mini disseration kabir nigam

Download Mini Disseration Kabir Nigam

Post on 13-Apr-2017

84 views

Category:

Documents

2 download

Embed Size (px)

TRANSCRIPT

  • 1

    A Survey of the Neuronal Mechanisms

    Underlying CNS Injury and the Barriers

    Preventing Successful Recovery

    By Kabir Nigam

  • 2

    TABLE OF CONTENTS

    Abstract.........pg. 3

    Introduction........pg. 4

    Astrocytes.........pg. 9

    Developmental Molecules...pg. 13

    Oligodendrocytes.....pg. 15

    Regeneration......pg. 19

    Conclusion.......pg. 24

    References.......pg. 27

  • 3

    ABSTRACT

    Injuries to the central nervous system can be caused by either physical impact or by

    restriction of blood flow to its constituents. These injuries often have very serious

    consequences, in which full rehabilitation is rare. The main reason for this is that

    upon injury, the affected area turns into an environment where axonal regeneration

    is not possible. This includes the formation of a dense glial scar, the secretion of

    repulsive growth factors, and upregulation of glycoproteins that induce actin

    depolymerization. Strategies to overcome such inhibition include studying the

    intercellular mechanisms by which these molecules act, and targeting either the

    molecule itself or downstream secondary molecules that these inhibitory

    components affect, with the greater goal of blocking the transduction of their signals

    and creating an environment that is permissible to neuronal growth.

  • 4

    INTRODUCTION

    The central nervous system is perhaps the most complex system known to the

    human race, with over 100 billion nerve cells making hundreds of trillions of

    synaptic connections (Koch & Laurent, 1999). It governs the vital functions that

    sustain life, and is thus a priority in terms of biomedical study. Given its complexity,

    the CNS is still relatively a black box, a massive uncharted territory of current

    exploration. Damage to the cells that encompass the CNS often has devastating

    results that severely impair the affected individual, if not resulting in death. Thus, it

    is important to study how the CNS responds to such insult, as through

    understanding the natural mechanisms that mediate recovery, we can use medical

    technology and research to facilitate this process.

    There are three main types of CNS injury: traumatic brain injury, spinal cord injury

    and ischemia. The first is defined as sudden physical damage to the brain, either

    through impact to the intact skull or physical penetration of actual brain tissue

    (Finnie & Blumbergs, 2002). Spinal cord injury is physical damage to the spine,

    again through impact or penetration that damages the axons that encompass the

    spinal cord, which carry information from the brain to the body and vice versa

    (McDonald & Sadowsky, 2002). Ischemia involves the restriction of blood to

    neurons, often as a result of a stroke, restricting them of oxygen and glucose that is

    necessary for proper cellular function (Aarts & Tymianski, 2005).

  • 5

    Approximately 200,000 people die each year in the United States from brain

    injuries, with an additional 500,000 hospitalized for treatment. About 10% of

    surviving individuals have continuing disabilities that may impair their

    ability to live independently In the US, approximately 8,000 new cases of

    spinal cord injury occur each year, and an estimated 450,000 people in the

    country live with the condition. (Physicians Desk Reference)

    Neuroinflammation is a relatively recent term within neuroscience that defines the

    CNSs response process to injury. It has only been within the past decade that

    scientists discovered that the brain exhibits immune activity unique to that of the

    rest of the body. This response process is highly complex, and is not fully

    understood, however the study of neuroinflammation has become a very hot topic

    in modern neuroscience, with many labs dedicating their research to studying this

    process.

  • 6

    Figure adapted from Nature Reviews Neuroscience (Popovich & Longbrake, 2008)

  • 7

    There are a multitude of different aspects of the neuroinflammatory process that

    have been identified, and research shows these aspects, though acutely beneficial in

    the healing process, can also be harmful (Nakajima & Kohsaka, 2001). Such aspects

    are largely mediated by the activation of astrocytes and microglia, two types of glial

    cells that play important roles in maintaining proper neuronal functionality.

    Astrocytes help provide nutrients to nervous tissue and maintain extracellular ion

    balances, while microglia are the macrophages of the CNS, constantly clearing

    pathogens and extracellular debris through phagocytosis (Nakajima & Kohsaka,

    2001; Kimelberg & Nedergaard, 2010). But upon CNS insult, these cells quickly

    respond by producing inflammatory mediators. Microglia are activated by CNS

    damage or infection, and are recruited rapidly to the area of injury. The presence of

    damaged cells causes microglia to produce cytokines and chemokines that can

    either damage or protect neighboring cells. Cytokines can cross the bloodbrain

    barrier to recruit mediators like leukocytes originating from the periphery (Lucas et

    al., 2009). Astrocytes are most known for their ability to form scars that isolate

    damaged tissue from healthy tissue, minimizing the spread of infection and cellular

    damage while allowing for the damaged area to heal through the reorganization of

    blood vessels that provide factors necessary for proper healing (Stichel & Mller,

    1998).

    However despite promoting the healing of damaged tissue, neuroinflammation,

    otherwise known as gliosis, has effects that inhibit axonal regeneration, severing

    proper communication between the affected region and the rest of the brain, thus

  • 8

    resulting in a loss of function. The purpose of this paper will be to investigate what

    factors inhibit axonal regeneration and to discuss therapeutic techniques that show

    promise with regards to overcoming regenerative failure.

  • 9

    ASTROCYTES

    Upon CNS insult, astrocytes quickly react by forming what is known as a glial scar.

    This process involves the proliferation as well as morphological and functional

    changes within astrocytes. Such cells are known as reactive astrocytes (Fawcett &

    Asher, 1999; Sofroniew, 2005). Proliferation has been marked by a strong increase

    in the synthesis of Glial Fibrillary Acidic Protein and an increase in extracellular

    matrix molecules (Wilhelmsson et al., 2006). The proliferation of astrocytes serves

    to form a dense web of interconnected tissue that surrounds and fills the vacant

    spaces caused by degenerating and dead neuronal tissue (Stichel & Mller, 1998).

    This layer of cells functions to protect surrounding healthy tissue from being

    damaged by potential microbial agents, while maintaining a homeostatic

    environment and protecting the damaged are from other proinflammatory

    molecules, growth factors, and free radicals (Rolls et al., 2009). Additionally,

    astrocytes mediate the revascularization of the damaged tissue that promotes repair

    by providing the affected area with nutritional and metabolic support. However,

    reactive astrocytes also produce molecules that chemically inhibit neuronal growth,

    preventing full recovery of the damaged area in the long-term (Huang et al., 2014).

    The most obvious explanation for this inhibitory mechanism is that the density of

    the glial scar is so strong that it provides a mechanical barrier that prevents

    anything from getting into the area it surrounds (Windle & Chambers, 1950).

    However what seems to play a bigger role are the inhibitory molecules that are

  • 10

    upregulated upon reactive astrogliosis, as it has been shown that axonal

    regenerative failure will still occur in vitro when the glial scar is removed from the

    neuroinflammatory environment (Rudge and Silver, 1990). Such molecules include

    Semaphorin 3 (Pasterkamp et al., 2001), ephrin-B2 (Bundesen et al., 2003) and

    chondroitin sulfate proteoglycans (Jones et al., 2003). Evidence that supports the

    environment as a factor in axonal regenerative failure includes micro-

    transplantation of adult dorsal root ganglion cells into either intact host glial

    environment or a damaged one. Though these sensory axons regenerate rapidly

    over long distances within adult white matter tracts of the brain and spinal cord, as

    the growing adult neurons reach an area of CNS damage, with associated

    inflammatory infiltrates and inhibitory molecules, the axons convert into a

    dystrophic state and are unable to continue (Fitch & Silver, 2008).

    Chondroitin sulfate proteoglycans are strongly upregulated following CNS injury.

    There are various types of CPSGs that are differentially expressed that have been

    shown to inhibit neuronal growth (Snow et al., 1990; Jones et al., 2003). Degradation

    of CPSGs following injury is shown to partially enhance axonal growth in animals

    (Lee et al., 2010). Cleavage of the glycosaminoglycan side chains by Chondroitinase

    ABC also makes the environment substantially more permissive to neuronal

    outgrowth, suggesting that the inhibitory effect on axonal regeneration is primarily

    dependent on the sulfation pattern of GAG chains, since preventing GAG sulfat