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Zimering MB. Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson's Disease. J Endocrinol Diabetes. 2018;5(2)doi: 10.15226/2374-6890/5/2/01102.
Zimering, M. B. (2018). Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson's Disease. Journal of endocrinology and diabetes, 5(2), . https://doi.org/10.15226/2374-6890/5/2/01102
Zimering, Mark B. "Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson's Disease." Journal of endocrinology and diabetes vol. 5,2 (2018). doi: https://doi.org/10.15226/2374-6890/5/2/01102
Zimering MB. Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson's Disease. J Endocrinol Diabetes. 2018;5(2). doi: 10.15226/2374-6890/5/2/01102. Epub 2018 May 10. PMID: 29888323; PMCID: PMC5990037.
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J Endocrinol Diabetes. 2018;5(2). doi: 10.15226/2374-6890/5/2/01102. Epub 2018 May 10.

Circulating Neurotoxic 5-HT2A Receptor Agonist Autoantibodies in Adult Type 2 Diabetes with Parkinson's Disease.

Journal of endocrinology and diabetes

Mark B Zimering

Affiliations

  1. Endocrinology, Veterans Affairs New Jersey Healthcare System, East Orange, NJ & Rutgers/Robert Wood Johnson Medical School, New Brunswick, NJ, USA.

PMID: 29888323 PMCID: PMC5990037 DOI: 10.15226/2374-6890/5/2/01102

Abstract

AIMS: To test whether circulating neurotoxic autoantibodies increase in adult type 2 diabetes mellitus with Parkinson's disease (PD) or dementia. To identify the G-protein coupled receptor on neuroblastoma cells mediating neural inhibitory effects in diabetic Parkinson's disease plasma autoantibodies. To determine the mechanism of accelerated neuroblastoma cell death and acute neurite retraction induced by diabetic Parkinson's disease and dementia autoantibodies.

METHODS: Protein-A eluates from plasma of twelve older adult male diabetic patients having Parkinson's disease (n=10) or dementia (n=2), and eight age-matched control diabetic patients were tested for ability to cause accelerated N2A neuroblastoma cell death and acute neurite retraction. Specific antagonists of G protein coupled receptors belonging to the G alpha q subfamily of heterotrimetric G-proteins, the phospholipase C/inositol triphosphate/Ca2+ pathway, or the RhoA/Rho kinase pathway were tested for ability to block diabetic Parkinson's disease/dementia autoantibody-induced neurite retraction or N2A accelerated cell loss. Sequential Liposorber LA-15 dextran sulfate cellulose/protein-A affinity chromatography was used to obtain highly-purified fractions of diabetic Parkinson's disease autoantibodies.

RESULTS: Mean accelerated neuroblastoma cell loss induced by diabetic Parkinson's disease or dementia autoantibodies significantly exceeded (P = 0.001) the level of N2A cell loss induced by an identical concentration of the diabetic autoantibodies in control patients without these two co-morbid neurodegenerative disorders. Co-incubation of diabetic Parkinson's disease and dementia autoantibodies with two-hundred nanomolar concentrations of M100907, a highly selective 5-HT2AR antagonist, completely prevented autoantibody-induced accelerated N2A cell loss and neurite retraction. A higher concentration (500 nM-10μM) of alpha-1 adrenergic, angiotensin II type 1, or endothelin A receptor antagonists did not substantially inhibit autoantibody-induced neuroblastoma cell death or prevent neurite retraction. Antagonists of the inositol triphosphate receptor (2-APB, 50μM), the intracellular calcium chelator (BAPTA-AM, 30 μM) and Y27632 (10 μM), a selective RhoA/Rho kinase inhibitor, each completely blocked acute neurite retraction induced by sixty nanomolar concentrations of diabetic Parkinson's disease autoantibodies. Co-incubation with 2-APB (1-2 μM) for 8 hours' prevented autoantibody-induced N2A cell loss. The highly-purified fraction obtained after Liposorber LA/protein-A affinity chromatography in hypertriglyceridemic diabetic dementia and Parkinson's disease plasmas had apparent MWs > 30 kD, and displayed enhanced N2A toxicity requiring substantially higher concentrations of 5-HT2AR antagonists (M100907, ketanserin, spiperone) to effectively neutralize.

CONCLUSION: These data suggest increased autoantibodies in older adult diabetes with Parkinson's disease or dementia cause accelerated neuron loss via the 5-hydroxytryptamine 2 receptor coupled to inositol triphosphate receptor-mediated cytosolic Ca2+ release.

Keywords: 5-HT2A receptor; Parkinson’s disease; autoantibodies; dementia; diabetes

Conflict of interest statement

Conflict of Interest The author reports no financial conflict of interest that would affect the objectivity of the presented findings.

References

  1. Mov Disord. 2004 Sep;19(9):1020-8 - PubMed
  2. Arch Dermatol Res. 2006 Aug;298(3):99-106 - PubMed
  3. Curr Pharm Des. 2008;14(16):1601-5 - PubMed
  4. Brain Res Bull. 2000 Apr;51(6):499-505 - PubMed
  5. Brain Res. 2002 Jan 11;924(2):133-40 - PubMed
  6. Parkinsonism Relat Disord. 2016 Jan;22 Suppl 1:S41-6 - PubMed
  7. J Parkinsons Dis. 2013;3(4):493-514 - PubMed
  8. Neurobiol Dis. 2006 Mar;21(3):618-25 - PubMed
  9. Urol Int. 1984;39(4):232-5 - PubMed
  10. J Lipid Res. 1999 Jan;40(1):1-16 - PubMed
  11. Front Endocrinol (Lausanne). 2016 Sep 08;7:123 - PubMed
  12. Arthritis Rheum. 1965 Aug;8:538-50 - PubMed
  13. Neuroscience. 1996 Aug;73(4):979-87 - PubMed
  14. Diabetes Res Clin Pract. 2011 Jul;93(1):95-105 - PubMed
  15. Free Radic Biol Med. 2013 Dec;65:658-66 - PubMed
  16. Pharmacol Res. 2016 Jan;103:123-31 - PubMed
  17. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):823-8 - PubMed
  18. J Endocrinol Diabetes. 2016;3(1):null - PubMed
  19. Neurology. 2004 Oct 12;63(7):1181-6 - PubMed
  20. Am J Pathol. 2007 May;170(5):1725-38 - PubMed
  21. Nat Genet. 2017 Oct;49(10 ):1511-1516 - PubMed
  22. Brain. 2005 Nov;128(Pt 11):2665-74 - PubMed
  23. Am J Epidemiol. 2003 Jun 1;157(11):1015-22 - PubMed
  24. Nature. 1997 Oct 30;389(6654):990-4 - PubMed
  25. J Neural Transm Park Dis Dement Sect. 1990;2(1):45-57 - PubMed
  26. Gastroenterology. 1995 Dec;109(6):1791-800 - PubMed
  27. Respir Res. 2007 Apr 02;8:29 - PubMed
  28. Leuk Lymphoma. 2002 Feb;43(2):251-5 - PubMed
  29. Brain Res. 1990 Sep 3;526(2):303-7 - PubMed
  30. J Endocrinol Diabetes. 2017;4(4):null - PubMed
  31. Endocr Pract. 2010 Sep-Oct;16(5):842-50 - PubMed
  32. Ther Apher Dial. 2003 Feb;7(1):73-7 - PubMed
  33. Blood Vessels. 1991;28(6):537-41 - PubMed
  34. Cardiovasc Psychiatry Neurol. 2012;2012:367516 - PubMed
  35. Diabetes Care. 2007 Apr;30(4):842-7 - PubMed

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