- Email: [email protected]
ACE inhibitors worsen inflammatory pain
Correspondence / Medical Hypotheses 72 (2009) 753–761 [6] Feldmann RG, Paul NL. Identity of emotional triggers in epilepsy. J Nerv Ment Dis 1976;162:345–53. [7] Goldstein LH. J Neurol Neurosur Psychiat 1997;63:137–42. [8] Beyenburg S, Mitchell AJ, Schmidt D, Elger CE, Reuber M. Anxiety in patients with epilepsy: systematic review and suggestions for clinical management. Epilepsy Behav 2005;7(2):161–71 [September]. [9] de Souza EA, Salgado PC. A psychosocial view of anxiety and depression in epilepsy. Epilepsy Behav 2006 Feb;8(1):232–8.
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Harinder Jaseja G.R. Medical College,Physiology Department, Near Paliwal Health Club, 8, C-Block, Harishanker-Puram, Lashkar, Gwalior, M.P. 474009, India Tel.: +91 751 2631147 E-mail address: [email protected]
doi:10.1016/j.mehy.2009.01.013
ACE inhibitors worsen inflammatory pain High blood pressure is a very frequent pathology in the elderly, as is chronic pain which is often a result of inflammatory disorders such as osteoarthritis. Hence it is not uncommon for elderly patients suffering from painful inflammatory disorders to be taking ACE inhibitors for concomitant high blood pressure. However, use of ACE inhibitors to reduce hypertension in humans and rats decreases pain thresholds independent of the effects on blood pressure [1,2]. Physiologically, this may be because ACE inhibitors enhance the effects of bradykinin on nociceptors at the site of tissue damage thereby worsening pain. Bradykinin is a polypeptide formed in the blood; it is a potent vasodilator of certain blood vessels, increases vascular permeability and most importantly is involved in mediating pain. Intradermal injection of bradykinin in humans produces a dosedependent pain and a heat hyperalgesia, indicating that bradykinin both excites and sensitizes human nociceptors [3]. Local inflammation following tissue damage triggers the release of bradykinin produced by kallikrein mediated enzymatic cleavage of kininogen at the site of tissue injury and inflammation. Once formed bradykinin is degraded by two enzymes carboxypeptidase-N, also known as kininase-1, and angiotensin converting enzyme (ACE), also called kininase-2. ACE removes the C-terminal dipeptide from bradykinin which leads to its inactivation. ACE inhibitors lead to an increase in bradykinin due to decreased degradation and also to a decrease in angiotensin (a vasoconstrictor), for which they are used in the treatment of hypertension.
Degradation of bradykinin by ACE has been studied in cultured human endothelial cells by direct measurement of bradykinin where the half-life was increased 9-fold [4]. ACE inhibitors have also been shown to potentiate the effect of bradykinin on their B2 receptors independently of inhibiting bradykinin breakdown [5]. This has been interpreted as being caused by cross talk between ACE and the B2 receptor. References [1] Guasti L et al. Treatment with enalapril modifies the pain perception pattern in hypertensive patients. Hypertension 1998;31(5):1146–50. [2] Irvine RJ, White JM, Head RJ. The renin angiotensin system and nociception in spontaneously hypertensive rats. Life Sci 1995;56(13):1073–8. [3] Manning DC et al. Pain and hyperalgesia after intradermal injection of bradykinin in humans. Clin Pharmacol Ther 1991;50(6):721–9. [4] Grafe M et al. Effect of angiotensin-converting-enzyme inhibition on bradykinin metabolism by vascular endothelial cells. Am J Physiol 1993;264(5 Pt 2):H1493–7. [5] Erdos EG, Deddish PA, Marcic BM. Potentiation of bradykinin actions by ACE inhibitors. Trends Endocrinol Metab 1999;10(6):223–9.
Alan Fein Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030, United States Tel.: +1 860 679 2263; fax: +1 860 679 1269 E-mail address: [email protected]
doi:10.1016/j.mehy.2009.01.012
Can curry protect the brain from bilirubin toxicity? Unconjugated bilirubin (UCB) is a pigment resulting from the degradation of heme, and deposition of this pigment in the central nervous system (CNS) is the major factor causing bilirubin encephalopathy during severe neonatal hyperbilirubinemia. However, the exact mechanisms of bilirubin encephalopathy still remain unclear. Bilirubin toxicity to neurons has been reported in previous studies, recent studies have described compromised astrocyte function following bilirubin exposure [1]. Relatively high concentrations of bilirubin have been found in the myelin fraction of rat brain after intravenous administration of radiolabelled bilirubin, suggesting that myelin and myelin forming cells might be another target of bilirubin in the CNS [2]. Curcumin (diferuloyl methane), the natural yellow pigment in turmeric, is isolated from the rhizomes of the plant Curcuma longa.
In the South and Southeast Tropical Asian countries, turmeric has been used for centuries as a spice to give the specific flavor and yellow color to curry [3]. We hypothesiesed that curcumin can reduce bilirubin-induced damage in neuronal cells. Short exposure to UCB leads to an increase of extracellular glutamate and highly enhances the release of tumor necrosis factor-a (TNF-a) and interleukin (IL)-1b, while it inhibits the production of IL-6. Moreover, co-incubation with lipopolysaccharide (LPS), used to mimic infection, further enhanced the secretion of proinflammatory cytokines, without changing either the release of glutamate or IL-6 secretion [4]. In vitro studies show that curcumin inhibited LPS induced production of TNF-a, IL-1b and IL-8 by a human monocytic macrophage cell line. For instance, TNF-a induced expression of leukocyte adhesion proteins, such as intercellular adhesion mole-
757
Harinder Jaseja G.R. Medical College,Physiology Department, Near Paliwal Health Club, 8, C-Block, Harishanker-Puram, Lashkar, Gwalior, M.P. 474009, India Tel.: +91 751 2631147 E-mail address: [email protected]
doi:10.1016/j.mehy.2009.01.013
ACE inhibitors worsen inflammatory pain High blood pressure is a very frequent pathology in the elderly, as is chronic pain which is often a result of inflammatory disorders such as osteoarthritis. Hence it is not uncommon for elderly patients suffering from painful inflammatory disorders to be taking ACE inhibitors for concomitant high blood pressure. However, use of ACE inhibitors to reduce hypertension in humans and rats decreases pain thresholds independent of the effects on blood pressure [1,2]. Physiologically, this may be because ACE inhibitors enhance the effects of bradykinin on nociceptors at the site of tissue damage thereby worsening pain. Bradykinin is a polypeptide formed in the blood; it is a potent vasodilator of certain blood vessels, increases vascular permeability and most importantly is involved in mediating pain. Intradermal injection of bradykinin in humans produces a dosedependent pain and a heat hyperalgesia, indicating that bradykinin both excites and sensitizes human nociceptors [3]. Local inflammation following tissue damage triggers the release of bradykinin produced by kallikrein mediated enzymatic cleavage of kininogen at the site of tissue injury and inflammation. Once formed bradykinin is degraded by two enzymes carboxypeptidase-N, also known as kininase-1, and angiotensin converting enzyme (ACE), also called kininase-2. ACE removes the C-terminal dipeptide from bradykinin which leads to its inactivation. ACE inhibitors lead to an increase in bradykinin due to decreased degradation and also to a decrease in angiotensin (a vasoconstrictor), for which they are used in the treatment of hypertension.
Degradation of bradykinin by ACE has been studied in cultured human endothelial cells by direct measurement of bradykinin where the half-life was increased 9-fold [4]. ACE inhibitors have also been shown to potentiate the effect of bradykinin on their B2 receptors independently of inhibiting bradykinin breakdown [5]. This has been interpreted as being caused by cross talk between ACE and the B2 receptor. References [1] Guasti L et al. Treatment with enalapril modifies the pain perception pattern in hypertensive patients. Hypertension 1998;31(5):1146–50. [2] Irvine RJ, White JM, Head RJ. The renin angiotensin system and nociception in spontaneously hypertensive rats. Life Sci 1995;56(13):1073–8. [3] Manning DC et al. Pain and hyperalgesia after intradermal injection of bradykinin in humans. Clin Pharmacol Ther 1991;50(6):721–9. [4] Grafe M et al. Effect of angiotensin-converting-enzyme inhibition on bradykinin metabolism by vascular endothelial cells. Am J Physiol 1993;264(5 Pt 2):H1493–7. [5] Erdos EG, Deddish PA, Marcic BM. Potentiation of bradykinin actions by ACE inhibitors. Trends Endocrinol Metab 1999;10(6):223–9.
Alan Fein Department of Cell Biology, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06030, United States Tel.: +1 860 679 2263; fax: +1 860 679 1269 E-mail address: [email protected]
doi:10.1016/j.mehy.2009.01.012
Can curry protect the brain from bilirubin toxicity? Unconjugated bilirubin (UCB) is a pigment resulting from the degradation of heme, and deposition of this pigment in the central nervous system (CNS) is the major factor causing bilirubin encephalopathy during severe neonatal hyperbilirubinemia. However, the exact mechanisms of bilirubin encephalopathy still remain unclear. Bilirubin toxicity to neurons has been reported in previous studies, recent studies have described compromised astrocyte function following bilirubin exposure [1]. Relatively high concentrations of bilirubin have been found in the myelin fraction of rat brain after intravenous administration of radiolabelled bilirubin, suggesting that myelin and myelin forming cells might be another target of bilirubin in the CNS [2]. Curcumin (diferuloyl methane), the natural yellow pigment in turmeric, is isolated from the rhizomes of the plant Curcuma longa.
In the South and Southeast Tropical Asian countries, turmeric has been used for centuries as a spice to give the specific flavor and yellow color to curry [3]. We hypothesiesed that curcumin can reduce bilirubin-induced damage in neuronal cells. Short exposure to UCB leads to an increase of extracellular glutamate and highly enhances the release of tumor necrosis factor-a (TNF-a) and interleukin (IL)-1b, while it inhibits the production of IL-6. Moreover, co-incubation with lipopolysaccharide (LPS), used to mimic infection, further enhanced the secretion of proinflammatory cytokines, without changing either the release of glutamate or IL-6 secretion [4]. In vitro studies show that curcumin inhibited LPS induced production of TNF-a, IL-1b and IL-8 by a human monocytic macrophage cell line. For instance, TNF-a induced expression of leukocyte adhesion proteins, such as intercellular adhesion mole-