT inhibitor entacapone on haemodynamics and peripheral Catecholamine Metabolism during exercise.
British journal of clinical pharmacology, 1993Co-Authors: Stig Sundberg, Ari Illi, Mika Scheinin, Juha Akkila, T. KeränenAbstract:1. Catechol-O-methyltransferase (COMT) inhibition might be assumed to potentiate the effects of circulating Catecholamines, particularly under conditions of enhanced Catecholamine release. 2. The purpose of the present study was to establish whether the novel COMT inhibitor, entacapone, changes haemodynamic responses and Catecholamine Metabolism during exercise. 3. Entacapone was given orally to 12 healthy male subjects (age 23-30 years) in increasing single doses from 0 mg (control day) to 200 mg. A submaximal exercise test was performed on a bicycle ergometer, and blood pressure, heart rate and ECG were recorded. The concentrations of noradrenaline, adrenaline, DHPG (3,4-dihydroxyphenylglycol), MHPG (3-methoxy-4-hydroxyphenyl-glycol) and, DOPAC (3,4-dihydroxyphenylacetic acid) in plasma were determined. 4. Entacapone did not influence haemodynamics or ECG at rest or during exercise. 5. Entacapone did not influence plasma Catecholamine levels, either at rest or during exercise. However, it altered the metabolic profile of Catecholamines, which was shown by increases in the plasma concentrations of the monoamine oxidase-dependent metabolites DHPG (by up to 100%) and DOPAC (by up to 53%), and by a decrease of the COMT-dependent metabolite MHPG (by up to 29%).
Johannes F G Neuhaus - One of the best experts on this subject based on the ideXlab platform.
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Catecholamine Metabolism induces mitochondrial dna deletions and leads to severe adrenal degeneration during aging
Neuroendocrinology, 2017Co-Authors: Johannes F G Neuhaus, Olivier R Baris, Anne Kittelmann, Katrin Becker, Markus A Rothschild, Rudolf J WiesnerAbstract:Background: Aging is a multifactorial process characterized by organ loss of function and degeneration, but the mechanisms involved remain elusive. We have shown recently that Catecholamine Metabolism drives the accumulation of mitochondrial DNA (mtDNA) deletions in dopaminergic cells, which likely contribute to their degeneration during aging. Here we investigated whether the well-documented degeneration and altered function of adrenals during aging is linked to Catecholamine production in the medulla followed by accumulation of mtDNA deletions. Material and Methods: We analyzed adrenal medullary and cortical samples of both murine and human origin covering a wide range of ages for mtDNA deletion content, mtDNA copy number, mitochondrial and cellular integrity as well as aging-related tissue changes such as fibrosis. Results: Indeed, we demonstrate in mice and humans that the adrenal medulla accumulates a strikingly high amount of mtDNA deletions with age, causing mitochondrial dysfunction in the adrenal medulla, but also in the cortex, accompanied by apoptosis and, more importantly, by severe inflammation and remarkable fibrosis. Additionally, a concomitant and dramatic loss of medullary and cortical cells is observed in old animals. Conclusion: Our results show that accumulation of mtDNA deletions, and the ensuing mitochondrial dysfunction, is a hallmark of adrenal aging, further strengthening the hypothesis that Catecholamine Metabolism is detrimental to mtDNA integrity, mitochondrial function and cell survival. Moreover, the cell loss potentially induced by mitochondrial dysfunction could explain the decline in adrenal hormonal and steroidal secretion during aging.
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Catecholamine Metabolism drives generation of mitochondrial dna deletions in dopaminergic neurons
Brain, 2014Co-Authors: Johannes F G Neuhaus, Olivier R Baris, Simon Hess, Natasha Moser, Hannsjorg Schroder, Shankar J Chinta, Julie K Andersen, Peter Kloppenburg, Rudolf J WiesnerAbstract:Accumulation of mitochondrial DNA deletions is observed especially in dopaminergic neurons of the substantia nigra during ageing and even more in Parkinson's disease. The resulting mitochondrial dysfunction is suspected to play an important role in neurodegeneration. However, the molecular mechanisms involved in the preferential generation of mitochondrial DNA deletions in dopaminergic neurons are still unknown. To study this phenomenon, we developed novel polymerase chain reaction strategies to detect distinct mitochondrial DNA deletions and monitor their accumulation patterns. Applying these approaches in in vitro and in vivo models, we show that Catecholamine Metabolism drives the generation and accumulation of these mitochondrial DNA mutations. As in humans, age-related accumulation of mitochondrial DNA deletions is most prominent in dopaminergic areas of mouse brain and even higher in the Catecholaminergic adrenal medulla. Dopamine treatment of terminally differentiated neuroblastoma cells, as well as stimulation of dopamine turnover in mice over-expressing monoamine oxidase B both induce multiple mitochondrial DNA deletions. Our results thus identify Catecholamine Metabolism as the driving force behind mitochondrial DNA deletions, probably being an important factor in the ageing-associated degeneration of dopaminergic neurons.