Background: The components of the immune system have been indicated to be linked with the neurotoxicity in Alzheimer's disease (AD). The participation of the immune system in the neurodegeneration in a rat model of colchicine-induced AD has not been explored. Methods: In the present study, hippocampal neurodegeneration along with reactive oxygen species (ROS), nitrite and TNF-α in the hippocampus and some systemic immune responses were measured after 15 and 21 days of intracerebroventricular colchicine injection in rats and again after oral administration of different doses of the anti-inflammatory drug naproxen in AD rats. Results: Chromatolysis and amyloid plaques were found along with higher ROS, nitrite and TNF-α levels in the hippocampus of colchicine-induced AD rats, and these changes were prevented by naproxen in a dose-dependent manner. Alterations in immunological parameters [increased phagocytic activity of white blood cells and splenic polymorphonuclear cells (PMN), increased cytotoxicity and decreased leucocyte adhesive inhibition index (LAI) of splenic mononuclear cells (MNC)] were also observed in colchicine-injected rats, which showed a dose-dependent recovery after oral administration of naproxen in AD rats. The number of plaques, chromatolysis of Nissl granules, TNF-α, nitrite and ROS levels in the hippocampus, phagocytic activity of splenic PMN and LAI of splenic MNC in AD rats showed greater changes in the 21- than in the 15-day study, and the recovery of these parameters after administration of naproxen differed between the two study durations. Conclusion: The present study shows that colchicine-induced neurodegeneration is time dependent and mediated by cyclooxygenase-induced neuroinflammation, which is reflected in the systemic immunological responses.

1.
Berg L, McKeel DW Jr, Miller JP, Baty J, Morris JC: Neuropathological indexes of Alzheimer's disease in demented and nondemented persons aged 80 years and older. Arch Neurol 1993;50:349-358.
2.
Braak H, Braak E: Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging 1997;18:351-357.
3.
Braak H, Braak E: Evolution of neuronal changes in the course of Alzheimer's disease. J Neural Transm Suppl 1998;53:127-140.
4.
Braak H, Braak E, Bohl J, Bratzke H: Evolution of Alzheimer's disease related cortical lesions. J Neural Transm Suppl 1998;54:97-106.
5.
Huberman M, Shalit F, Roth-Deri I, Gutman B, Brodie C, Ko HE, Sredini B: Correlation of cytokine secretion by mononuclear cells of Alzheimer patients and their disease stage. J Neuroimmunol 1999;52:147-152.
6.
Jellinger KA, Bancher C: AD neuropathology. Neurology 1996;46:1186-1187.
7.
Brion JP: Neurofibrillary tangles and Alzheimer's disease. Eur Neurol 1998;40:130-140.
8.
Blennow K, Leon MJ, Zeterberg H: Alzheimer's disease. Lancet 2006;368:387-403.
9.
Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002;297:353-356.
10.
Armstrong RA: Plaques and tangles and the pathogenesis of Alzheimer's disease. Folia Neuropathol 2006;44:1-11.
11.
Swerdlow RH, Khan SM: A ‘mitochondrial cascade hypothesis' for sporadic Alzheimer's disease. Med Hypotheses 2004;63:8-20.
12.
Petrisic MA: Amyloid cascade hypothesis: is it true for sporadic Alzheimer's disease. Periodicum Biologorum UDC 2008;110:17-25.
13.
Popp J, Schaper K, Kölsch H, Cvetanovska G, Rommel F, Klingmüller D, Dodel R, Wüllner U, Jessen F: CSF cortisol in Alzheimer's disease and mild cognitive impairment. Neurobiol Aging 2009;30:498-500.
14.
Rai S, Kamat PK, Nath C, Shukla R: A study on neuroinflammation and NMDA receptor function in STZ (ICV) induced memory impaired rats. J Neuroimmunol 2013;254:1-9.
15.
Blum-Degen D, Müller T, Kuhn W, Gerlach M, Przuntek H, Riederer P: Interleukin-1β and interleukin-6 are elevated in the cerebrospinal fluid of Alzheimer's and de novo Parkinson's disease patients. Neurosci Lett 1995;202:17-20.
16.
Alvarez A, Cacaelos R, Sanpedro C, García-Fantini M, Aleixandre M: Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging 2007;28:533-536.
17.
McGeer PL, McGeer E, Rogers J, Sibley J: Anti-inflammatory drugs and Alzheimer disease. Lancet 1990;335:1037.
18.
Breitner JC, Baker LD, Montine TJ, Meinert CL, Lyketsos CG, Ashe KH, Brandt J, Craft S, Evans DE, Green RC, Ismail MS, Martin BK, Mullan MJ, Sabbagh M, Tariot PN; ADAPT Research Group: Extended results of the Alzheimer's disease anti-inflammatory prevention trial. Alzheimers Dement 2011;7:402-411.
19.
Pasero G, Marson P: A short history of anti-rheumatic therapy. III. Non steroidal anti-inflammatory drugs (in Italian). Reumatismo 2010;62:225-232.
20.
Dhull DK, Jindal A, Dhull RK, Aggarwal S, Bhateja D, Padi SSV: Neuroprotective effect of cyclooxygenase inhibitors in ICV-STZ induced sporadic Alzheimer's disease in rats. J Mol Neurosci 2012;46:223-235.
21.
Morteau O: Prostaglandins and inflammation: the cyclooxygenase controversy. Arch Immunol Ther Exp (Warsz) 2000;48:473-480.
22.
Yasojima K, Schwab C, McGeer EG, McGeer PL: Distribution of cyclooxygenase-1 and cyclooxygenase-2 mRNAs and proteins in human brain and peripheral organs. Brain Res 1999;830:226-236.
23.
Zarghi A, Arfaei S: Selective COX-2 inhibitors: a review of their structure-activity relationships. Iran J Pharm Res 2011;10:655-683.
24.
Britschgi M, Wyss-Coray T: Systemic and acquired immune responses in Alzheimer's disease. Int Rev Neurobiol 2007;82:205-233.
25.
Shalit F, Sredni B, Stern L, Kott E, Huberman M: Elevated interleukin-6 secretion levels by mononuclear cells of Alzheimer's patients. Neurosci Lett 1994;174:130-132.
26.
Soleret SB, Fioravantla M, Pascale AL, Ferrari E, Govoni S, Battaini F: Increased natural killer cell cytotoxicity in Alzheimer's disease may involve protein kinase C dysregulation. Neurobiol Aging 1998;19:191-199.
27.
Giménez-Llort L, Maté I, Manassra R, Vida C, De La Fuente M: Peripheral immune system and neuroimmune communication impairment in a mouse model of Alzheimer's disease. Ann NY Acad Sci 2012;1262:74-84.
28.
Kumar A, Seghal N, Naidu PS, Padi SSV, Goyal R: Colchicines-induced neurotoxicity as an animal model of sporadic dementia of Alzheimer's type. Pharmacol Rep 2007;59:274-283.
29.
Ganguly R, Guha D: Alteration of brain monoamines & EEG wave pattern in rat model of Alzheimer's disease & protection by Moringa oleifera. Indian J Med Res 2008;128:744-751.
30.
Pitchaimani V, Arumugam S, Thandavarayan RA, Thiyagarajan MK, Aiyalu R, Sreedhar R, Nakamura T, Watanabe JK: Nootropic activity of acetaminophen against colchicine induced cognitive impairment in rats. J Clin Biochem Nutr 2012;50:241-244.
31.
Paxinos G, Watson CR, Emson PC: AChE-stained horizontal sections of the rat brain in stereotaxic coordinates. J Neurosci Methods 1980;3:129-149.
32.
Csölle C, Sperlágh B: Peripheral origin of IL-1β production in the rodent hippocampus under in vivo systemic bacterial lipopolysaccharide (LPS) challenge and its regulation by P2X(7) receptors. J Neuroimmunol 2010;219:38-46.
33.
Csölle C, Sperlágh B: Endocannabinergic modulation of interleukin-1β in mouse hippocampus under basal conditions and after in vivo systemic lipopolysaccharide stimulation. Neuroimmunomodulation 2011;18:226-231.
34.
Socci DJ, Bjugstad KB, Jones HC, Pattisapu JV, Arendash GW: Evidence that oxidative stress is associated with the pathophysiology of inherited hydrocephalus in the H-Tx rat model. Exp Neurol 1999;155:109-117.
35.
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR: Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 1982;126:131-138.
36.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193:265-275.
37.
Maluish AE, Halliday WJ: Hemocytometer leukocyte adherence technique. Cancer Res 1979;39:625-626.
38.
Oben JA, Foreman JC: A simple quantitative fluorimetric assay of in vitro phagocytosis in human neutrophils. J Immunol Methods 1998;112:99-103.
39.
Hudson L, Hay FC: Polymorphonuclear (PMN) assay for neutrophil phagocytic activity; in Hudson L, Hay FC: Practical Immunology. Oxford, Blackwell, 1980, vol 2, pp 29-31.
40.
Weidmann E, Brieger J, Jahn B, Hoelzer D, Bergmann L, Mitrou PS: Lactate dehydrogenase-release assay: a reliable, nonradioactive technique for analysis of cytotoxic lymphocyte-mediated lytic activity against blasts from acute myelocytic leukemia. Ann Hematol 1995;70:153-158.
41.
Dutta G, Mondal N, Goswami A, Majumdar D, Ghosh T: Effects of electrolytic lesion of medial septum on some immune responses in rats. Neuroimmunomodulation 2011;18:232-239.
42.
Cox G: Neuropathological techniques; in Bancroft JD, Stevens A (eds): Theory and Practice of Histological Techniques. New York, Churchill Livingstone, 1977, vol 1, pp 258-259.
43.
Stevens A, Bancroft JD: Proteins and nucleic acids; in Bancroft JD, Stevens A (eds): Theory and Practice of Histological Techniques. New York, Churchill Livingstone, 1977, vol 1, pp 129.
44.
Nakayama T, Sawada T: Involvement of microtubule integrity in memory impairment caused by colchicines. Pharmacol Biochem Behav 2002;71:119-138.
45.
Frijlink HW, Franssen EJ, Eissens AC, Oosting R, Lerk CF, Meijer DK, Golby A, Silverberg G, Race E, Gabrieli S, O'Shea J, Knierim K, Stebbins G, Gabrieli J: Memory encoding in Alzheimer's disease: an fMRI study of explicit and implicit memory. Brain 2005;128:773-787.
46.
Kim S, Chang E, Kumar R, Klimov DK: Naproxen interferes with the assembly of Aβ oligomers implicated in Alzheimer's disease. Biophys J 2011;100:2024-2032.
47.
Yang F, Lim GP, Begum AN, Ubeda OJ, Simmons MR, Ambegaokar SS, Chen P, Kayed R, Glabe CG, Frautschy SA, Cole GM: Curcumin inhibits formation of amyloid β oligomers and fibrils, binds plaques, and reduces amyloid in vivo. J Biol Chem 2005;280:5892-5901.
48.
Naxen, Naproxen. http://www.medsafe.govt.nz/profs/datasheet/n/naxentab.pdf (accessed July 6, 2013).
49.
Kumar A, Seghal N, Padi SV, Naidu PS: Differential effects of cyclooxygenase inhibitors on intracerebroventricular colchicine-induced dysfunction and oxidative stress in rats. Eur J Pharmacol 2006;551:58-66.
50.
Gehrmann J, Matsumoto Y, Kreutzberg GW: Microglia: intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 1995;20:269-287.
51.
Wilson L: Microtubules as targets for drug and toxic chemical action: the mechanisms of colchicine and vinblastine; in Clarkson TW, Sagar PR, Syversen TLM (eds): The Cytoskeleton - A Target for Toxic Agents. New York, Plenum, 1986, pp 37-52.
52.
Emerich DF, Walsh TJ: Cholinergic cell loss and cognitive impairments following intraventricular or intradentate colchicines. Brain Res 1990;517:157-167.
53.
Koo EH, Sisodia SS, Archer DR, Martin U, Weideman A, Beyreuther K, Fischer P, Masters CL, Price DL: Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci USA 1990;87:1561-1565.
54.
Koo EH, Sisodia SS, Archer DR, Martin U, Weideman A, Beyreuther K, Fischer P, Masters CL, Price DL: Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci USA 1990;87:1561-1565.
55.
Wisniewski H, Terry RD: Experimental colchicine encephalopathy. I. Induction of neurofibrillary degeneration. Lab Invest 1967;17:577-587.
56.
Klatzo I, Wisniewski H, Streicher E: Experimental production of neurofibrillary degeneration. I. Light microscopic observations. J Neuropathol Exp Neurol 1965;24:187-199.
57.
Hirsch EC, Hunot S: Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol 2009;8:382-97.
58.
Aloisi F: Immune Function of Microglia. Glia 2001;36:165-179.
59.
Nyoman G, Darmadipura S: The role of microglia as prime component of CNS immune system in acute and chronic neuroinflammation. Folia Med Indones 2007;43:54-58.
60.
Mallat M, Chamak B: Brain macrophages: neurotoxic or neurotrophic effector cells? J Leukoc Biol 1994;56:416-422.
61.
Minton K: Immune mechanisms in neurological disorders: protective or destructive? Trends Immunol 2001;22:655-657.
62.
Streit WJ: Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 2002;40:133-139.
63.
Streit WJ: Microglial-neuronal interactions. J Chem Neuroanat 1993;6:261-266.
64.
Ji L, Li LP, Schnitzer T, Du H, Prasad PV: Intra-renal oxygenation in rat kidneys during water loading: effects of cyclooxygenase (COX) inhibition and nitric oxide (NO) donation. J Magn Reson Imaging 2010;32:383-387.
65.
Amer M, Bead VR, Bathon J, Blumenthal RS, Edwards DN: Use of nonsteroidal anti-inflammatory drugs in patients with cardiovascular disease: a cautionary tale. Cardiol Rev 2010;18:204-212.
66.
Goulding NJ, Flower RJ: Glucocorticoids and the immune system; in Buckingham JC, Gillies GE, Cowell A (eds): Stress, Stress Hormone and the Immune System. New York, Wiley, 1993, pp 199-223.
67.
Swabb DF, Raadsheer FC, Endert E, Hoffman MA, Kamphorst W, Ravid R: Increased cortisol levels in aging and Alzheimer's disease in postmortem cerebrospinal fluid. J Neuroendocrinol 1994;6:681-687.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.