Nowadays, is composed of pluripotent cells leading
Nowadays,scientists are investigating and researching different ways to modify CNS´senvironment in order to alter cell´s behaviour and induce the axon´sreconstruction process upregulating the inhibitory factors, hoping to one daybe able to reverse brain and spinal cord injuries.Byand large, after considering all things, it can be appreciated the fact thatone of the factors that more conditions neuroregeneration are the differentcell types that can be found as well as the environment that surrounds them andthe CNS and PNS for instance. Asthe embryonic evolution of the CNS and PNS is based on different pathways, thesurrounding environment would differ too, giving therefore rise to specificallycell types with a precise survival capacity and regeneration potential based oncell’s reaction as a genetic factor (“Boundless anatomy and physiology”).
Thecontrast between the CNS and PNS that was exposed in the essay may have emergedfrom an early embryo differentiation as CNS is formed by the neural tubestructure and its assembly, whereas the PNS is primarily constituted by theestablishment of the neural crest. PNS is composed of pluripotent cells leadingto the development of a huge variety of cell type that would induce theformation of the neural crest, which would posteriorly be converted into theganglia and glia, sympathetic and parasympathetic neurones. Inspite of all the molecules that inhibit axon restoration development in theCNS, there are some factors that may also induce neuronal growth. One of thesemolecules is known as the cyclic adenosine monophosphatase (cAMP), usually referredto as a neurological second messenger that affects the neuron development.
cAMPlevel is usually altered when a PNS injury occurs, but it can be increased inthe CNS throughout an intra-ganglionic injection of dibutyryl Camp, which wouldmime the growth effect in the lesion, stimulating sensory axons reconstruction.Rolipram, for example, increments cAMP quantity inducing thus regeneration(Bomze et. al 2001). Someother inhibitory factors as well as alternative inhibitory pathways involvingsignalling can be found outside the glia or the myelin such as, for example, theevidence proposed by recent studies considering the epidermal growth factorreceptor as being one of the components that would promote regenerationdeficiency. Additionally, if we refer to the intrinsic development and growthof the damaged neuron, as it was stated before, one of the molecules that wouldsupport the process but achieves distinct levels of upregulation is the RAGsand, as in the CNS its expression is quite moderate, the effect it has isassociated with regeneration failure (Pernold, K.
et. al 2007). When the CNS is injured, an astroglial woundis formed impeding the restoration process to take place, leading to a physicalobstacle composed principally by CSPGs molecules, that after being regulated byastrocytes that have been previously reactivated, would consequently beexcreted in the extracellular membrane space and bound to it. Unfortunately, areceptor for this molecule has not been determined yet, but a variety ofstudies shows that a factor able to interfere with CSPG would stimulate andimprove CNS regeneration (Asher, R. et.
al 2000). MAIsare mainly related to oligodendrocytes and include factors such as Nogo-A, MAG(myelin-associated glycoprotein), OMgp (oligodendrocyte myelin glycoprotein),associated with Nogo-66 receptor 1 factor which activates neuronal growthinhibition and, even though MAG factors limit axonal regeneration, it wasstated that their inhibitory role is not as effective as the one Nogo factorsundergo (Atwal et. al 2008).Thereare two main classes of molecules that would inhibit CNS regeneration:myelin-associated inhibitors (MAIs) and chondroitin sulphate proteoglycans(CSPGs). There are also some autonomous factors related to cells that lead toregeneration failure, which means that even without inhibitory molecules, CNSaxons would still not be able to recover as easily as the peripheral onesbecause its neurons do not regulate properly the growth associated genes (Bomzeet. al 2001).
Asit was mentioned previously, the environment is a factor that has a big impact inthe regeneration process and it plays an important role in understanding whyaxonal reconstruction is limited in the CNS. Therecently assembled growth cone starts to reuse material creating a promptsupply for the axon, process facilitated by the action of the local synthesisedproteins, inducing the beginning of the regeneration process. Moreover, recentlyit has been outlined the importance of protein expression control during thetriggering of precise signalling factors throughout the axonal reconstruction(Park, M. et.
al 2013).Inaddition, one more signalling wave is perceived a few hours postinjury, usuallybetween 4 and 6 hours, aiming to comprise the principal injury signal composedof proteins that are locally synthesised and translated in the wounded axon.Furthermore, JNK associating protein joins axon vesicles to the damaged siteand transport back the injury signal by a retrograde pathway along the microtubules.Whilst the resting potential of the membrane is re-established, the axon mayform a growth cone or a retraction bulb, this last one considered to be thenon-growing counterparts of the growth cones where the growth failure isassociated to the non-stabilization of the microtubules (Erturk, A. et. al2007).Immediatelyafter the PNS is injured a prompt deluge of calcium happens at a harm axon tipthat scopes over 1 Mm in concentration (Bradke, F. et.
al 2012). This intenseascent in intracellular calcium is fundamental for activating axon recovery asneurons in a free-calcium condition neglect to start axon outgrowth (Spira M.E.et.al 1997). The calcium wave induces chromatin rebuilding leading to the firstconnection between the damaged tip and the soma (Cho, Y. et.
al 2013) and, asthe cytoskeleton endure restoration, it has been determined that its sealingrate is proportional to the calcium-regulated proteins that take part in theprocess. As a consequence of this series of events, the soma experiences chromatolysiseliminating, therefore, the excitatory inputs preserving just the inhibitoryones that would communicate with the damaged soma (Spejo, A., Oliveira, A.
2014).Immediatelyafter an injury is produced, the regeneration pathway begins stimulatingchemical changes and the upregulation of a large number of genes, known as RAGsin the PNS -some of them directly involved in neuronal regeneration-. It isalso undergone the local synthesis of proteins, alterations in the membraneexcitability and signals communication reaching the soma are also expected(Erna A. et.al 2016). Conversely, PNS regenerationis robust due to the stimulatory response Schwann cells develop on the axonalregeneration, which contrasts the inhibitory reaction of oligodendroglia(Siegel G. J. et.
al 1999). Scavenger cells play a really important role in theaxon reconstruction as it clears away the debris, along with the macrophages,in a relatively small amount of time and excrete factors that stimulate Schwanncells to secrete growth factors in order to start the neurodegenerativeprocess, re-establishing connections towards the old pathway and remyelinatingthe isolation sheets that were lost during injury, restoring both motor andsensory functions (Müller J. 2013). CNSneuronal regeneration fails because the habitat that surrounds the lesioninhibits the axon’s reconstruction not enabling thus the plasticity process totake place (Fawcett, JW. et.
al 2012), and, moreover, the regrowth responseprovided by CNS axons is weak and uncertain). It’s immune and glial cells wouldaggravate the deterioration throughout the time the oligodendrocytes and growthfactors would produce inhibitory material on one hand and, the astrocytesactions would lead to an obstruction at the lesion site not allowing neuronalprocesses to pass through and execute its functions on the other hand.Furthermore, the debris that results from isolated materials as a contusionconsequence requires a great amount of time to be cleared away, inhibiting,therefore, the axon repair system (Zhao R.
R. et. al 2013). Chromatolysisis also found in both structures and induces the reorganization of theprincipal structures which includes nucleus and endoplasmic reticulum as wellas an increase in their volume not allowing consequently Nissl bodiesorganization to function correctly by disrupting its placement as Nisslbody-free axonal cytoskeleton assemble in the middle of the axon and nucleusstructures. It is more commonly appreciated in the CNS rather than in the PNS asneurodegeneration leading to death is contemplated (Mcllwain, D.L, Hoke, V. B.2005) although, it may be a reversible process if neuronal death has not beenreached yet, being therefore able to restore its distal structure (Boron, F.
, Boulpaep,L. 2017). Oneof the principal factors that can be found both in the CNS and PNS is theWallerian degeneration where its molecular activity, as well as its cellularcomposition, promote the restoration of axons into targeted tissues by aninnate immune response acting on the contusion section and producing likewaysloss of distal structure due to the lesion site.
The post-traumatic events andresults that Wallerian degeneration endure varies regarding cells type, asSchwann cells -possessors of an amazing remyelination efficacy – amongst others,are present in the PNS whereas microglia and oligodendrocytes are found takingpart of the CNS regeneration mechanism respectively. Although Wallerian degenerationis found in both sites of the nervous system, the process is not as effectivein the CNS as in the PNS (Rotshenker, J. 2011). BothCNS and PNS possess the ability to regenerate after a trauma is produced, eachone undertaking a specific pathway leading to some main differences betweenthem such as, for example, the existing long-distance and almost instantaneousrecovery of the PNS nerve deterioration and the extremely limitation of an axonreconstruction in the CNS (Huebner and Strittmattern 2010).
Despite thecontrast that may be found between these two routes, there are also a fewessential similarities between them that may be crucial to understanding howthey function and which pathways are required in order to undertake them, evenif the repair course would differ afterwards. Theaxon regeneration following an injury of the central nervous system (CNS) andperipheral nervous system (PNS) is of particular importance since itsneurological functional capacity and effective functionality can be recovered.