Neural and axonal regeneration in the central and peripheral nervous system. The peripheral nerves contain several afferent and efferent axons running from somatic and visceral receptors to the central nervous system and back to skeletal muscles, smooth muscle of internal organs and vessels and to different types of glands. Periferal nerves contain two kinds of axons, myelinated and unmyelinated ones.
These are wrapped by the connective tissue of the endoneurium. The myelin is made by Schwann cells, they are curled around the axon and the many layers of the cell membrane create a sheath around the neurite.
Bands of axons are wrapped by a new connective tissue layer, the perineurium, and the whole nerve is covered by the epineurium. In the central nervous system neurons located in the gray matter are connected to eachother by axons, the axons running between the same regions are called tracts, and these together form the white matter.
There is no connective tissue covering in the parenchyma of the brain and the spinal cord, myelin covering is produced by one type of glial cells, the oligodendrocytes in a similar manner as it is done by the Schwann cells in the periphery. However one oligodendrocyte can participiate in the production of the myelin cover chondroitin akos drug more than 60 axons, in the peripheral nerves one Schwann cell is limited to one axon.
Some of the axons are unmyelinated in the central nervous system as well. Chondroitin akos drug 1. Although the constituents and the degenerative processes after injury are similar in the central and peripheral nervous system, there are marked differences in the degree and speed of regeneration. While the axons in the peripheral nerves may fully regenerate in the supportive environment maintained by the Schwann cells, the axons of the central nervous system are unable to regrow in the growth inhibitory milieu of the brain and spinal cord.
First we have a look at the axonal and neuronal changes occuring after peripheral nerve injury, next the differences will be discussed, which causes the limited regeneration in the central nervous system. Peripheral nerve injury Damage to a peripheral nerve leads to a complete or incomplete loss of motor, sensory and vegetative functions conducted by the nerve.
Mechanism of peripheral nerve injury Distraction: damage caused by traction: one of the most frequent type. If the shift is big enough complete tear of the nerve can occur, but more often the continuity of the connective tissue chondroitin akos drug is left intact. It is usually accompanied with extremity fractures, where the nerve runs close to the bone, for example the damage of the radial nerve nervus radialis in humerus fracture.
Laceration: for example cutting with a knife. Often the injury is not complete, continuity of a part of the nerve is left intact.
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In experimental models this type of injury is the easiest to simulate, so its pathomechanism is the most well known. Compression: for example nerve entrapment syndromes. The continuity of the nerve is preserved, in the pathomechanism of injury mechanical and ischemic factors play a role together.
Lost functions in the peripheral nervous system can be compensated by 3 main processes: 1. The most succesfull functional restoration requires the regeneration of the axon, which is the result of special degenerative and subsequent regenerative processes. Pathophysiology of periferal nerve injury The axon segment distal to the injury degenerates soon after the injury.
A cascade of events start in the neuron detached from its axon, which is called chromatolysis. The degeneration distal to the injury creates an environment adequate for the growing new axon, while metabolic changes in the cell body help the regrowth of the axon.
The specific degenerative changes distal to the injured axon after peripheral nerve injury were first described by Augustus Waller in and it is called Wallerian degeneration after him. The occurence of Wallerian degeneration is needed for a successfull axon regeneration.
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After axonal injury calcium ions get into the axon and activate proteases, which causes the disintegration and dissolution of the axolemma and axoplasma as well as the myelin sheath distal to the injury site in hours. Degeneration reaches the proximal axon end on a short segment as well. Phenotypical changes take place in the Schwann cells, the transcription of genes responsible for the production of myelin proteins ceases and transcription of regeneration associated genes starts.
The dedifferentiated Schwann cells proliferate, start to ingest myelin debris, and produce cytokines and neurotrophic factors. Around the degrading axon a sheath of Schwann cells remains in place band of Büngnerwhich directs the growing axon to the original target organ.
There is a significant role of infiltrating macrophages as well, in the phagocytosis of the myelin and in the functional changes of the Schwann cells. Chemokins, produced by Schwann cells attract a great number of these chondroitin akos drug in the vicinity of the distal axon segment from the 3rd day of injury.
They remain approximately 1 month around the distal axon segment, most of the myelin is degraded by them. The degradation fájdalomcsillapítás a kéz ízületeiben myelin has a key role in axon regeneration, because it contains proteins which inhibit axon growth. Degradation processes last months. At the end the distal nerve segment is replaced by the endoneurinal sheath, which is lined on the inside by denervated Schwann cells.
As the denervated Schwann cells, as well the macrophages produce neurotrophic factors, which has further role in the stimulation of axon growth.
Figure 4. The retrograd degeneration of the proximal axon segment usually extends until the first node of Ranvier. The cell body belonging to the damaged axon suffers characteristic morphological changes called chromatolysis. The rough endoplasmic reticulum tigroid or Nissl bodies disappears microscopically, the nucleus swells and is shifted to the periphery of the cell, the dendritic tree shrinks. These morphological changes are followed by remarkable metabolic changes, owing to which, the cell by modifying gene expression, gets into a growth promoting state, required for axon regeneration instead of the previous synaptic signaling supportive state.
The production of lipids, structure proteins, like tubulin, actin, neurotrophic factors and cell adhesion molecules needed for axon growth is increased. This fenotypic alteration of the neuron chondroitin akos drug axonal injury is started by several factors. First retrograd action potentials reach the cell body induced by the sodium and calcium ion inflow at the site of injury. These will cause calcium inflow in the cell as well.
The increased intracellular calcium concentration activates signal transduction pathways responsible for the alteration of cell function.
Later the functional modification is maintained by the absence of neurotrophic factors, like nerve growth factor NGFbrain derived neurotrophic factor BDNFwhich otherwise reaches the cell body by chondroitin akos drug transport from the Schwann cells, and target organs. The regenerative state of the neuron is further maintained by the citokines from activated Schwann cells and macrophages.
So, the success of regeneration depends notably on the capability of the neurons to change their phenotype in order to facilitate axon growth. But phenotypical changes after nerve injury do not end in all cases in the switch to a regenerative state, if axonregeneration is unsuccesfull part of the neurons will suffer apoptotic or necrotic death.
The cellular response of the neuron to axon injury seems to start with chromatolysis and this early degenerative pathway chondroitin akos drug lead to regeneration and survival or to cell death.
Cell death is more frequent in proximal injuries of the nerve. Regeneration following peripheral nerve injury Under ideal conditions, the neuron getting into the growing state and surrounded by the axon growth promotional environment created by the Schwann cells starts to rebuild the missing distal segment of the neurite from the proximal stump and reinnervates the original target organ.
However the anticipated degree of regeneration depends on the severity of nerve injury as well, and peripheral nerve injuries are clinically classified according to this.
The former, recently less frequently used Seddon classification has 3 types of injury: neurapraxia, axonotmesis and neurotmesis. Neurapraxia is the most benign type, continuity of the axon is unaffected, functional loss is only transient. It is probably caused by temporary disturbances in ion currents or partial demyelinisation following the injury.
In the case of axonotmesis the axon and the myelin sheath is torn, Wallerian degeneration of the distal nerve segment occurs and denervation is complete. However, the connective tissue sheaths endo- peri and epineurium remain intact and makes entire chondroitin akos drug recovery possible by leading the growing axon exactly to its former end organ.
During neurotmesis nerve continuity is lost, functional loss is complete and recovery is usually possible only after surgical nerve repair, because spontaneous reinnervation is very limited due to the splitting of the connective tissue framework and the scar hindering axon growth.
Figure 2. An other well accepted classification differentiates 5 types of nerve injury Sunderland according to severity. The first grade corresponds to neurapraxia, the second to axonotmesis, in the third degree injury the endoneurium is torn, but overall nerve continuity is unaffected. Spontaneous regeneration is possible in this case, but because of scar formation inside the nerve and misguided reinnervation, regeneration is incomplete.
In fourth and fifth grade injuries nerve continuity is lost, regeneration is possible only after surgical nerve repair. However, if the gap between the nerve stubs is less than 2cm some spontaneous functional recovery may happen, a gap more than 4cm leads to total functional loss. In serious injuries with significant tissue damage regeneration does not start until Wallerian degeneration has chondroitin akos drug, in milder injuries it can begin soon after the injury.
In first and second degree injuries former functions usually recover, faster in neurapraxia, as soon as the conduction block has ceased and later in fájdalom a csípőízületben, where a new axon has to be grown.
In more severe injuries, where the endoneurium is damaged as well, the growing axons can get into the surrounding tissue or be misleaded into inappropriate endoneurial tube, for example a sensory axon to the place of a motor axon, or axons running to different kind of receptors are arthrosis megszabadulni az ízületi fájdalmaktól. According to this functional axon loss recovery of neurological functions occurs only partially relative to the severity of injury.
The axons unable to reach the distal nerve stump tangle and form a neurinoma composed of connective tissue and growing axonal ends. With time months the connective tissue of the endoneurium in the distal nerve stump is thickened and if the growing axon has not reached it yet, it can even be occluded decreasing the possibilities chondroitin akos drug further regeneration.
Regeneration following nerve injury may last for months. The speed of axonregeneration depends on the protein and lipid synthesis in the cell body. Axon growth can begin in the first 24h after the injury but it can be delayed for weeks following a more sever injury. The speed of axon growth depends on the tissue resistance between the axon stump and the target organ as well. In proximal injuries, where the distal segment is reached by the growing new axon only after a significant delay, the diameter of the endoneurial tubes can decrease notably, which can explain the terminal slow of axon growth.
Due to the difficulty for the growing axon to bridge wide gaps, bulky scar tissue further delay can occur in severe injuries. Although it may happen spontaneously, surgical repair can augment recovery by abolishing gaps, decreasing scar formation. However surgery is not guarantee for appropriate orientation either, axons can grow into functionally inappropriate endoneurial tubes or can not reach them at all, lead to axon loss.
Neurotropism, that would direct the axon to its original endoneurial tube, has not been observed yet. The more severe the injury is, the more significant the retrograd degeneration affecting the proximal stump is and it increases the distance required to be bridged. If the axon grows into an endoneurial tube in the distal segment, there is a good probability to reach the end organ. The growth cone of the axon advances in close contact with the Schwann cells, hogyan lehet csökkenteni a hüvelykujj ízületének fájdalmát direct it by contact and chemotactic signals.
For example NGF receptors appear on the surface of the Schwann cells and bonded NGF is presented to the growth cone, then it is transported in a retrograd way to the cell body to sustain the growth program.
Additionally, adhesion molecules are expressed on the growth cone to help progression by binding to extracellular matrix proteins. If the target organ reached by the axon is not the appropriate one for that neuron further maturation, myelination does not occur and axon may degenerate.
This is the case as well, when during the long axon growth degenerative changes in the target organ hinder the establishment of functional connection. Atrophy in muscle fibers occurs soon after denervation, accompanied with augmentation chondroitin akos drug connective tissue, but motor end plates remain capable of functional connections up to 1 year. Denervated sensory receptors are able to build functional connections for 1 or even several years too. In first and second degree injuries restoration of sensation can be complete even after months of denervation, in more sever injuries recovery is never complete due to axon loss and cross reinnervation.
Recovery of motor functions is often limited as well. Causes are muscle or nerve related ones. The contractility of reinnervated muscle chondroitin akos drug attenuated byintramuscular fibrosis.
Physiotherapy, electrical muscle stimulation can decrease the propagation of connective tissue in muscle until reinnervation has not been finished. Axon loss and cross reinnervation can occur in muscle as well, leading to reduction in functional recovery.
Complete functional recovery is preceded by the maturation of the axon in the form of remyelination and widening of its diameter. These processes start with the growing of the new axon but an active connection with the target organ is necessary for its completion.
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Regenerative capability of peripheral neurons persist for 12 months after the injury. Although axon regeneration in the peripheral nervous system is possible, several factors are responsible for the often partial functional recovery. Regeneration in the central nervous system Although the neurons chondroitin akos drug the central nervous system and the axons building the tracts of the white matter are very együttes kezelés tinédzserben to the axons and neurons of the peripheral nervous system, moreover cell bodies of the peripheral nerves are located partially inside the brain and spinal cord, the possibilities of axon regeneration in the central nervous system are very limited compared to the nearly full regeneration of the peripheral ones.
Early in the 20th century Ramón y Cajal supposed that these differences are rather due to environmental effects than intrinsic features of the neurons. A good example to the effect of environmental factors is the response to injury of the two axons of the dorsal root ganglion.
Two axons belong to the pseudounipolar neurons of the sensory ganglion, one conducts electrical stimulus from systemic receptors to a sarok ízületi gyulladásának kezelése cell body, the other from the cell body towards other neurons in the spinal cord. The former axon belongs to the peripheral nerve, the later to the central nervous system. Following experimental transection of the axons, the peripheral one regenerates, the other does not howeverthey belong to the same neuron.
If the inhibiting effect of the environment is circumvented for example by placing a peripheral nerve graft into the spinal cord or an implant made up of Schwann cells, some axon regeneration can be observed even in the central axon. Tha Wallerian degeneration of the distal chondroitin akos drug segment following axon injury takes place in the central nervous system as well similar to the peripheral nerves.
Chondroitin akos drug injury has to be not necessarily the rupture of the axon, for example in diffuse axonal injury, one kind of head trauma, the ion permeability of the axolemma changes owing to trauma induced shear forces and significant influx of sodium and calcium ions occurs.
The increased intraaxonal calcium concentration activates proteases, which are responsible for the degradation of the distal axon segment.
When the continuity of the axon is injured, a specific formation the retraction ball evolves on the proximal axon stump, because anterograd transport from the cell body continues and the axon end swells accordingly. The removal of myelin degradation products of central nervous system oligodendrocytes is a glükózamin / kondroitin arány slower process than in the peripheral nervous system. While it ends in weeks in the periphery, it lasts for months in the central nervous system.
Activated microglia cells start to digest the myelin, but their capability to phagocytise myelin is not sufficient for its full removal, consequently axon growth inhibitory factors found in the myelin remain on the site. Oligodendrocytes do not go hogyan lehet kezelni a bursitis ízületeket similar changes as Schwann cells, dedifferentation towards stimulation of axon growth does not occur.