NERVOUS SYSTEM

REGENERATION OF NERVOUS SYSTEM

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APA YANG MENJADI TUJUAN PEMBELAJARAN KITA?

• Keterkaitan dengan kepentingan (calon) sarjana kedokteran (Sked) dan dokter (dr)

• Memahami & menjelaskan regenerasi sistem saraf

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WHAT DAMAGES NERVES?

Nerves can be damaged either through trauma or disease.

Nerve trauma may be incurred through motor vehicle accidents, severe falls, lacerations, and typing. Traumatic nerve injury, such as carpal tunnel syndrome, is caused by the compression of nerves. Other trauma, such as falls and motor vehicle accidents, may lead to the severance of nerves.

Diseases that damage nerves include multiple sclerosis, diabetes, spina bifida, and polio. Multiple sclerosis, for example, causes the breakdown of the insulating myelin surrounding axons.

MULTIPLE SCLEROSIS

• also known as "disseminated sclerosis" or "encephalomyelitis disseminata", is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms.[1]

• Disease onset usually occurs in young adults, and it is more common in women.[1] It has a prevalence that ranges between 2 and 150 per 100,000.[2] MS was first described in 1868 by Jean-Martin Charcot.[3]

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NEUROREGENERATION

• Neuroregeneration refers to the regrowth or repair of nervous tissues, cells or cell products.

• Such mechanisms may include generation of new neurons, glia, axons, myelin, or synapses.

• Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms and especially the extent and speed.

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PERIPHERAL NERVOUS SYSTEM REGENERATION

• Neuroregeneration in the peripheral nervous system (PNS) occurs to a significant degree.[5]

• Axonal sprouts form at the proximal stump and grow until they enter the distal stump.

• The growth of the sprouts are governed by chemotactic factors secreted from Schwann cells (neurolemmocytes).

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CENTRAL NERVOUS SYSTEM REGENERATION

• Unlike peripheral nervous system injury, injury to the central nervous system is not followed by extensive regeneration.

• It is limited by the inhibitory influences of the glial and extracellular environment.

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INHIBITION OF AXONAL REGROWTH

1. Chondroitin sulfate proteoglycans: astrocytes up regulate the production of chondroitin sulfate proteoglycans. Astrocytes are a predominant type of glial cell in the central nervous system that provide many functions including damage mitigation, repair, and glial scar formation.

2. Keratan sulfate proteoglycans: Like the chondroitin sulfate proteoglycans, keratan sulfate proteoglycan (KSPG) production is up regulated in reactive astrocytes as part of glial scar formation. KSPGs have also been shown to inhibit neurite outgrowth extension, limiting nerve regeneration. Keratan sulfate, also called keratosulfate, is formed from repeating disaccharide galactose units and N-acetylglucosamines.

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WHY CAN'T THE CNS HEAL DAMAGED NERVES ITSELF?

In the CNS, there seem to be two "glial culprits" that inhibit axon regeneration.

These are oligodendrocytes and astrocytes. Both play key roles in CNS support and

metabolism. It is logical to ask hear, "why on earth would

the body ever want to inhibit regenerative ability?" The body has a good answer.

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CLINICAL TREATMENTS

1. Surgery

2. Autologous nerve grafting

3. Allografts and xenografts

4. Nerve guidance conduit

5. Immunisation

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HOW CAN NERVE DAMAGE BE FIXED?

• Methylprednisolon

• Sygen

• Guidance Channels

• Stem Cells

• Growth Factors

• Gene Therapy

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Spinal Cord 50, 259-263 (April 2012)

• Central nervous system regeneration does not occur

• L S Illis

• Results:There is no evidence for CNS regeneration.

• Conclusion: A century of research focussed on the lesion site has been unproductive. An alternative field of research must be developed and the best candidate is the undamaged CNS.

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Cell Stem Cell. 2012 Jan 6;10(1):96-103.

• Rejuvenation of regeneration in the aging central nervous system.

• Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN, Wagers AJ, Franklin RJ.

• Source: MRC Centre for Stem Cell Biology and Regenerative Medicine & Cambridge Centre for Brain Repair & Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK.

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Abstract

• Remyelination is a regenerative process in the central nervous system (CNS) that produces new myelin sheaths from adult stem cells. The decline in remyelination that occurs with advancing age poses a significant barrier to therapy in the CNS, particularly for long-term demyelinating diseases such as multiple sclerosis (MS). Here we show that remyelination of experimentally induced demyelination is enhanced in old mice exposed to a youthful systemic milieu through heterochronic parabiosis. Restored remyelination in old animals involves recruitment to the repairing lesions of blood-derived monocytes from the young parabiotic partner, and preventing this recruitment partially inhibits rejuvenation of remyelination. These data suggest that enhanced remyelinating activity requires both youthful monocytes and other factors, and that remyelination-enhancing therapies targeting endogenous cells can be effective throughout life.

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NANOMEDICINE OPENS THE WAY FOR NERVE CELL REGENERATION

ScienceDaily (May 20, 2007) The ability to regenerate nerve cells in the body could reduce the

effects of trauma and disease in a dramatic way. In two presentations at the NSTI Nanotech 2007 Conference, researchers describe the use of nanotechnology to enhance the regeneration of nerve cells.

In the first method, developed at the University of Miami, researchers show how magnetic nanoparticles (MNPs) may be used to create mechanical tension that stimulates the growth and elongation of axons of the central nervous system neurons.

The second method from the University of California, Berkeley uses aligned nanofibers containing one or more growth factors to provide a bioactive matrix where nerve cells can regrow.

REGENERATING THE DAMAGED CENTRAL NERVOUS SYSTEM

• Philip J. Horner & Fred H. Gage

• Nature Vol 407 26 October 2007 963-70

• It is self-evident that this adult mammalian brain and spinal cord do not regenerate after injury, but recent discoveries have forced a reconsideration of this accepted principle. Advanceds in our understanding of how the brain develops have provided a rough blueprint for how we may bring about regeneration in the damaged brain. Studies in developmental neurobiology, intracelluar signalling and neuroimmunology are bringing the regeneration field closer to success. Notwithstanding theses advances, clear and indisputable evidence for adult functional regeneration remains to be shown.

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ACCELERATED NERVE REGENERATION IN MICE BY UPREGULATED EXPRESSION OF INTERLEUKIN (IL) 6

AND IL-6 RECEPTOR AFTER TRAUMA

• H.Hirota, H.Kiyama, T.Kishimoto and T.Taga

• JEM 183(6) 2627-34• Abstract

• In this study we aimed to examine a role for interleukin 6 (IL-6) and its receptor (IL-6R) in perpheral nerve regeneration in vivo. We first observed that cultured mouse embryonic dorsal root ganglia exhibited dramatic neurite extension by simultaneous addition of IL-6 and soluble IL-6R (sIL-6R), a complex that is known to interact with and activate signal transducing receptor component, gp130. After injury in the hypoglossal nerve in adult mice by ligation, immunoreactivity to IL-6 was upregulated in Schwann cells at the lesional site as well as in the cell bodies of hypoglossal neurons in the brain stem. .....

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