Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment?

Neuropsychiatric Disease and Treatment

Volumn 5, Issue 1, 2009, Pages 81-89

  Staines, Donald R ^a,b   Brenu, Ekua W ^b   Marshall Gradisnik, Sonya ^b  

^a QUEENSLAND HEALTH   (Australia)

^b BOND UNIVERSITY   (Australia)

Author keywords

Adenylate cyclase; Chronic fatigue syndrome; Cyclic AMP; Multiple sclerosis; Parkinson's disease; Phosphodiesterase inhibitors; Vasoactive neuropeptides; Virchow Robin spaces

Indexed keywords

ADENYLATE CYCLASE; CYCLIC AMP; HYPOPHYSIS ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE; HYPOPHYSIS ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE RECEPTOR; HYPOPHYSIS ADENYLATE CYCLASE ACTIVATING POLYPEPTIDE RECEPTOR 1; IMIPRAMINE; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 10; PHOSPHODIESTERASE INHIBITOR; ROLIPRAM; VASOACTIVE INTESTINAL POLYPEPTIDE; VASOACTIVE INTESTINAL POLYPEPTIDE RECEPTOR; VASOACTIVE INTESTINAL POLYPEPTIDE RECEPTOR 1; VASOACTIVE INTESTINAL POLYPEPTIDE RECEPTOR 2;

ALLERGIC ENCEPHALOMYELITIS; AMYOTROPHIC LATERAL SCLEROSIS; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; AUTOIMMUNITY; BLOOD BRAIN BARRIER; CHRONIC FATIGUE SYNDROME; CLINICAL TRIAL; DRUG EFFICACY; DRUG INDUCED HEADACHE; HUMAN; IMMUNOMODULATION; IMMUNOPATHOGENESIS; MENTAL DISEASE; MULTIPLE SCLEROSIS; NAUSEA; NEUROIMMUNOLOGY; NEUROPROTECTION; NONHUMAN; PARKINSON DISEASE; REGULATORY T LYMPHOCYTE; REVIEW; VOMITING;

EID: 70449699765     PISSN: 11766328     EISSN: 11782021     Source Type: Journal    
DOI: None     Document Type: Review

References (107)

1. Ghaffar O, Feinstein A. The neuropsychiatry of multiple sclerosis: a review of recent developments. Curr Opin Psychiatry. 2007;20:278-285 (Pubitemid 46588302)
2. Galvin JE. Cognitive change in Parkinson disease. Alzheimer Dis Assoc Disord. 2006;20:302-310
3. Phukan J, Pender NP, Hardiman O. Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol. 2007;6:994-1003. (Pubitemid 47562321)
4. Michiels V, Cluydts R. Neuropsychological functioning in chronic fatigue syndrome: a review. Acta Psychiatr Scand. 2001;103:84-93. (Pubitemid 32147128)
5. Vaudry D, Gonzalez BJ, Basille M, et al. Pituitary adenylate cyclase-activating polypeptide and its receptors: from structure to functions. Pharmacol Rev. 2000;52:269-324. (Pubitemid 30368434)
6. Zhou CJ, Shioda S, Yada T, et al. PACAP and its receptors exert pleiotropic effects in the nervous system by activating multiple signalling pathways. Curr Protein Pept Sci. 2002;3:423-439 (Pubitemid 34778185)
7. Brenneman DE. Neuroprotection: a comparative view of vasoactive intestinal peptide and pituitary adenylate cyclase-activating peptide. Peptides. 2007;28:1720-1726
8. Delgado M, Leceta J, Ganea D. Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the production of inflammatory mediators by activated microglia. J Leukoc Biol. 2003;73:155-164 (Pubitemid 36125686)
9. Igarashi Y, Utsumi H, Chiba H, et al. Glial cell line-derived neurotrophic factor induces barrier function of endothelial cell forming the blood-brain barrier. Biochem Biophys Res Commun. 1999;261:108-112 (Pubitemid 29371626)
10. Baranczyk-Kuzma A, Audus KL, Guillot FL, et al. Effects of selected vasoactive substances on adenylate cyclase activity in brain, isolated brain microvessels and primary cultures of brain microvessel endothelial cells. Neurochem Res. 1992;17:209-214
11. Correale J, Villa A. The blood-brain-barrier in multiple sclerosis: functional roles and therapeutic targeting. Autoimmunity. 2007;40:148-160
12. Rite I, Machado A, Cano J, et al. Blood-brain barrier disruption induces in vivo degeneration of nigral dopaminergic neurons. J Neurochem. 2007;101:1567-1582 (Pubitemid 46848862)
13. Garbuzova-Davis S, Haller E, Saporta S, et al. Ultrastructure of blood-brain barrier and blood-spinal cord barrier in SOD1 mice modelling ALS. Brain Res. 2007;1157:126-137 (Pubitemid 46935078)
14. Ozturk MH, Aydinogoz U. Comparison of MR signal intensities of cerebral perivascular (Virchow-Robin) and subarachnoid spaces. Comput Assist Tomogr. 2002;26:902-904
15. Esiri MM, Gay D. Immunological and neuropathological significance of the Virchow-Robin space. J Neurol Sci. 1990;100(1-2):3-8.
16. Zhang ET, Inman CB, Weller RO. Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J Anat. 1990;170:111-123
17. Bechmann I, Galea I, Perry VH. What is the blood-brain barrier (not)? Trends Immunol. 2007;28:5-11. (Pubitemid 46001619)
18. Becher B, Bechmann I, Greter M. Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognise the brain. J Mol Med. 2006;84:532-543 (Pubitemid 43992845)
19. Takeda N, Murozono M, Watanabe S, et al. Neuroprotective effects of novel derivatives of vasoactive intestinal peptide and pituitary adenylate cyclase-activating peptide in two brain ischemic models on mice. Masui. 2005;54:240-248 (Pubitemid 40515704)
20. Banks WA, Uchida D, Arimura A, et al. Transport of pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier and the prevention of ischemia-induced death of hippocampal neurons. Ann N Y Acad Sci. 1996;805:270-277 (Pubitemid 27058027)
21. Masmoudi-Kouki O, Gandolfo P, Castel H, et al. Role of PACAP and VIP in astroglial functions. Peptides. 2007;28:1753-1760 (Pubitemid 47361428)
22. Vauquelin G, von Mentzer B. 2007. G-protein coupled receptors. Molecular Pharmacology. New Jersey: Wiley.
23. Delgado M, Abad C, Martinez C, et al. PACAP in immunity and inflammation. Ann N Y Acad Sci. 2003;992:141-157
24. Koga S, Morris S, Ogawa S, et al. TNF modulates endothelial properties by decreasing cAMP. Am J Physiol. 1995;268:C1104-13.
25. Tomimoto H, Akiguchi I, Akiyama H, et al. T-cell infiltration and expression of MHC class II antigen by macrophages and microglia in a heterogeneous group in leukoencephalopathy. Am J Pathol. 1993;143:579-586 (Pubitemid 24058213)
26. Zhang ET, Mikkelsen JD, Fahrenkrug J, et al. Prepro-vasoactive intestinal polypeptide-derived peptide sequences in cerebral blood vessels of rats: on the functional anatomy of metabolic autoregulation. J Cereb Blood Flow Metab. 1991;11:932-938
27. Odoardi F, Kawakami N, Klinkert WE, et al. Blood-borne soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease. Proc Natl Acad Sci U S A. 2007;104:18625-18630 (Pubitemid 350210747)
28. Romagnani S. Regulation of the T cell response. Clin Exp Allergy. 2006;36:1357-1366
29. Delgado M, Chorny A, Gonzalez-Rey E, et al. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T cells in vivo. J Leukoc Biol. 2005;78:1327-1338
30. Leceta J, Gomariz RP, Martinez C, et al. Vasoactive intestinal peptide regulates Th17 function in autoimmune inflammation. Neuroimmunomodulation. 2007;14(3-4):134-138 (Pubitemid 350249107)
31. Oukka M. Interplay between pathogenic Th17 and regulatory T cells. Ann Rheum Dis. 2007;66:S87-90. (Pubitemid 350032642)
32. Stromnes IM, Cerretti LM, Liggitt D, et al. Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat Med. 2008;14:337-342 (Pubitemid 351347910)
33. Ricciardelli I, Lindey KJ, Londie M, et al. Anti tumour necrosis-alpha therapy increases the number of FOXP3 (+) regulatory T cells in children affected by Crohn's disease. Immunology. 2008;125:178-183
34. Vandenbark AA, Culbertson NE, Bartholomew RM, et al. Therapeutic vaccination with trivalent T cell receptor (TCR) peptide vaccine restores deficient FoxP3 expression and TCR recognition in subjects with multiple sclerosis. Immunology. 2008;123:66-78.
35. van Horssen J, Bo L, Vos CM, et al. Basement membrane proteins in multiple sclerosis-associated inflammatory cuffs: potential role influx and transport of leukocytes. J Neuropath Exp Neurol. 2005;64:722-729 (Pubitemid 41177113)
36. Gay FW. Early cellular events in multiple sclerosis. Intimations of an extrinsic myelinolytic antigen. Clin Neurol Neurosurg. 2006;108:234-240
37. Gordon TP, Bolstad AI, Rischumeller M, et al. Autoantibodies in primary Sjogren's syndrome: new insights into mechanisms of autoantibody diversification and disease pathogenesis. Autoimmunity. 2001;34:123-132
38. Delgado M, Ganea D. Inhibition of IFN-gamma-induced janus kinase-1-STAT1 activation in macrophages by vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. J Immunol. 2000;165:3051-3057 (Pubitemid 30728155)
39. Broadwell RD, Sofroniew MV. Serum proteins bypass the blood-brain fluid barriers for extracellular entry to the central nervous system. Exp Neurol. 1993;120:245-263
40. Mueller CA, Schluesener HJ, Conard S, et al. Spinal cord injury induces lesional expression of the proinflammatory and antiangiogenic cytokine EMAP II. J Neurotrauma. 2003;20:1007-1015 (Pubitemid 37288560)
41. Shiratori K, Mrowka M, Toussaint A, et al. Extreme unilateral widening of Virchow-Robin spaces: case report. Neuroradiology. 2002;44:990-992 (Pubitemid 36104558)
42. Gross PM, Wall KM, Pang JJ, et al. Microvascular specialization promoting rapid interstitial solute dispersion in nucleus tractus solitarius. Am J Physiol. 1990;259:R1131-8.
43. Gross PM. Morphology and physiology of capillary systems in subregions of the subfornical organ and area postrema. Can J Physiol Pharmacol. 1991;69:1010-1025
44. Nichol KE, Kim R, Cotman CW. Bcl-2 family protein behaviour in frontotemporal dementia implies vascular involvement. Neurology. 2001;56(11 Suppl 4):S35-40. (Pubitemid 32539646)
45. Martin JA, Craft DK, Su JH, et al. Astrocytes degenerate in frontotemporal dementia: possible relation to hypoperfusion. Neurobiol Aging. 2001;22:195-207.
46. Osawa A, Maeshima S, Shimamoto Y, et al. Relationship between cognitive function and regional cerebral blood flow in different types of dementia. Disabil Rehabil. 2004;26:739-745 (Pubitemid 38878406)
47. Patankar YF, Mitra D, Varma A, et al. Dilatation of the Virchow-Robin space is a sensitive indicator of cerebral microvascular disease: study in elderly patients with dementia. AJNR Am J Neuroradiol. 2005;26:1512-1520 (Pubitemid 43733454)
48. Nakano S, Asada T, Yamashita F, et al. Relationship between antisocial behaviour and regional cerebral blood flow in frontotemporal dementia. Neuroimage. 2006;32:301-306 (Pubitemid 44081969)
49. Ichise M, Salit IE, Abbey SE, et al. Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. Nuel Med Commun. 1992;13:767-772
50. Yoshiuchi K, Farakas J, Natelson BH. Patients with chronic fatigue syndrome have reduced absolute cortical blood flow. Clin Physiol Funct Imaging. 2006;26:83-86 (Pubitemid 43337536)
51. Lewis DH, Mayberg HS, Fischer ME, et al. Monozygotic twins discordant for chronic fatigue syndrome: regional cerebral blood flow SPECT. Radiology. 2001;219:766-773
52. Zhou J, Kong H, Hua X, et al. Altered blood-brain barrier integrity in adult aquaporin-4 knockout mice. Neuroreport. 2008;19:1-5. (Pubitemid 351339611)
53. Jarius S, Paul F, Franciotta D, et al. Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica. Nat Clin Pract Neurol. 2008;4:202-214
54. Chu JY, Chung SC Lam AK, et al. Phenotypes developed in secretin receptor-null mice indicated a role for secretion in regulating renal water reabsorption. Mol Cell Biol. 2007;27:2499-2511
55. Lee M, Lee SJ, Choi HJ, et al. Regulation of AQP4 protein expression in rat brain astrocytes: role of P2X7 receptor activation. Brain Res. 2008;1195:1-11.
56. Kausz M, Murai Z, Arimura A, et al. Distribution of pituitary adenylate cyclase activating polypeptide (PACAP) immunoreactive elements in the brain stem of rats studied by immunohistochemistry. Neurobiology (Bp). 1999;7:19-31. (Pubitemid 30353073)
57. Reglodi D, Tamas A, Lubics A, et al. Morphological and functional effects of PACAP in 6-hydroxydopamine-induced lesion of the substantia nigra in rats. Regul Pept. 2004;123(1-3):85-94. (Pubitemid 39424153)
58. Dejda A, Sokolowska P, Nowak JZ. Neuroprotective potential of three neuropeptides PACAP, VIP and PHI. Pharmacol Rep. 2005;57:307-320 (Pubitemid 41030690)
59. Wang G, Qi C, Fan GH, et al. PACAP protects neuronal differentiated PC12 cells against the neurotoxicity induced by a mitochondrial complex 1 inhibitor, rotenone. FEBS Lett. 2005;579:4005-4011 (Pubitemid 40961903)
60. Vaudry D, Pamantung TF, Basille M, et al. PACAP protects cerebellar granule neurons against oxidative stress-induced apoptosis. Eur J Neurosci. 2002;15:1451-1460 (Pubitemid 35477975)
61. Delgado M, Ganea D. Neuroprotective effect of vasoactive intestinal peptide (VIP) in a mouse model of Parkinson's disease by blocking microglial activation. FASEB J. 2003;17:944-946
62. Werdelin L, Gjerris A, Boysen G, et al. Neuropeptides and neural cell adhesion molecule (NCAM) in CSF from patients with ALS. Acta Neurol Scand. 1989;79:177-181 (Pubitemid 19076987)
63. Iwasaki Y, Ikeda K, Ichikawa Y, et al. Vasoactive intestinal peptide influences neurite outgrowth in cultured rat spinal cord neurons. Neurol Res. 2001;23:851-854 (Pubitemid 33096906)
64. Sun W, Hong J, Zang YC, et al. Altered expression of vasoactive intestinal peptide receptors in T lymphocytes and aberrant Th1 immunity in multiple sclerosis. Int Immunol. 2006;18:1691-1700 (Pubitemid 44884031)
65. Barnett MH, Sutton I. The pathology of multiple sclerosis: a paradigm shift. Curr Opin Neurol. 2006;19:242-247 (Pubitemid 43804677)
66. Balabanov R, Beaumont T, Dore-Duffy P. The role of central nervous system microvascular pericytes in activation of antigen-primed splenic T-lymphocytes. J Neurosci Res. 1999;55:578-587 (Pubitemid 29117616)
67. Conti AC, Blendy JA. Regulation of antidepressant activity by cAMP response element binding proteins. Mol Neurobiol. 2004;30:143-155 (Pubitemid 41271213)
68. Itoh T, Tokukura M, Abe K. Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressive behaviour, CRE-binding activity and BDNF level in learned helplessness rats. Eur J Pharmacol. 2004;498(1-3):135-142 (Pubitemid 39208072)
69. Knuuttila JE, Toronen P, Castren E. Effects of antidepressant drug imipramine on gene expression in rat prefrontal cortex. Neurochem Res. 2004;29:1235-1244 (Pubitemid 39023497)
70. Sommer N, Loschmann PA, Northoff GH, et al. The antidepressant rolipram suppresses cytokine production and prevents autoimmune encephalomyelitis. Nat Med. 1995;1:244-248
71. Castro A, Jerez MJ, Gil C, et al. Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: advances in the development of specific phosphodiesterase inhibitors. Med Res Rev. 2005;25:229-244 (Pubitemid 40299847)
72. Kambayashi T, Wallin RP, Ljunggren HG. cAMP-elevating agents suppress dendritic function. J Leukoc Biol. 2001;70:903-910 (Pubitemid 33151129)
73. Beshay E, Prud'homme GJ. Inhibitors of phosphodiesterase isoforms III or IV suppress islet-cell nitric oxide production. Lab Invest. 2001;81:1109-1117 (Pubitemid 32772071)
74. Beshay E, Croze F, Prud'homme GJ. The phosphodiesterase inhibitors pentoxifylline and rolipram suppress macrophage activation and nitric oxide production in vitro and in vivo. Clin Immunol. 2001;98:272-279 (Pubitemid 32150617)
75. Abbas N, Zou LP, Pelidou SH, et al. Protective effect of Rolipram in experimental autoimmune neuritis: protection is associated with down-regulation of IFN-gamma and inflammatory chemokines as well as up-regulation of IL-4 in peripheral nervous system. Autoimmunity. 2000;32:93-99 (Pubitemid 30767573)
76. Dal Piaz V, Giovannoni MP. Phosphodiesterase 4 inhibitors, structurally unrelated to rolipram, as promising agents for the treatment of asthma and other pathologies. Eur J Med Chem. 2000;35:463-480 (Pubitemid 30395096)
77. Xu H, Strassmann G, Chan CC, et al. Protective effect of the type IV phosphodiesterase inhibitor rolipram in EAU: protection is independent of IL-10- inducing activity. Invest Ophthalmol Vis Sci. 1999;40:942-950 (Pubitemid 29153260)
78. Martinez I, Puerta C, Redondo C, et al. Type IV phosphodiesterase inhibition in experimental allergic encephalomyelitis of Lewis rats: sequential gene expression analysis of cytokines, adhesion molecules and the inducible nitric oxide synthase. J Neurol Sci. 1999;164:13-23. (Pubitemid 29256068)
79. Staines DR. Are multiple sclerosis and amyotrophic lateral sclerosis autoimmune disorders of endogenous vasoactive neuropeptides? Med Hypotheses. 2008;70:413-418
80. Staines DR. Is Parkinson's disease an autoimmune disorder of endogenous vasoactive neuropeptides? Med Hypotheses. 2007;69:1208-1211
81. Staines DR. Postulated vasoactive neuropeptide autoimmunity in fatigue-related conditions: a brief review and hypothesis. Clin Devel Immunol. 2006;13:25-39.
82. Staines DR. Phosphodiesterase inhibitors may be indicated in the treatment of postulated vasoactive neuropeptide autoimmune fatigue-related disorders. Med Hypotheses. 2006;66:203-204
83. Benagiano V, Virgintino D, Maiorano E, et al. VIP-like immunoreactivity within neurons and perivascular neuronal processes of the human cerebral cortex. Eur J Histochem. 1996;40:53-56 (Pubitemid 26311919)
84. Henning RJ, Sawmiller DR. Vasoactive intestinal peptide: cardiovascular effects. Cardiovasc Res. 2001;49:27-37.
85. Monahan AJ, Warren M, Carvey PM. Neuroinflammation and peripheral immune infiltration in Parkinson's disease: an autoimmune hypothesis. Cell Transplant. 2008;17:363-372 (Pubitemid 351717339)
86. Desai BS, Monahan AJ, Carvey PM, et al. Blood-brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy. Cell Transplant. 2007;16:285-299
87. Niebroj-Dobosz I, Dziewulska D, Janik P. Auto-antibodies against proteins of spinal cord cells in cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Folia Neuropathol. 2006;44:191-196 (Pubitemid 44613893)
88. Pender MP, Greer JM. Immunology of multiple sclerosis. Curr Allergy Asthma Rep. 2007;7:285-292
89. Delgado M, Ganea D. Anti-inflammatory neuropeptides: A new class of endogenous immunoregulatory agents. Brain Behav Immun. Epub 2008 Jun 14.
90. Wuerfel J, Haertle M, Waiczies H, et al. Perivascular spaces - MRI marker of inflammatory activity in the brain? Brain. 2008;131:2332-2340
91. Strong MJ. The syndromes of frontotemporal dysfunction in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. Epub 2008 Aug 27.
92. Costantino CM, Baecher-Allan C, Hafler DA. Multiple sclerosis and regulatory T cells. J Clin Immunol. Epub 2008 Sep 2.
93. Gonzalez-Rey E, Varela N, Chorny A, et al. Therapeutical approaches of vasoactive intestinal peptide as a pleiotropic immunomodulator. Curr Pharm Des. 2007;13:1113-1139 (Pubitemid 46744821)
94. Menniti FS, Faraci WS, Schmidt CJ. Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov. 2006;5:660-670 (Pubitemid 44151604)
95. Paintlia AS, Paintlia MK, Singh I, et al. Combination therapy of lovastatin and rolipram provides neuroprotection and promotes neurorepair in inflammatory demyelination model of multiple sclerosis. Glia. Epub 2008 Aug 20.
96. Folcik VA, Smith T, O'Bryant S, et al. Treatment with BBB022A or rolipram stabilizes the blood-brain barrier in experimental autoimmune encephalomyelitis: an additional mechanism for the therapeutic effect of type IV phosphodiesterase inhibitors. J Neuroimmunol. 1999;97(1-2):119-128 (Pubitemid 29301421)
97. Dinter H. Phosphodiesterase type 4 inhibitors: potential in the treatment of multiple sclerosis? BioDrugs. 2000;13:87-94. (Pubitemid 30146435)
98. Weishaar RE, Cain MH, Bristol JA. A new generation of phosphodiesterase inhibitors: multiple molecular forms of phosphodiesterase and the potential for drug selectivity. J Med Chem. 1985;28:537-545
99. Giorgi M, D'Angelo V, Esposito Z, et al. Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias in hemiparkinsonian rats: new aspects in the pathogenetic mechanisms. Eur J Neurosci. 2008;28:941-950
100. Yang L, Calingasan NY, Lorenzo BJ, et al. Attenuation of MPTP neurotoxicity by rolipram, a specific inhibitor of phosphodiesterase IV. Exp Neurol. 2008;211:311-314
101. Tomimatsu N, Arakawa Y. Survival-promoting activity of pituitary adenylate cyclase-activating polypeptide in the presence of phosphodiesterase inhibitors on rat motoneurons in culture: cAMP-protein kinase A-mediated survival. J Neurochem. Epub 2008 Sep 18.
102. Lu J, Zheng MH, Yan J, et al. Effects of vasoactive intestinal peptide on phenotypic and functional maturation of dendritic cells. Int Immunopharmacol. 2008;8:1449-1454
103. Delgado M, Pozo D, Ganea D. The significance of vasoactive intestinal peptide in immunomodulation. Pharmacol Rev. 2004;56:249-290 (Pubitemid 38720831)
104. Carson MJ. Microglia as liaisons between the immune and central nervous systems: functional implications for multiple sclerosis. Glia. 2002;40:218-231 (Pubitemid 35337379)
105. Pocock JM, Kettenmann H. Neurotransmitter receptors on microglia. Trends Neurosci. 2007;30:527-535
106. Bender AT, Beavo JA. Cyclic nucleotide phosphodieskrases: molecular regulation to clinical use. Pharmacol Rev. 2006;58:488-520.
107. Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57:178-201.