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Cardiovascular Psychiatry and Neurology
Volume 2009 (2009), Article ID 545263, 5 pages
http://dx.doi.org/10.1155/2009/545263
Hypothesis

Receptors as a Transducer in the Co-Occurrence of Neurological/Psychiatric and Cardiovascular Disorders: A Hypothesis

Department of Pharmacology and Anesthesiology, University of Padova, Largo “E.Meneghetti” 2, 35131 Padova, Italy

Received 23 May 2009; Accepted 19 June 2009

Academic Editor: Hari Manev

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.

Abstract

Background. Over-stimulation of the purinergic 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 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-1 , are key players in the pathophysiology of neurological, psychiatric, and cardiovascular diseases. Critically, this premise is based on a role for the receptor in triggering a rise in these cytokines. Given the broad distribution of 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 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 receptor antagonists and their application to limit the co-occurrence of neurological, psychiatric, and cardiovascular disorders.

1. Background

The P2X7 receptor (P2X7R) was originally described in cells of hematopoietic origin, and mediates the influx of Ca2+ and Na+ ions as well as the release of proinflammatory cytokines. P2X7Rs may affect cell death through their ability to regulate the processing and release of interleukin-1 (IL-1 ), a key mediator in neurodegeneration, chronic inflammation, and, perhaps, some psychiatric diseases [1]. There is now ample evidence that elevated IL-1 levels, associated in many cases with P2X7R activation, occur in Alzheimer’s disease, spinal cord injury, proinflammatory tissue trauma, neuropathic and inflammatory pain, and depressive illness. Preliminary, albeit intriguing observations suggest that elevated blood pressure may be associated with polymorphic variations in the P2X7R gene. Collectively, these findings have led us to propose a hypothesis in which the P2X7R is viewed as a common transducer of communication between the nervous, immune, and cardiovascular systems, whereby receptor over-activation may lead to the co-occurrence of neurological and psychiatric disorders with cardiovascular disorders, and vice versa.

2. Presentation of the Hypothesis

2.1. P2X7R as a Transducer in the Co-Occurrence of Neurological/Psychiatric and Cardiovascular Disorders

ATP-sensitive P2X7Rs are localized on cells of hematopoietic lineage including mast cells, erythrocytes, monocytes, peripheral macrophages, dendritic cells, T- and B-lymphocytes, epidermal Langerhans cells, and glial cells in the CNS [2, 3]. Activation of P2X7Rs leads to rapid changes in intracellular calcium concentrations, release of the proinflammatory cytokine IL-1 and following prolonged exposure, the formation of cytotoxic pores in plasma membranes. P2X7Rs could affect IL-1 also via the 5-lipoxygenase pathway; that is, P2X7R activation leads to leukotriene formation (e.g., in astrocytes) [4] and leukotrienes increase IL-1 expression and release [5]. Both the localization and functional consequences of P2X7R activation indicate a role in inflammatory processes. Activated immune cells (lymphocytes) [6], macrophages [7], microglia [8], and platelets [9], and dying cells may release high concentrations of ATP into the extracellular space [10], while extracellular ATP concentrations increase under inflammatory conditions in vivo [11] and in response to tissue trauma [12]. In addition, proinflammatory cytokines and bacterial products upregulate P2X7R expression and increase its sensitivity to extracellular ATP [13].

We hypothesize that proinflammatory cytokines, in particular IL-1 , are key players in the pathophysiology of neurological, psychiatric, and cardiovascular diseases. Critically, this premise is based on a role for the P2X7R in triggering a rise in these cytokines. One of the most striking features of ATP is its unmatched ability to promote massive release of mature IL-1 from lipopolysaccaride primed mononuclear phagocytes and other cell types, including microglia [14]. ATP-driven maturation and release of IL-1 are specifically mediated by the P2X7 receptor for extracellular ATP [15, 16]. Given the broad distribution of P2X7Rs in nervous, immune, and vascular tissue cells, this receptor is proposed as playing a common transductional role in linking the nervous, immune, and cardiovascular systems. We also hypothesize that P2X7R over-activation may lead to the co-occurrence of neurological and psychiatric disorders with cardiovascular disorders (Figure 1).

545263.fig.001
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 P2X7 purinergic receptor plays a pivotal role in linking these disorders, as a result of elevated levels of extracellular ATP and the release of proinflammatory cytokines such as interleukin-1 (IL-1 ) and tumor necrosis factor- (TNF- ). AD, Alzheimer's disease.

These speculative hypotheses are based on an extensive body of published studies describing proinflammatory cytokine elevations and P2X7R over-activity in neurodegenerative diseases, pain, depression, and cardiovascular disease. Activation of P2X7Rs provides an inflammatory stimulus [17], and P2X7R-deficient mice have substantially attenuated inflammatory responses [15, 18]. Acute spinal cord injuries produce highly inflammatory environments [19]. In rats subjected to spinal cord injury, areas surrounding the traumatic lesion displayed an abnormally high and sustained pattern of ATP release, and delivery of a P2X7R antagonist after acute impact injury improved functional recovery and diminished cell death in the peritraumatic zone [20]. P2X7R-like immunoreactivity was upregulated around -amyloid plaques in a transgenic mouse model of Alzheimer's disease, and was regionally localized with activated microglia and astrocytes [21]. Up-regulation of P2X7Rs on microglia is seen after ischemia in the cerebral cortex of rats [22], and on reactive astrocytes in multiple sclerosis autopsy brain tissue [23]. Genetic and pharmacological approaches have been used to show that P2X7R activation on microglia is necessary for microglial cell-mediated injury of neurons [24].

Phenotypic data from P2X7R null mice provide important evidence for participation of this channel in proinflammatory tissue trauma. There is a lower incidence and severity of collagen antibody-induced arthritis in P2X7R knockout mice [25], and inflammatory and neuropathic hypersensitivity is completely absent to both mechanical and thermal stimuli in these mice [18]. Moreover, P2X7R is upregulated in human dorsal root ganglia and injured nerves obtained from chronic neuropathic pain patients [18]. Endogenous IL-1 levels are increased in the nervous system in response to trauma associated with mechanical damage, ischemia, seizures, and hyperexcitability [26].

There appears to be a strong relationship between depression and immunological dysfunction in depressed patients [27]. Cytokines like IL-1 are suggested to be involved in the pathophysiology of depression, and excessive secretion of macrophage cytokines (IL-1 , tumor necrosis factor- , interferon- ) could be a potential causative factor [28]. Central and systemic administration of proinflammatory cytokines to animals induces “sickness behavior”, which is characterized by many of the physiological and behavioral changes associated with depression [27, 29]. Clinical use of cytokines (e.g., interferon- ) produces depressive-like symptoms that can be attenuated with antidepressant treatment [30], and major depressive illness is associated with significant elevations in the density of microglia and hypersecretion of proinflammatory cytokines, suggesting that the latter could be involved in the etiopathogenesis of depression [3134].

Apoptotic cell death occurs in a number of vascular diseases, including atherosclerosis and hypertension [35]. Shear stress that occurs during changes in blood flow causes a substantial release of ATP from vascular endothelial cells [36]. ATP may also be released from cardiomyocytes in ischemic or hypoxic conditions [37]. P2X7R-associated production of proinflammatory cytokines like tumor necrosis factor- could promote endothelial cell apoptosis [34], and play a role in vascular remodeling in hypertension [38]. P2X receptor channels are involved in transducing aldosterone-mediated signaling in the distal renal tubule and are potential candidate genes for blood pressure regulation [39]. On an intriguing note, there is evidence to suggest that elevated nighttime diastolic blood pressure is associated with single nucleotide polymorphisms of the P2X7R gene [40]. P2X7Rs are expressed in human saphenous vein myocytes [41], and venous diseases may favor conditions allowing P2X7R activation and lysis of venous myocytes. ATP released after hypoxia, stress and inflammation, or membrane damage, conditions found in the vessel wall of varicose veins, may lead to P2X7R-induced pore formation, the disorganization and loss of contractile myocytes in the muscle layers of the media of varicose veins, and venous disease.

Fibroblasts are a key structural element of the arterial wall known to play a major role in atherosclerosis and diabetic angiopathy [42]. Fibroblasts from type-2 diabetes patients are characterized by a hyperactive purinergic loop [43].

3. Testing the Hypothesis

Retrospective studies inform us, for example, that depression is recognized as having high prevalence in several medical conditions including infectious, autoimmune, and neurodegenerative diseases, conditions associated with a proinflammatory status [28, 44]. Increasing evidence now points to a strong relationship between depression and immunological dysfunction in depressed patients, while clinical use of cytokines produces depressive-like symptoms responsive to antidepressant treatment [30]. While depression and cardiovascular comorbidity have been recognized for some time [45], a proinflammatory link has only recently been investigated [46]. Although a first step, these correlations are not definitive proof of our concept. More extensive prospective studies are required to confirm the above, and to investigate whether a link exists 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 cardiovascular complications. This would then need to be followed with a demonstration that pharmacological block of P2X7Rs provides therapeutic benefit in these conditions.

4. Implications of the Hypothesis

If a strong link between neurological, psychiatric and, cardiovascular disorders could be established, then within this framework P2X7R activity can be viewed as playing a common transductional (“gatekeeper”) role in the development of comorbidity between the nervous, immune, and cardiovascular systems. The outcome, if positive, would provide the impetus for further development and clinical application of selective and potent P2X7R antagonists.

References

  1. S. D. Skaper, P. Debetto, and P. Giusti, “P2X7 receptors in neurological and cardiovascular disorders,” Cardiovascular Psychiatry and Neurology. In press.
  2. R. A. North, “Molecular physiology of P2X receptors,” Physiological Reviews, vol. 82, no. 4, pp. 1013–1067, 2002. View at Publisher · View at Google Scholar · View at PubMed
  3. A. Surprenant, F. Rassendren, E. Kawashima, R. A. North, and G. Buell, “The cytolytic P2Z receptor for extracellular ATP identified as a P2X receptor (P2X7 ),” Science, vol. 272, no. 5262, pp. 735–738, 1996. View at Publisher · View at Google Scholar
  4. P. Ballerini, R. Ciccarelli, F. Caciagli, et al., “P2X7 receptor activation in rat brain cultured astrocytes increases the biosynthetic release of cysteinyl leukotrienes,” International Journal of Immunopathology and Pharmacology, vol. 18, no. 3, pp. 417–430, 2005.
  5. E. Porreca, P. Conti, C. Feliciani, et al., “Cysteinyl-leukotriene D4 induced IL-1β expression and release in rat vascular smooth muscle cells,” Atherosclerosis, vol. 115, no. 2, pp. 181–189, 1995. View at Publisher · View at Google Scholar
  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.
  7. A. Sikora, J. Liu, C. Brosnan, G. Buell, I. Chessel, and B. R. Bloom, “Cutting edge: purinergic signaling regulates radical-mediated bacterial killing mechanisms in macrophages through a P2X7-independent mechanism,” Journal of Immunology, vol. 163, no. 2, pp. 558–561, 1999.
  8. D. Ferrari, P. Chiozzi, S. Falzoni, et al., “ATP-mediated cytotoxicity in microglial cells,” Neuropharmacology, vol. 36, no. 9, pp. 1295–1301, 1997. View at Publisher · View at Google Scholar
  9. R. Beigi, E. Kobatake, M. Aizawa, and G. R. Dubyak, “Detection of local ATP release from activated platelets using cell surface-attached firefly luciferase,” American Journal of Physiology, vol. 276, no. 1 45-1, pp. C267–C278, 1999.
  10. G. R. Dubyak and C. el-Moatassim, “Signal transduction via P2-purinergic receptors for extracellular ATP and other nucleotides,” The American Journal of Physiology, vol. 265, no. 3, part 1, pp. C577–606, 1993.
  11. E. R. Lazarowski, R. C. Boucher, and T. K. Harden, “Constitutive release of ATP and evidence for major contribution of ecto-nucleotide pyrophosphatase and nucleoside diphosphokinase to extracellular nucleotide concentrations,” Journal of Biological Chemistry, vol. 275, no. 40, pp. 31061–31068, 2000. View at Publisher · View at Google Scholar · View at PubMed
  12. K. Nieber, D. Eschke, and A. Brand, “Brain hypoxia: effects of ATP and adenosine,” Progress in Brain Research, vol. 120, pp. 287–297, 1999. View at Publisher · View at Google Scholar
  13. B. D. Humphreys and G. R. Dubyak, “Modulation of P2X7 nucleotide receptor expression by pro- and anti-inflammatory stimuli in THP-1 monocytes,” Journal of Leukocyte Biology, vol. 64, no. 2, pp. 265–273, 1998.
  14. F. Di Virgilio, P. Chiozzi, D. Ferrari, et al., “Nucleotide receptors: an emerging family of regulatory molecules in blood cells,” Blood, vol. 97, no. 3, pp. 587–600, 2001. View at Publisher · View at Google Scholar
  15. M. Solle, J. Labasi, D. G. Perregaux, et al., “Altered cytokine production in mice lacking P2X7 receptors,” Journal of Biological Chemistry, vol. 276, no. 1, pp. 125–132, 2001. View at Publisher · View at Google Scholar · View at PubMed
  16. D. Ferrari, C. Pizzirani, E. Adinolfi, et al., “The P2X7 receptor: a key player in IL-1 processing and release,” Journal of Immunology, vol. 176, no. 7, pp. 3877–3883, 2006.
  17. R. Le Feuvre, D. Brough, and N. Rothwell, “Extracellular ATP and P2X7 receptors in neurodegeneration,” European Journal of Pharmacology, vol. 447, no. 2-3, pp. 261–269, 2002. View at Publisher · View at Google Scholar
  18. I. P. Chessell, J. P. Hatcher, C. Bountra, et al., “Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain,” Pain, vol. 114, no. 3, pp. 386–396, 2005. View at Publisher · View at Google Scholar · View at PubMed
  19. R. W. Keane, A. R. Davis, and W. D. Dietrich, “Inflammatory and apoptotic signaling after spinal cord injury,” Journal of Neurotrauma, vol. 23, no. 3-4, pp. 335–344, 2006. View at Publisher · View at Google Scholar · View at PubMed
  20. X. Wang, G. Arcuino, T. Takano, et al., “P2X7 receptor inhibition improves recovery after spinal cord injury,” Nature Medicine, vol. 10, no. 8, pp. 821–827, 2004. View at Publisher · View at Google Scholar · View at PubMed
  21. L. K. Parvathenani, S. Tertyshnikova, C. R. Greco, S. B. Roberts, B. Robertson, and R. Posmantur, “P2X7 mediates superoxide production in primary microglia and is up-regulated in a transgenic mouse model of Alzheimer's disease,” Journal of Biological Chemistry, vol. 278, no. 15, pp. 13309–13317, 2003. View at Publisher · View at Google Scholar · View at PubMed
  22. H. Franke, A. Günther, J. Grosche, et al., “P2X7 receptor expression after ischemia in the cerebral cortex of rats,” Journal of Neuropathology and Experimental Neurology, vol. 63, no. 7, pp. 686–699, 2004.
  23. L. Narcisse, E. Scemes, Y. Zhao, S. C. Lee, and C. F. Brosnan, “The cytokine IL-1β transiently enhances P2X7 receptor expression and function in human astrocytes,” GLIA, vol. 49, no. 2, pp. 245–258, 2005. View at Publisher · View at Google Scholar · View at PubMed
  24. S. D. Skaper, L. Facci, A. A. Culbert, et al., “P2X7 receptors on microglial cells mediate injury to cortical neurons in vitro,” GLIA, vol. 54, no. 3, pp. 234–242, 2006. View at Publisher · View at Google Scholar · View at PubMed
  25. J. M. Labasi, N. Petrushova, C. Donovan, et al., “Absence of the P2X7 receptor alters leukocyte function and attenuates an inflammatory response,” Journal of Immunology, vol. 168, no. 12, pp. 6436–6445, 2002.
  26. O. Touzani, H. Boutin, J. Chuquet, and N. Rothwell, “Potential mechanisms of interleukin-1 involvement in cerebral ischaemia,” Journal of Neuroimmunology, vol. 100, no. 1-2, pp. 203–215, 1999. View at Publisher · View at Google Scholar
  27. H. Anisman and Z. Merali, “Cytokines, stress, and depressive illness,” Brain, Behavior, and Immunity, vol. 16, no. 5, pp. 513–524, 2002. View at Publisher · View at Google Scholar
  28. R. S. Smith, “The macrophage theory of depression,” Medical Hypotheses, vol. 35, no. 4, pp. 298–306, 1991. View at Publisher · View at Google Scholar
  29. H. Anisman, Z. Merali, M. O. Poulter, and S. Hayley, “Cytokines as a precipitant of depressive illness: animal and human studies,” Current Pharmaceutical Design, vol. 11, no. 8, pp. 963–972, 2005. View at Publisher · View at Google Scholar
  30. M. R. Kraus, A. Schäfer, H. Faller, H. Csef, and M. Scheurlen, “Paroxetine for the treatment of interferon-α-induced depression in chronic hepatitis C,” Alimentary Pharmacology and Therapeutics, vol. 16, no. 6, pp. 1091–1099, 2002. View at Publisher · View at Google Scholar
  31. J. Steiner, H. Bielau, R. Brisch, et al., “Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide,” Journal of Psychiatric Research, vol. 42, no. 2, pp. 151–157, 2008. View at Publisher · View at Google Scholar · View at PubMed
  32. M. Maes, “Major depression and activation of the inflammatory response system,” Advances in Experimental Medicine and Biology, vol. 461, pp. 25–46, 1999. View at Publisher · View at Google Scholar
  33. C. Tuglu, S. H. Kara, O. Caliyurt, E. Vardar, and E. Abay, “Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder,” Psychopharmacology, vol. 170, no. 4, pp. 429–433, 2003. View at Publisher · View at Google Scholar · View at PubMed
  34. S. Alesci, P. E. Martinez, S. Kelkar, et al., “Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 5, pp. 2522–2530, 2005. View at Publisher · View at Google Scholar · View at PubMed
  35. Z. Mallat and A. Tedgui, “Apoptosis in the vasculature: mechanisms and functional importance,” British Journal of Pharmacology, vol. 130, no. 5, pp. 947–962, 2000. View at Publisher · View at Google Scholar · View at PubMed
  36. G. Burnstock, “Release of vasoactive substances from endothelial cells by shear stress and purinergic mechanosensory transduction,” Journal of Anatomy, vol. 194, no. 3, pp. 335–342, 1999. View at Publisher · View at Google Scholar
  37. A. K. Dutta, R. Z. Sabirov, H. Uramoto, and Y. Okada, “Role of ATP-conductive anion channel in ATP release from neonatal rat cardiomyocytes in ischaemic or hypoxic conditions,” Journal of Physiology, vol. 559, no. 3, pp. 799–812, 2004. View at Publisher · View at Google Scholar · View at PubMed
  38. G. H. Gibbons, “Autocrine-paracrine factors and vascular remodeling in hypertension,” Current Opinion in Nephrology and Hypertension, vol. 2, no. 2, pp. 291–298, 1993. View at Publisher · View at Google Scholar
  39. Y. Zhang, D. Sanchez, J. Gorelik, et al., “Basolateral P2X4-like receptors regulate the extracellular ATP-stimulated epithelial Na+ channel activity in renal epithelia,” American Journal of Physiology, vol. 292, no. 6, pp. F1734–F1740, 2007. View at Publisher · View at Google Scholar · View at PubMed
  40. J. Palomino-Doza, T. J. Rahman, P. J. Avery, et al., “Ambulatory blood pressure is associated with polymorphic variation in P2X receptor genes,” Hypertension, vol. 52, no. 5, pp. 980–985, 2008. View at Publisher · View at Google Scholar · View at PubMed
  41. C. Cario-Toumaniantz, G. Loirand, A. Ladoux, and P. Pacaud, “P2X7 receptor activation-induced contraction and lysis in human saphenous vein smooth muscle,” Circulation Research, vol. 83, no. 2, pp. 196–203, 1998.
  42. E. Duner, F. Di Virgilio, R. Trevisan, M. R. Cipollina, G. Crepaldi, and R. Nosadini, “Intracellular free calcium abnormalities in fibroblasts from non-insulin-dependent diabetic patients with and without arterial hypertension,” Hypertension, vol. 29, no. 4, pp. 1007–1013, 1997.
  43. A. Solini, P. Chiozzi, A. Morelli, et al., “Enhanced P2X7 activity in human fibroblasts from diabetic patients: a possible pathogenetic mechanism for vascular damage in diabetes,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 7, pp. 1240–1245, 2004. View at Publisher · View at Google Scholar · View at PubMed
  44. M. Maes, “Evidence for an immune response in major depression: a review and hypothesis,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 19, no. 1, pp. 11–38, 1995. View at Publisher · View at Google Scholar
  45. A. H. Glassman, “Depression and cardiovascular comorbidity,” Dialogues in Clinical Neuroscience, vol. 9, no. 1, pp. 9–17, 2007.
  46. J. C. Stewart, K. L. Rand, M. F. Muldoon, and T. W. Kamarck, “A prospective evaluation of the directionality of the depression-inflammation relationship,” Brain, Behavior, and Immunity. In press. View at Publisher · View at Google Scholar · View at PubMed