The Effect of Caffeine on the Myelin Repair Following Experimental Demyelination Induction in the Adult Rat Hippocampus

Journal of Cell and Molecular Research

Article 2, Volume 8, Issue 1 - Serial Number 15, January 0, Pages 15-24   

Document Type: Research Articles

DOI: 10.22067/jcmr.v8i1.49336

Abstract

Multiple sclerosis is characterized by the loss of oligodendrocytes and demyelination of axons. In this study, the
effect of caffeine on spatial memory in rats was investigated following demyelination induction by lysolecithin
(LPC). The expression of Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Olig2
(oligodendrocyte lineage marker) genes was also assessed in the hippocampus. Animals were divided into seven
groups; control group: animals received normal saline by stereotaxic intrahippocampal injection in Dentate Gyrus
(DG) area; LPC group: animals received 2 μl lysolecithin by stereotaxic intrahippocampal injection in DG area (they
were evaluated 7, 14, and 28 days after LPC injection; Caffeine- treated group: animals were treated with caffeine at
doses of 30 mg/kg intraperitoneally for 7, 14, and 28 days after receiving LPC. Behavioral study was performed using
Radial Arm Maze. Moreover, the RT- PCR was carried out for gene expression investigation. The demyelination and
defective remyelination were noticeable on 28th day which suggests the demyelination decline caused by caffeine.
Behavioral study showed that on the post-lesion days, the food finding time in the LPC group was significantly higher
than that of the control group. Caffeine consumption significantly attenuated the food finding time in the treatment
compared to the LPC group. The RT-PCR analysis indicated that the lysolecithin decreased the MBP expression
especially on days 7 and 14 and conversely increased the Olig2 and GFAP expression. In addition, the caffeine
enhanced the expression of MBP compared to that of the LPC group and reduced the Olig2 and GFAP expressions.
Our results demonstrated that caffeine could increase the remyelination process in hippocampus and improve the
spatial memory following demyelination induction by the LPC.

Keywords

Demyelination; Remyelination; Lysolecithin; Hippocampus; Caffeine

References

Aandahl E. M., Moretto W. J., Haslett P. A.,

Vang T., Bryn T. and Tasken K. (2002)

Inhibition of antigen-specific T cell proliferation and cytokine production by

protein kinase A type 1. Journal of

Immunology 169: 802-808.

2. Allaman I., Lengacher S., Magistretti P. J.

and Pellerin L. (2003) A2B receptor

activation promotes glycogen synthesis in

astrocytes through modulation of gene

expression. American Journal of Cell

Physiology 284: 696–707.

3. Barres B. A. (1991) New roles for glia.

Journal of Neurosciences 11: 3685-3694.

4. Baumann N. and Pham-Dinh D. (2001)

Biology of oligodendrocyte and myelin in

the mammalian central nervous system.

Physiological Reviews 81: 871–927

5. Bignami A. and Dahl D. (1995) Gliosis.

Neuroglia. Oxford University Press,

NewYork. 843-858.

6. Dehghan S., Javan M., Pourabdolhossein F.,

Mirnajafi-Zadeh J. and Baharvand H.

(2012) Basic Fibroblast Growth Factor

Potentiates Myelin Repair Following

Induction of Experimental Demyelination

in Adult Mouse Optic Chiasm and

Nerves. Journal of Molecular Neurosciences

48: 77–85.

7. Dixon A. K., Gubitz A. K., Sirinathsinghji

D. J., Richardson P. J. and Freeman T. C.

(1996) Tissue Distribution of adenosine

receptor mRNAs in the rat. Brazilian

Journal of Pharmacology 118: 1461-1468.

8. Fancy S. P. J., Zhao C. and Franklin R. J. M.

(2004) Increased expression of Nkx2.2

and Olig2 identifies reactive

oligodendrocyte progenitor cells

responding to demyelination in the adult

CNS. Molecular and Cellular Neurosciences

27: 247–254.

9. Franklin R. J. M. and French-Constant C.

(2008) Remyelination in the CNS: from

biology to therapy. Nature Reviews

Neuroscience 9: 839– 855.

10. Franklin R. J. M. (2002) Why does

remyelination fail in multiple sclerosis.

Nature Reviews Neuroscience 3: 705–714.

11. Frederick T. J. and Miller S. D. (2006)

Future of multiple sclerosis therapy:

combining antigen-specific immunotherapy

with strategies to promote myelin repair.

Future Neurology 1: 489–503.

12. Gomes F. C. A., Paulin D. and Moura Neto

V. (1999) Glial fibrillary acidic protein

(GFAP): modulation by growth factors and

its implication in astrocyte differentiation.

Brazilian Journal of Medical and Biological

Research 32: 619-631.

13. Goudarzvand M., Javan M. and Mirnajafi-

Zadeh J. (2010) Vitamins E and D3

attenuate demyelination and potentiate

remyelination processes of hippocampal

formation of rats following local Injection

of ethidium bromide. Cellular and

Molecular Neurobiology 30: 289–299.

14. Horrigan L. A., Kelly J. A. and Connor T. J.

(2006) Immunomodulatory effects of

caffeine: Friend or foe. Pharmacology

Therapeutics 111: 877–892.

15. Jordan C., Friedrich V. J. R. and Dubois-

Dalcq M. (1989) In situ hybridization

analysis of myelin gene transcripts in

developing mouse spinal cord. Journal of

Neurosciences 9: 248–257.

16. Keegan B. M. and Noseworthy J. H. (2002)

Multiple sclerosis. Annual Review of

Medicine 53: 285-302.

17. Khezri Sh., Javan M., Goudarzvand M.,

Semnanian S. and Baharvand H. (2013)

Dibutyryl Cyclic AMP inhibits the

progression of experimental autoimmune

encephalomyelitis and potentiates

recruitment of endogenous neural stem

cells. Journal of Molecular Neuroscience 5:

298- 306.

18. Ligon K. L., Kesari S., Kitada M., Sun T.,

Arnett H. A. and Alberta J. A. (2006)

Development of NG2 neural progenitor cells

requires Olig2 gene function. Proceedings

of the National Academy of Sciences of the

United States of America 103: 7853–7858.

19. Liu Z., Hu X., Cai J., Liu B., Peng X. and

Wegner M. (2007) Induction of

oligodendrocyte differentiation by Olig2

and Sox10: Evidence for reciprocal

interactions and dosage-dependent

mechanisms. Developmental Biology 302:

683–693.

20. Makinodan M., Tatsumi K., Okuda H.,

Manabe T., Yamauchi T., Noriyama Y.,

Kishimoto T. and Wanaka A. (2008)

Lysophosphatidyl choline induces delayed

myelination in the juvenile ventral

hippocampus and behavioral alterations in

adulthood. Neurochemistry International

53: 374–381.

21. McDonald W. I. and Ron M. A. (1999)

Multiple sclerosis: the disease and its

manifestations. Philosophical Transaction

of the Royal Society of London Series B

Biological Sciences 354: 1615-1622.

22. MCGurk S. R., Lvin E. D. and Butcher L. L. (1989) Radial arm maze performance in rats

is impaired by a combination of nicotinic

cholinergic and D2 dopaminergic antagonist

Drugs. Psychopharmacology 99: 371-373.

23. Menn B., Garcia-Verdugo J. M., Yaschine

C., Gonzalez-Perez O., Rowitch D. and

Alvarez-Buylla A. (2006) Origin of

oligodendrocytes in the subventricular

zone of the adult brain. Journal of

Neurosciences 26: 790-797.

24. Messersmith D. J., Murtie J. C., Le T. Q.,

Frost E. E. and Armstrong R. C. (2000)

Fibroblast growth factor 2 (FGF2) and fgf

receptor expression in an experimental

demyelinating disease with extensive

remyelination. Journal of neuroscience

Research 62: 241–256.

25. Mozafari S., Javan M., Sherafat M. A.,

Mirnajafi-zade J., Heibatollahi M., Pour-

Beiranvand S., Tiraihi T. and Ahmadiani A.

(2011) Analysis of structural and

molecular events associated with adult rat

optic chiasm and nerves demyelination and

remyelination; possible role for 3rd ventricle

proliferating cells. Neuromolecular

Medicine 13: 138-150.

26. Nakafuku M., Nakatomi H. and Kuriu T.

(2002) Regeneration of hippocampal

pyramidal neurons after ischemic brain

injury by recruitment of endogenous neural

progenitors. Cell 110: 429–444.

27. Paxinos G. and Watson C. (2007) The rat

brain in stereotaxic coordinates (6th ed.).

New York: Academic press.

28. Pittock S. J. and Lucchinetti C. F. (2007)

The pathology of MS: new insights and

potential clinical applications. Neurologist

13: 45–56.

29. Raff M. C., Miller R. H. and Noble M.

(1983) A glial progenitor cell that develops

in vitro into an astrocyte or an

oligodendrocyte depending on culture

medium. Nature 303: 390-396.

30. Ribeiro J. A. and Sebastiao A. M. (2010)

Caffeine and adenosine. Journal of

Alzheimer Disease 20: 3-15.

31. Setzu A., Ffrench-Constant C. and Franklin

R. J. M. (2004) CNS axons retain their

competence for myelination throughout life.

Glia 45: 307–311.

32. Sherafat M. A., Javan M., Mozafari S.,

Mirnajafi-Zadeh J. and Motamedi F. (2012)

Castration attenuates myelin repair

following lysolecithin induced

demyelination in rat optic chiasm: An

evaluation using visual evoked potential,

marker genes expression and myelin

staining. Neurochemical Research 36:

1887–1895.

33. Shivane A. G. and Chakrabarty A. (2007)

Multiple sclerosis and demyelination.

Current Diagnosis Pathology 13: 193–202.

34. Smith A., Brice C., Nash J., Rich N. and

Nutt D. J. (2003) Caffeine and central

noradrenaline: effects on mood, cognitive

performance, eye movements and

cardiovascular function. Journal of

Psychopharmacology 17: 283–292.

35. Tarbali S., Khezri Sh. and Heidari R. (2013)

Effect of vitamin D3 on improvement of

learning and spatial memory following

demyelination induction in hippocampal

CA1 area of rat. Journal of Physiology and

Pharmacology 17: 449-460.

36. Tomassini V. and Pozzilli C. (2009) Sex

hormones, brain damage and clinical course

of multiple sclerosis. Journal of

Neurological Sciences. 286: 35–39.

37. Vela J. M., Molina-Holgado E., Arevalo-

Martin A., Almazan G. and Guaza C. (2002)

Interleukin-1 regulates proliferation and

differentiation of oligodendrocyte

progenitor cells. Molecular and Cellular

Neuroscience 20: 489–502.

38. Wallace V. C., Cottrell D. F., Brophy P. J.

and Fleetwood-Walker S. M. (2003) Focal

lysolecithin induced demyeliation of

peripheral afferents results in neuropathic

pain behavior that is attenuated by

cannabinoids. Journal of Neuroscience 23:

3221-3233.

39. Webb A., Clark P., Skepper J., Compston A.

and Wood A. (1995) Guidance of

oligodendrocytes and their progenitors by

substratum topography. Journal of Cell

Science 108: 2747-2760.

40. Wentz C. T. and Magavi S. P. (2009)

Caffeine alters proliferation of neuronal

precursors in the adult hippocampus.

Neuropharmacology 56: 994-1000.

41. Zhang S. C., Goetz B. D., Carre J. L. and

Duncan I. D. (2001) Reactive microglia in

dysmyelination and demyelination. Glia 34:

101–109.

42. Zhang S. C., Ge B. and Duncan I. D. (1999)

Adult brain retains the potential to generate

oligodendroglial progenitors with extensive

myelination capacity. Proceedings of

National Academic Sciences 96: 4089–

4094. Journal of Cell and Molecular Research (2016) 8 (1), 15-24

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