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P 2 Hindawi Publishing Corporation Cardiovascular Psychiatry and Neurology Volume 2009, Article ID 545263, 5 pages doi:10.1155/2009/545263 Hypothesis P2X Receptors as a Transducer in the Co-Occurrence of Neurological/Psychiatric and Cardiovascular Disorders: A Hypothesis Stephen D. Skaper and Pietro Giusti Department of Pharmacology and Anesthesiology, University of Padova, Largo “E.Meneghetti” 2, 35131 Padova, Italy Correspondence should be addressed to Stephen D. Skaper, stephen.skaper@unipd.it Received 23 May 2009; Accepted 19 June 2009 Recommended by Hari Manev Background. Over-stimulation of the purinergic P2X receptor may bring about cellular dysfunction and injury in settings of neurodegeneration, chronic inflammation, as well as in psychiatric and cardiovascular diseases. Here we speculate how P2X receptor over-activation may lead to the co-occurrence of neurological and psychiatric disorders with cardiovascular disorders. Presentation. We hypothesize that proinflammatory cytokines, in particular interleukin-1β, are key players in the pathophysiology of neurological, psychiatric, and cardiovascular diseases. Critically, this premise is based on a role for the P2X receptor in triggering a rise in these cytokines. Given the broad distribution of P2X receptors in nervous, immune, and vascular tissue cells, this receptor is proposed as central in linking the nervous, immune, and cardiovascular systems. Testing. Investigate, retrospectively, whether a bidirectional link can be established between illnesses with a proinflammatory component (e.g., inflammatory and chronic neuropathic pain) and cardiovascular disease, for example, hypertension, and whether patients treated with anti-inflammatory drugs have a lower incidence of disease complications. Positive outcome would indicate a prospective study to evaluate therapeutic efficacy of P2X receptor antagonists. Implications. It should be stressed that sufficient direct evidence does not exist at present supporting our hypothesis. However, a positive outcome would encourage the further development of P2X receptor antagonists and their application to limit the co-occurrence of neurological, psychiatric, and cardiovascular disorders. Copyright © 2009 S. D. Skaper and P. Giusti. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1. Background as a common transducer of communication between the nervous, immune, and cardiovascular systems, whereby The P2X receptor (P2X R) was originally described in cells 7 7 receptor over-activation may lead to the co-occurrence of 2+ of hematopoietic origin, and mediates the influx of Ca and neurological and psychiatric disorders with cardiovascular Na ions as well as the release of proinflammatory cytokines. disorders, and vice versa. P2X Rs may affect cell death through their ability to regulate the processing and release of interleukin-1β (IL-1β), a key mediator in neurodegeneration, chronic inflammation, and, 2. Presentation of the Hypothesis perhaps, some psychiatric diseases [1]. Thereisnow ample evidence that elevated IL-1β levels, associated in many cases 2.1. P2X R as a Transducer in the Co-Occurrence of Neurolog- with P2X R activation, occur in Alzheimer’s disease, spinal ical/Psychiatric and Cardiovascular Disorders. ATP-sensitive cord injury, proinflammatory tissue trauma, neuropathic P2X Rs are localized on cells of hematopoietic lineage and inflammatory pain, and depressive illness. Preliminary, including mast cells, erythrocytes, monocytes, peripheral albeit intriguing observations suggest that elevated blood macrophages, dendritic cells, T- and B-lymphocytes, epider- pressure may be associated with polymorphic variations in mal Langerhans cells, and glial cells in the CNS [2, 3]. Activa- the P2X R gene. Collectively, these findings have led us tion of P2X Rs leads to rapid changes in intracellular calcium 7 7 to propose a hypothesis in which the P2X Risviewed concentrations, release of the proinflammatory cytokine 7 2 Cardiovascular Psychiatry and Neurology Neurological disorders (AD, spinal cord injury, tissue trauma) ATP P2X R Glial or endothelial cell IL-1β,TNF-α Progressive Cardiovascular Psychiatric disorders neurodegeneration, disorders (depression) neuropathic & chronic inflammatory pain Figure 1: Schematic representation of potential interactions between the cardiovascular and nervous systems, which may lead to the co- occurrence of cardiovascular, neurological, and psychiatric disorders. In this hypothesis, the P2X purinergic receptor plays a pivotal role in linking these disorders, as a result of elevated levels of extracellular ATP and the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β)and tumornecrosisfactor-α (TNF-α). AD, Alzheimer’s disease. IL-1β and following prolonged exposure, the formation of These speculative hypotheses are based on an extensive cytotoxic pores in plasma membranes. P2X Rs could affect body of published studies describing pro-inflammatory IL-1β also via the 5-lipoxygenase pathway; that is, P2X R cytokine elevations and P2X R over-activity in neurodegen- 7 7 activation leads to leukotriene formation (e.g., in astrocytes) erative diseases, pain, depression, and cardiovascular disease. [4] and leukotrienes increase IL-1β expression and release Activation of P2X Rs provides an inflammatory stimulus [5]. Both the localization and functional consequences of [17], and P2X R-deficient mice have substantially attenuated P2X R activation indicate a role in inflammatory processes. inflammatory responses [15, 18]. Acute spinal cord injuries Activated immune cells (lymphocytes) [6], macrophages [7], produce highly inflammatory environments [19]. In rats microglia [8], and platelets [9], and dying cells may release subjected to spinal cord injury, areas surrounding the high concentrations of ATP into the extracellular space traumatic lesion displayed an abnormally high and sustained [10], while extracellular ATP concentrations increase under pattern of ATP release, and delivery of a P2X R antagonist inflammatory conditions in vivo [11] and in response to after acute impact injury improved functional recovery and tissue trauma [12]. In addition, pro-inflammatory cytokines diminished cell death in the peritraumatic zone [20]. P2X R- and bacterial products upregulate P2X R expression and like immunoreactivity was upregulated around β-amyloid increase its sensitivity to extracellular ATP [13]. plaques in a transgenic mouse model of Alzheimer’s disease, We hypothesize that pro-inflammatory cytokines, in and was regionally localized with activated microglia and particular IL-1β, are key players in the pathophysiology astrocytes [21]. Up-regulation of P2X Rs on microglia is seen of neurological, psychiatric, and cardiovascular diseases. after ischemia in the cerebral cortex of rats [22], and on Critically, this premise is based on a role for the P2X Rin reactive astrocytes in multiple sclerosis autopsy brain tissue triggering a rise in these cytokines. One of the most striking [23]. Genetic and pharmacological approaches have been features of ATP is its unmatched ability to promote massive used to show that P2X R activation on microglia is necessary release of mature IL-1β from lipopolysaccaride primed for microglial cell-mediated injury of neurons [24]. mononuclear phagocytes and other cell types, including Phenotypic data from P2X R null mice provide impor- microglia [14]. ATP-driven maturation and release of IL- tant evidence for participation of this channel in pro- 1β are specifically mediated by the P2X receptor for inflammatory tissue trauma. There is a lower incidence and extracellular ATP [15, 16]. Given the broad distribution of severity of collagen antibody-induced arthritis in P2X R P2X Rs in nervous, immune, and vascular tissue cells, this knockout mice [25], and inflammatory and neuropathic receptor is proposed as playing a common transductional hypersensitivity is completely absent to both mechanical role in linking the nervous, immune, and cardiovascular and thermal stimuli in these mice [18]. Moreover, P2X R systems. We also hypothesize that P2X R over-activation may is upregulated in human dorsal root ganglia and injured lead to the co-occurrence of neurological and psychiatric nerves obtained from chronic neuropathic pain patients [18]. disorders with cardiovascular disorders (Figure 1). Endogenous IL-1 levels are increased in the nervous system Cardiovascular Psychiatry and Neurology 3 in response to trauma associated with mechanical damage, to antidepressant treatment [30]. While depression and ischemia, seizures, and hyperexcitability [26]. cardiovascular comorbidity have been recognized for some There appears to be a strong relationship between depres- time [45], a proinflammatory link has only recently been sion and immunological dysfunction in depressed patients investigated [46]. Although a first step, these correlations [27]. Cytokines like IL-1β are suggested to be involved in are not definitive proof of our concept. More extensive the pathophysiology of depression, and excessive secretion prospective studies are required to confirm the above, of macrophage cytokines (IL-1β, tumor necrosis factor-α, and to investigate whether a link exists between illnesses interferon-γ) could be a potential causative factor [28]. with a proinflammatory component (e.g., inflammatory Central and systemic administration of proinflammatory and chronic neuropathic pain) and cardiovascular disease, cytokines to animals induces “sickness behavior”, which for example, hypertension, and whether patients treated is characterized by many of the physiological and behav- with anti-inflammatory drugs have a lower incidence of ioral changes associated with depression [27, 29]. Clinical cardiovascular complications. This would then need to use of cytokines (e.g., interferon-α) produces depressive- be followed with a demonstration that pharmacological like symptoms that can be attenuated with antidepressant block of P2X Rs provides therapeutic benefit in these treatment [30], and major depressive illness is associated conditions. with significant elevations in the density of microglia and hypersecretion of proinflammatory cytokines, suggesting 4. Implications of the Hypothesis that the latter could be involved in the etiopathogenesis of depression [31–34]. If a strong link between neurological, psychiatric and, Apoptotic cell death occurs in a number of vascular cardiovascular disorders could be established, then within diseases, including atherosclerosis and hypertension [35]. this framework P2X R activity can be viewed as playing a Shear stress that occurs during changes in blood flow causes common transductional (“gatekeeper”) role in the develop- a substantial release of ATP from vascular endothelial cells ment of comorbidity between the nervous, immune, and [36]. ATP may also be released from cardiomyocytes in cardiovascular systems. The outcome, if positive, would ischemic or hypoxic conditions [37]. P2X R-associated pro- provide the impetus for further development and clinical duction of proinflammatory cytokines like tumor necrosis application of selective and potent P2X R antagonists. factor-α could promote endothelial cell apoptosis [34], and play a role in vascular remodeling in hypertension [38]. P2X References receptor channels are involved in transducing aldosterone- mediated signaling in the distal renal tubule and are potential [1] S.D.Skaper, P. Debetto, andP.Giusti, “P2X receptors candidate genes for blood pressure regulation [39]. On an in neurological and cardiovascular disorders,” Cardiovascular intriguing note, there is evidence to suggest that elevated Psychiatry and Neurology. In press. nighttime diastolic blood pressure is associated with single [2] R. A. North, “Molecular physiology of P2X receptors,” Physio- nucleotide polymorphisms of the P2X R gene [40]. P2X Rs 7 7 logical Reviews, vol. 82, no. 4, pp. 1013–1067, 2002. are expressed in human saphenous vein myocytes [41], [3] A. Surprenant, F. Rassendren, E. Kawashima, R. A. North, and and venous diseases may favor conditions allowing P2X R G. Buell, “The cytolytic P receptor for extracellular ATP 7 2Z identified as a P2X receptor (P2X ),” Science, vol. 272, no. activation and lysis of venous myocytes. ATP released after 7 5262, pp. 735–738, 1996. hypoxia, stress and inflammation, or membrane damage, [4] P. Ballerini, R. Ciccarelli, F. Caciagli, et al., “P2X7 receptor conditions found in the vessel wall of varicose veins, may lead activation in rat brain cultured astrocytes increases the to P2X R-induced pore formation, the disorganization and biosynthetic release of cysteinyl leukotrienes,” International loss of contractile myocytes in the muscle layers of the media Journal of Immunopathology and Pharmacology, vol. 18, no. 3, of varicose veins, and venous disease. pp. 417–430, 2005. Fibroblasts are a key structural element of the arterial [5] E. Porreca, P. Conti, C. Feliciani, et al., “Cysteinyl-leukotriene wall known to play a major role in atherosclerosis and D4 induced IL-1β expression and release in rat vascular diabetic angiopathy [42]. Fibroblasts from type-2 diabetes smooth muscle cells,” Atherosclerosis, vol. 115, no. 2, pp. 181– patients are characterized by a hyperactive purinergic loop 189, 1995. [43]. [6] A. Filippini, R. E. Taffs, T. Agui, and M. V. Sitkovsky, “Ecto- ATPase activity in cytolytic T-lymphocytes. Protection from the cytolytic effects of extracellular ATP,” Journal of Biological Chemistry, vol. 265, no. 1, pp. 334–340, 1990. 3. Testing the Hypothesis [7] A. Sikora, J. Liu, C. Brosnan, G. Buell, I. Chessel, and B. R. Bloom, “Cutting edge: purinergic signaling reg- Retrospective studies inform us, for example, that depression ulates radical-mediated bacterial killing mechanisms in is recognized as having high prevalence in several medical macrophages through a P2X -independent mechanism,” Jour- conditions including infectious, autoimmune, and neurode- nal of Immunology, vol. 163, no. 2, pp. 558–561, 1999. generative diseases, conditions associated with a proinflam- [8] D. Ferrari, P. Chiozzi, S. Falzoni, et al., “ATP-mediated matory status [28, 44]. Increasing evidence now points to a cytotoxicity in microglial cells,” Neuropharmacology, vol. 36, strong relationship between depression and immunological no. 9, pp. 1295–1301, 1997. dysfunction in depressed patients, while clinical use of [9] R. Beigi, E. Kobatake, M. Aizawa, and G. R. Dubyak, cytokines produces depressive-like symptoms responsive “Detection of local ATP release from activated platelets using 4 Cardiovascular Psychiatry and Neurology cell surface-attached firefly luciferase,” American Journal of [27] H. Anisman and Z. Merali, “Cytokines, stress, and depressive Physiology, vol. 276, no. 1 45-1, pp. C267–C278, 1999. illness,” Brain, Behavior, and Immunity, vol. 16, no. 5, pp. 513– [10] G. R. Dubyak and C. el-Moatassim, “Signal transduction 524, 2002. via P2-purinergic receptors for extracellular ATP and other [28] R. S. Smith, “The macrophage theory of depression,” Medical nucleotides,” The American Journal of Physiology, vol. 265, no. Hypotheses, vol. 35, no. 4, pp. 298–306, 1991. 3, part 1, pp. C577–606, 1993. [29] H. Anisman, Z. Merali, M. O. Poulter, and S. Hayley, [11] E. R. Lazarowski, R. C. Boucher, and T. K. Harden, “Consti- “Cytokines as a precipitant of depressive illness: animal and tutive release of ATP and evidence for major contribution of human studies,” Current Pharmaceutical Design, vol. 11, no. 8, ecto-nucleotide pyrophosphatase and nucleoside diphospho- pp. 963–972, 2005. kinase to extracellular nucleotide concentrations,” Journal of [30] M. R. Kraus, A. Schafer ¨ , H. Faller, H. Csef, and M. Scheurlen, Biological Chemistry, vol. 275, no. 40, pp. 31061–31068, 2000. “Paroxetine for the treatment of interferon-α-induced depres- [12] K. Nieber, D. Eschke, and A. Brand, “Brain hypoxia: effects of sion in chronic hepatitis C,” Alimentary Pharmacology and ATP and adenosine,” Progress in Brain Research, vol. 120, pp. Therapeutics, vol. 16, no. 6, pp. 1091–1099, 2002. 287–297, 1999. [31] J. Steiner, H. Bielau, R. Brisch, et al., “Immunological aspects [13] B. D. Humphreys and G. R. Dubyak, “Modulation of P2X in the neurobiology of suicide: elevated microglial density nucleotide receptor expression by pro- and anti-inflammatory in schizophrenia and depression is associated with suicide,” stimuli in THP-1 monocytes,” Journal of Leukocyte Biology, vol. Journal of Psychiatric Research, vol. 42, no. 2, pp. 151–157, 64, no. 2, pp. 265–273, 1998. 2008. [14] F. Di Virgilio, P. Chiozzi, D. Ferrari, et al., “Nucleotide [32] M. Maes, “Major depression and activation of the inflamma- receptors: an emerging family of regulatory molecules in blood tory response system,” Advances in Experimental Medicine and cells,” Blood, vol. 97, no. 3, pp. 587–600, 2001. Biology, vol. 461, pp. 25–46, 1999. [15] M. Solle, J. Labasi, D. G. Perregaux, et al., “Altered cytokine [33] C. Tuglu, S. H. Kara, O. Caliyurt, E. Vardar, and E. Abay, production in mice lacking P2X receptors,” Journal of Biolog- “Increased serum tumor necrosis factor-alpha levels and ical Chemistry, vol. 276, no. 1, pp. 125–132, 2001. treatment response in major depressive disorder,” Psychophar- [16] D. Ferrari, C. Pizzirani, E. Adinolfi, et al., “The P2X receptor: macology, vol. 170, no. 4, pp. 429–433, 2003. a key player in IL-1 processing and release,” Journal of [34] S. Alesci, P. E. Martinez, S. Kelkar, et al., “Major depression Immunology, vol. 176, no. 7, pp. 3877–3883, 2006. is associated with significant diurnal elevations in plasma [17] R. Le Feuvre, D. Brough, and N. Rothwell, “Extracellular ATP interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implica- and P2X7 receptors in neurodegeneration,” European Journal of Pharmacology, vol. 447, no. 2-3, pp. 261–269, 2002. tions,” Journal of Clinical Endocrinology and Metabolism, vol. [18] I. P. Chessell, J. P. Hatcher, C. Bountra, et al., “Disruption of 90, no. 5, pp. 2522–2530, 2005. the P2X purinoceptor gene abolishes chronic inflammatory [35] Z. Mallat and A. Tedgui, “Apoptosis in the vasculature: and neuropathic pain,” Pain, vol. 114, no. 3, pp. 386–396, 2005. mechanisms and functional importance,” British Journal of [19] R. W. Keane, A. R. Davis, and W. D. Dietrich, “Inflammatory Pharmacology, vol. 130, no. 5, pp. 947–962, 2000. and apoptotic signaling after spinal cord injury,” Journal of [36] G. Burnstock, “Release of vasoactive substances from endothe- Neurotrauma, vol. 23, no. 3-4, pp. 335–344, 2006. lial cells by shear stress and purinergic mechanosensory [20] X. Wang, G. Arcuino, T. Takano, et al., “P2X receptor transduction,” Journal of Anatomy, vol. 194, no. 3, pp. 335– inhibition improves recovery after spinal cord injury,” Nature 342, 1999. Medicine, vol. 10, no. 8, pp. 821–827, 2004. [37] A. K. Dutta,R.Z.Sabirov,H.Uramoto,and Y. Okada,“Role of [21] L. K. Parvathenani, S. Tertyshnikova, C. R. Greco, S. B. ATP-conductive anion channel in ATP release from neonatal Roberts, B. Robertson, and R. Posmantur, “P2X mediates rat cardiomyocytes in ischaemic or hypoxic conditions,” Journal of Physiology, vol. 559, no. 3, pp. 799–812, 2004. superoxide production in primary microglia and is up- regulated in a transgenic mouse model of Alzheimer’s disease,” [38] G. H. Gibbons, “Autocrine-paracrine factors and vascular remodeling in hypertension,” Current Opinion in Nephrology Journal of Biological Chemistry, vol. 278, no. 15, pp. 13309– 13317, 2003. and Hypertension, vol. 2, no. 2, pp. 291–298, 1993. [22] H. Franke, A. Gunther ¨ , J. Grosche, et al., “P2X receptor [39] Y. Zhang, D. Sanchez, J. Gorelik, et al., “Basolateral P2X -like expression after ischemia in the cerebral cortex of rats,” Journal receptors regulate the extracellular ATP-stimulated epithelial of Neuropathology and Experimental Neurology, vol. 63, no. 7, Na channel activity in renal epithelia,” American Journal of pp. 686–699, 2004. Physiology, vol. 292, no. 6, pp. F1734–F1740, 2007. [23] L. Narcisse, E. Scemes, Y. Zhao, S. C. Lee, and C. F. Brosnan, [40] J. Palomino-Doza, T. J. Rahman, P. J. Avery, et al., “Ambulatory “The cytokine IL-1β transiently enhances P2X receptor blood pressure is associated with polymorphic variation in expression and function in human astrocytes,” GLIA, vol. 49, P2X receptor genes,” Hypertension, vol. 52, no. 5, pp. 980–985, no. 2, pp. 245–258, 2005. [24] S. D. Skaper, L. Facci, A. A. Culbert, et al., “P2X receptors [41] C. Cario-Toumaniantz, G. Loirand, A. Ladoux, and P. Pacaud, “P2X receptor activation-induced contraction and lysis in on microglial cells mediate injury to cortical neurons in vitro,” GLIA, vol. 54, no. 3, pp. 234–242, 2006. human saphenous vein smooth muscle,” Circulation Research, vol. 83, no. 2, pp. 196–203, 1998. [25] J. M. Labasi, N. Petrushova, C. Donovan, et al., “Absence of the P2X receptor alters leukocyte function and attenuates an [42] E. Duner, F. Di Virgilio, R. Trevisan, M. R. Cipollina, G. Crepaldi, and R. Nosadini, “Intracellular free calcium abnor- inflammatory response,” Journal of Immunology, vol. 168, no. 12, pp. 6436–6445, 2002. malities in fibroblasts from non-insulin-dependent diabetic [26] O. Touzani, H. Boutin, J. Chuquet, and N. Rothwell, “Poten- patients with and without arterial hypertension,” Hyperten- tial mechanisms of interleukin-1 involvement in cerebral sion, vol. 29, no. 4, pp. 1007–1013, 1997. ischaemia,” Journal of Neuroimmunology, vol. 100, no. 1-2, pp. [43] A. Solini, P. Chiozzi, A. Morelli, et al., “Enhanced P2X 203–215, 1999. activity in human fibroblasts from diabetic patients: a possible Cardiovascular Psychiatry and Neurology 5 pathogenetic mechanism for vascular damage in diabetes,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 7, pp. 1240–1245, 2004. [44] M. Maes, “Evidence for an immune response in major dep- ression: a review and hypothesis,” Progress in Neuro- Psychopharmacology and Biological Psychiatry, vol. 19, no. 1, pp. 11–38, 1995. [45] A. H. Glassman, “Depression and cardiovascular comorbid- ity,” Dialogues in Clinical Neuroscience, vol. 9, no. 1, pp. 9–17, [46] J. C. Stewart, K. L. Rand, M. F. Muldoon, and T. W. Ka- marck, “A prospective evaluation of the directionality of the depression-inflammation relationship,” Brain, Behavior, and Immunity. In press. 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Hindawi Publishing Corporation
Copyright
Copyright © 2009 Stephen D. Skaper and Pietro Giusti. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2009/545263
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Abstract

Hindawi Publishing Corporation Cardiovascular Psychiatry and Neurology Volume 2009, Article ID 545263, 5 pages doi:10.1155/2009/545263 Hypothesis P2X Receptors as a Transducer in the Co-Occurrence of Neurological/Psychiatric and Cardiovascular Disorders: A Hypothesis Stephen D. Skaper and Pietro Giusti Department of Pharmacology and Anesthesiology, University of Padova, Largo “E.Meneghetti” 2, 35131 Padova, Italy Correspondence should be addressed to Stephen D. Skaper, stephen.skaper@unipd.it Received 23 May 2009; Accepted 19 June 2009 Recommended by Hari Manev Background. Over-stimulation of the purinergic P2X receptor may bring about cellular dysfunction and injury in settings of neurodegeneration, chronic inflammation, as well as in psychiatric and cardiovascular diseases. Here we speculate how P2X receptor over-activation may lead to the co-occurrence of neurological and psychiatric disorders with cardiovascular disorders. Presentation. We hypothesize that proinflammatory cytokines, in particular interleukin-1β, are key players in the pathophysiology of neurological, psychiatric, and cardiovascular diseases. Critically, this premise is based on a role for the P2X receptor in triggering a rise in these cytokines. Given the broad distribution of P2X receptors in nervous, immune, and vascular tissue cells, this receptor is proposed as central in linking the nervous, immune, and cardiovascular systems. Testing. Investigate, retrospectively, whether a bidirectional link can be established between illnesses with a proinflammatory component (e.g., inflammatory and chronic neuropathic pain) and cardiovascular disease, for example, hypertension, and whether patients treated with anti-inflammatory drugs have a lower incidence of disease complications. Positive outcome would indicate a prospective study to evaluate therapeutic efficacy of P2X receptor antagonists. Implications. It should be stressed that sufficient direct evidence does not exist at present supporting our hypothesis. However, a positive outcome would encourage the further development of P2X receptor antagonists and their application to limit the co-occurrence of neurological, psychiatric, and cardiovascular disorders. Copyright © 2009 S. D. Skaper and P. Giusti. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1. Background as a common transducer of communication between the nervous, immune, and cardiovascular systems, whereby The P2X receptor (P2X R) was originally described in cells 7 7 receptor over-activation may lead to the co-occurrence of 2+ of hematopoietic origin, and mediates the influx of Ca and neurological and psychiatric disorders with cardiovascular Na ions as well as the release of proinflammatory cytokines. disorders, and vice versa. P2X Rs may affect cell death through their ability to regulate the processing and release of interleukin-1β (IL-1β), a key mediator in neurodegeneration, chronic inflammation, and, 2. Presentation of the Hypothesis perhaps, some psychiatric diseases [1]. Thereisnow ample evidence that elevated IL-1β levels, associated in many cases 2.1. P2X R as a Transducer in the Co-Occurrence of Neurolog- with P2X R activation, occur in Alzheimer’s disease, spinal ical/Psychiatric and Cardiovascular Disorders. ATP-sensitive cord injury, proinflammatory tissue trauma, neuropathic P2X Rs are localized on cells of hematopoietic lineage and inflammatory pain, and depressive illness. Preliminary, including mast cells, erythrocytes, monocytes, peripheral albeit intriguing observations suggest that elevated blood macrophages, dendritic cells, T- and B-lymphocytes, epider- pressure may be associated with polymorphic variations in mal Langerhans cells, and glial cells in the CNS [2, 3]. Activa- the P2X R gene. Collectively, these findings have led us tion of P2X Rs leads to rapid changes in intracellular calcium 7 7 to propose a hypothesis in which the P2X Risviewed concentrations, release of the proinflammatory cytokine 7 2 Cardiovascular Psychiatry and Neurology Neurological disorders (AD, spinal cord injury, tissue trauma) ATP P2X R Glial or endothelial cell IL-1β,TNF-α Progressive Cardiovascular Psychiatric disorders neurodegeneration, disorders (depression) neuropathic & chronic inflammatory pain Figure 1: Schematic representation of potential interactions between the cardiovascular and nervous systems, which may lead to the co- occurrence of cardiovascular, neurological, and psychiatric disorders. In this hypothesis, the P2X purinergic receptor plays a pivotal role in linking these disorders, as a result of elevated levels of extracellular ATP and the release of pro-inflammatory cytokines such as interleukin-1β (IL-1β)and tumornecrosisfactor-α (TNF-α). AD, Alzheimer’s disease. IL-1β and following prolonged exposure, the formation of These speculative hypotheses are based on an extensive cytotoxic pores in plasma membranes. P2X Rs could affect body of published studies describing pro-inflammatory IL-1β also via the 5-lipoxygenase pathway; that is, P2X R cytokine elevations and P2X R over-activity in neurodegen- 7 7 activation leads to leukotriene formation (e.g., in astrocytes) erative diseases, pain, depression, and cardiovascular disease. [4] and leukotrienes increase IL-1β expression and release Activation of P2X Rs provides an inflammatory stimulus [5]. Both the localization and functional consequences of [17], and P2X R-deficient mice have substantially attenuated P2X R activation indicate a role in inflammatory processes. inflammatory responses [15, 18]. Acute spinal cord injuries Activated immune cells (lymphocytes) [6], macrophages [7], produce highly inflammatory environments [19]. In rats microglia [8], and platelets [9], and dying cells may release subjected to spinal cord injury, areas surrounding the high concentrations of ATP into the extracellular space traumatic lesion displayed an abnormally high and sustained [10], while extracellular ATP concentrations increase under pattern of ATP release, and delivery of a P2X R antagonist inflammatory conditions in vivo [11] and in response to after acute impact injury improved functional recovery and tissue trauma [12]. In addition, pro-inflammatory cytokines diminished cell death in the peritraumatic zone [20]. P2X R- and bacterial products upregulate P2X R expression and like immunoreactivity was upregulated around β-amyloid increase its sensitivity to extracellular ATP [13]. plaques in a transgenic mouse model of Alzheimer’s disease, We hypothesize that pro-inflammatory cytokines, in and was regionally localized with activated microglia and particular IL-1β, are key players in the pathophysiology astrocytes [21]. Up-regulation of P2X Rs on microglia is seen of neurological, psychiatric, and cardiovascular diseases. after ischemia in the cerebral cortex of rats [22], and on Critically, this premise is based on a role for the P2X Rin reactive astrocytes in multiple sclerosis autopsy brain tissue triggering a rise in these cytokines. One of the most striking [23]. Genetic and pharmacological approaches have been features of ATP is its unmatched ability to promote massive used to show that P2X R activation on microglia is necessary release of mature IL-1β from lipopolysaccaride primed for microglial cell-mediated injury of neurons [24]. mononuclear phagocytes and other cell types, including Phenotypic data from P2X R null mice provide impor- microglia [14]. ATP-driven maturation and release of IL- tant evidence for participation of this channel in pro- 1β are specifically mediated by the P2X receptor for inflammatory tissue trauma. There is a lower incidence and extracellular ATP [15, 16]. Given the broad distribution of severity of collagen antibody-induced arthritis in P2X R P2X Rs in nervous, immune, and vascular tissue cells, this knockout mice [25], and inflammatory and neuropathic receptor is proposed as playing a common transductional hypersensitivity is completely absent to both mechanical role in linking the nervous, immune, and cardiovascular and thermal stimuli in these mice [18]. Moreover, P2X R systems. We also hypothesize that P2X R over-activation may is upregulated in human dorsal root ganglia and injured lead to the co-occurrence of neurological and psychiatric nerves obtained from chronic neuropathic pain patients [18]. disorders with cardiovascular disorders (Figure 1). Endogenous IL-1 levels are increased in the nervous system Cardiovascular Psychiatry and Neurology 3 in response to trauma associated with mechanical damage, to antidepressant treatment [30]. While depression and ischemia, seizures, and hyperexcitability [26]. cardiovascular comorbidity have been recognized for some There appears to be a strong relationship between depres- time [45], a proinflammatory link has only recently been sion and immunological dysfunction in depressed patients investigated [46]. Although a first step, these correlations [27]. Cytokines like IL-1β are suggested to be involved in are not definitive proof of our concept. More extensive the pathophysiology of depression, and excessive secretion prospective studies are required to confirm the above, of macrophage cytokines (IL-1β, tumor necrosis factor-α, and to investigate whether a link exists between illnesses interferon-γ) could be a potential causative factor [28]. with a proinflammatory component (e.g., inflammatory Central and systemic administration of proinflammatory and chronic neuropathic pain) and cardiovascular disease, cytokines to animals induces “sickness behavior”, which for example, hypertension, and whether patients treated is characterized by many of the physiological and behav- with anti-inflammatory drugs have a lower incidence of ioral changes associated with depression [27, 29]. Clinical cardiovascular complications. This would then need to use of cytokines (e.g., interferon-α) produces depressive- be followed with a demonstration that pharmacological like symptoms that can be attenuated with antidepressant block of P2X Rs provides therapeutic benefit in these treatment [30], and major depressive illness is associated conditions. with significant elevations in the density of microglia and hypersecretion of proinflammatory cytokines, suggesting 4. Implications of the Hypothesis that the latter could be involved in the etiopathogenesis of depression [31–34]. If a strong link between neurological, psychiatric and, Apoptotic cell death occurs in a number of vascular cardiovascular disorders could be established, then within diseases, including atherosclerosis and hypertension [35]. this framework P2X R activity can be viewed as playing a Shear stress that occurs during changes in blood flow causes common transductional (“gatekeeper”) role in the develop- a substantial release of ATP from vascular endothelial cells ment of comorbidity between the nervous, immune, and [36]. ATP may also be released from cardiomyocytes in cardiovascular systems. The outcome, if positive, would ischemic or hypoxic conditions [37]. P2X R-associated pro- provide the impetus for further development and clinical duction of proinflammatory cytokines like tumor necrosis application of selective and potent P2X R antagonists. factor-α could promote endothelial cell apoptosis [34], and play a role in vascular remodeling in hypertension [38]. 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