Erythropoietin in neuroprotection

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Erythropoietin in neuroprotection is the use of the glycoprotein erythropoietin (Epo) for neuroprotection. Epo controls erythropoiesis, or red blood cell production.

Contents

Erythropoietin and its receptor were thought to be present in the central nervous system according to experiments with antibodies that were subsequently shown to be nonspecific. While erythropoietin alpha is capable of crossing the blood brain barrier via active transport, [1] concentrations in the central nervous system are very low. The possibility that Epo might have effects on neural tissues resulted in experiments to explore whether Epo might be tissue protective. The reported presence of Epo within the spinal fluid of infants and the expression of Epo-R in the spinal cord, suggested a potential role by Epo within the CNS therefore Epo represented a potential therapy to protect photoreceptors damaged from hypoxic pretreatment. [2]

In some animal studies, Epo has been shown to protect nerve cells from hypoxia-induced glutamate toxicity. [2] [3] Epo has also been reported to enhance nerve recovery after spinal trauma. Celik and associates investigated motor neuron apoptosis in rabbits with a transient global spinal ischemia model. [4] The functional neurological status of animals given RhEpo was better after recovery from anesthesia, and kept improving over a two-day period. The animals given saline demonstrated a poor functional neurological status and showed no significant improvements. These results suggested that RhEpo has both an acute and delayed beneficial action in ischemic spinal cord injury.

In contrast to these results, numerous studies have suggested that Epo had no neuroprotective benefit in animal models and EpoR was not detected in brain tissues using anti-EpoR antibodies that were shown to be sensitive and specific.[ citation needed ]

Development with mutant Epo and EpoR

While EpoR was reportedly detected in the embryonic brain, its role in brain development is unclear. In one study Epo stimulated neural progenitor cells and prevented apoptosis in the embryonic brain in mice. [5] Mice without EpoR demonstrated severe anemia, defective heart development, and eventually death around embryonic day 13.5 from apoptosis in the liver, endocardium, myocardium, and fetal brain. As early as embryonic day 10.5 the lack of EpoR can affect brain development by increasing fetal brain apoptosis and decreasing the number of neural progenitor cells. By exposing cultures of EpoR positive embryonic cortical neurons to stimulation by Epo administration, the cells decreased apoptosis, as opposed to the decrease in neuron generation in EpoR negative cells.

However it has been questioned whether EpoR may or may not be a determining factor for the nervous system function. [6] The contribution of Epo and EpoR to neuroprotection and development are not as clearly understood as its role in erythropoiesis in hematopoietic tissue. In a line of mice that expressed EpoR exclusively in hematopoietic cells, the mice developed normally had normal brains and brain function and were fertile, despite the lack of EpoR in nonhematopoietic tissue. Differential expression of EpoR between erythroid cells. Most notably, plasma Epo concentration is regulated by nonhematopoietic EpoR expression when the peak of plasma concentrations for induced anemia in mutant and wild-type mice. The expression of EpoR in nonhematopoietic tissue is dispensable in normal mouse development, but that the sensitivity of erythroid progenitors to Epo is regulated by the expression of EpoR.

Erythropoietin mutants R103-E and S100-E (though S100 in Epo doesn't exist) has been reported to be non-erythropoietin but retain the neuroprotective function. Epo with R103 mutation is a potent inhibitor of wild type Epo from binding to its receptor. Though, the viral vector expressed R103-E Epo mutant was shown to be inhibitory to the progression / development of nervous tissue damage in many models, it is not shown to recover the nervous tissue post damage. Given the associated risks, it would be foolish to administer / express Mutant as a preventive measure from neuronal injury. Hence, from a medical or commercial point of view, safe and feasible neuro-protective Epo mutants are not possible.

Quite a bit of research emphasis is on non erythropoietic but, neuroprotective Peptides of Erythropoietin. Peptide of Epo with amino acids 92-111 is neuroprotective while its erythropoietic potency is 10 fold less than the wild type.

A short peptide sequence from the erythropoietin molecule called JM4, has been found to be non-erythropoietic yet theoretically neuroprotective and is being readied for Stage 1 and 2 clinical studies. [7] [8]

Peripheral nervous system

Production and localization in PNS

Erythropoietin and its receptor are also reported in the peripheral nervous system, specifically in the bodies and axons of ganglions in the dorsal root, and at increased levels in Schwann cells after peripheral nerve injury. [9] The distribution of EpoR was different from Epo, specifically in some neuronal cell bodies in the dorsal root ganglion, endothelial cells, and Schwann cells of normal nerves. Most importantly, experiments with immunostaining revealed that the distribution and concentration of EpoR on Schwann cells doesn’t change after peripheral nerve injury. However those studies are of questionable significance since the antibodies were nonspecific to EpoR. Other research that suggested Epo is up-regulated according to mRNA expression in astrocytes and hypoxia-induced neurons, while EpoR is not. [10] A correlation between the expression of Epo-R in ganglion cells and binding to sensory receptors in the periphery like Pacini bodies and neuromuscular spindles suggests that Epo-R is related to touch regulation. [11]

Peripheral nerve injury

Site of injury

After nerve injury, the increased production of Epo may induce activation of certain cellular pathways, while the concentration of EpoR doesn’t change. In Schwann cells, increased erythropoietin levels may stimulate Schwann cell proliferation via JAK2 and ERK/MAP kinase activation to be explained later. Similar to stimulation of red blood cell precursor cells (erythrogenesis), erythropoietin stimulates non-differentiated Schwann cells to proliferate. [11]

Anti-apoptosis mechanisms

Although the mechanism is unclear, it is apparent that erythropoietin has anti-apoptotic action after central and peripheral nerve injury. Cross-talk between JAK2 and NF-κB signaling cascades has been demonstrated to be a possible factor in central nerve injury. Erythropoietin has also been shown to prevent axonal degeneration when produced by neighboring Schwann cells with nitrous oxide as the axonal injury signal. [12]

Mode of action

Direct and indirect effects

Erythropoietin exerts its neuroprotective role directly by activating transmitter molecules that play a role in erythrogenesis and indirectly by restoring blood flow. [13] Subcutaneous administration of RhEpo on cerebral blood flow autoregulation after experimental subarachnoid hemorrhage was studied. In different groups of male Sprague-Dawley Rats, the injection of Epo after induction of hemorrhage normalized the autoregulation of cerebral blood flow, while those treated with a vehicle showed no autoregulation.

Pathway

The pathway for erythropoietin in both the central and peripheral nervous systems begins with the binding of Epo to EpoR. This leads to the enzymatic phosphorylation of PI3-K and NF-κB and results in the activation of proteins that regulate nerve cell apoptosis. [14] Recent research shows that Epo activates JAK2 cascades which activate NF-κB, leading to the expression of CIAP and c-IAP2, two apoptosis-inhibiting genes. Research conducted in rat hippocampal neurons demonstrates that the protective role of Epo in hypoxia-induced cell death acts through extracellular signal-regulated kinases ERK1, ERK2 and protein kinase Akt-1/PKB. [15] The action of Epo is not limited to just promoting cell survival and that the inhibition of neural apoptosis underlies short latency protective effects of Epo after brain injury. Accordingly, the neurotrophic actions may demonstrate longer-latency effects, but more research needs to be conducted on its clinical safety and effectiveness.

Cerebral damage and inflammation

Additionally to the anti-apoptotic effect, Epo reduces inflammatory response during different types of cerebral injury via the NF-κB pathway. [16] The NF-κB pathway activated by Epo/EpoR phosphorylation plays a role in regulating inflammatory and immune response, in addition to preventing apoptosis due to cellular stress. [17] NF-κB proteins regulate immune response through B-lymphocyte control and T-lymphocyte proliferation. These proteins are all important for the expression of genes specific to immune and inflammatory response regulation.

Neuroprotective effects

As a neuroprotective agent erythropoietin has many functions: antagonizing glutamate cytotoxic action, enhancing antioxidant enzyme expression, reducing free radical production rate, and affecting neurotransmitter release. It exerts its neuroprotective effect indirectly through restoration of blood flow or directly by activating transmitter molecules in neurons that also play a role in erythrogenesis. Although apoptosis is not reversible, early intervention with neuroprotective therapeutic procedures such as erythropoietin administration may reduce the number of neurons that undergo apoptosis. [11]

Recombinant human EPO administration

The systemic administration of RhEpo has been shown to reduce dorsal root ganglion cell apoptosis. [18] While animals treated with RhEpo weren’t initially protected from mechanical allodynia after spinal nerve crush, a significantly improved recovery rate compared to animals not treated with RhEpo was demonstrated. This RhEpo therapy increased JAK2 phosphorylation, which has been found to be a key signaling step in Epo-induced neuroprotection by an anti-apoptotic mechanism. These findings demonstrate Epo therapy as a feasible treatment of neuropathic pain by reducing the protraction of pain after nerve injury. However, more studies need to be conducted to determine the optimal time and dosage for RhEpo treatment.

Neonatal brain injury

In infants with poor neurodevelopment, prematurity and asphyxia are typical problems. These conditions can lead to cerebral palsy, mental retardation, and sensory impairment. Hypothermia therapy for neonatal encephalopathy is a proven therapy for neonatal brain injury. However, recent research has demonstrated that high doses of recombinant erythropoietin can reduce or prevent this type of neonatal brain injury if administered early. [19] A high rate of neuronal apoptosis is evident in the developing brain due to initial overproduction. Neurons that are electrically active and make synaptic connections survive, while those that do not undergo apoptosis. While this is a normal phenomenon, it is also known that neurons in the developing brain are at an increased risk to undergo apoptosis in response to injury. A small amount of the RhEpo can cross the blood–brain barrier and protect against hypoxic-ischemia injury. Epo treatment has also shown to preserve hemispheric brain volume 6 weeks after neonatal stroke. [20] It demonstrated both neuroprotective effects and a direction towards neurogenesis in neonatal stroke without associated long-term difficulties.

Cognitive and behavioral effects

Systemic administration of RhEpo has also been shown to reduce lesion-associated behavioral impairment in hippocampally injured rats. [21] The study confirmed that Epo administration improved posttraumatic behavioral and cognitive abilities versus a saline control that experienced no improvement, although it had no detectable effect on task acquisition in non-lesioned animals. Epo is able to reduce or eliminate the consequences of mechanical injury to the hippocampus but also demonstrates possible therapeutic effects in other cognitive domains.

Dopaminergic neurons

Epo was shown to specifically protect dopaminergic neurons, which are closely tied into attention deficit hyperactivity disorder. [19] Specifically in mice, Epo demonstrated protective effects on nigral dopaminergic neurons in a mouse model of Parkinson's disease. [22] This recent experiment tested the hypothesis that RhEpo could protect dopaminergic neurons and improve the neurobehavioral outcome in a rat model of Parkinson's Disease. The intrastriatal administration of RhEpo significantly reduced the degree of rotational asymmetry, and the RhEpo-treated rats demonstrated improvement in skilled forearm use. These experiments demonstrated that intrastriatal administration of RhEpo can protect nigral dopaminergic neurons from 6-OHDA induced cell death and improve neurobehavioral outcome in a rat model of Parkinson's Disease.

Current treatment

Currently methylprednisolone (Medrol) is only pharmaceutical agent used to treat spinal cord trauma. [11] It is a corticosteroid that reduces damage to nerve cells and decreases inflammation near injury sites. It is typically administered within the first 8 hours after injury, but demonstrates poor results both in patients and experimental models. Some controversy has come about concerning the use of methylprednisolone because of its associated risks and poor clinical results, but it is the only medication available.

Neurotherapeutic role

If administered within a specific timeframe in experiments with erythropoietin in central nervous system, Epo has a favorable response in brain and spinal cord injuries like mechanical trauma or subarachnoid hemorrhages. [23] Research also demonstrates a therapeutic role in modulating neuronal excitability and acting as a trophic factor both in vivo and in vitro. [23] This administration of erythropoietin functions by inhibiting the apoptosis of sensor and motor neurons via stimulation of intracellular anti-apoptotic metabolic paths. The action of erythropoietin on Schwann cells and inflammatory response after neurological trauma also points to initial stimulation of nerve regeneration after peripheral nerve injury. [11]

Role in neurogenesis

Erythropoietin and its receptor have an essential role in neurogenesis, specifically in post-stroke neurogenesis and in the migration of neuroblasts to areas of neural injury. [24] Severe embryonic neurogenesis defects in animals that were null for Epo or EpoR genes are found. In EpoR knock-down animals, deletion of EpoR genes specific to the brain lead to a reduction in cell growth in the subventricular zone and impaired neurogenesis after stroke. This post-stroke neurogenesis was characterized by an impaired migration of neuroblasts in the peri-infarct cortex. This results is in agreement with the classical approach to Epo/EpoR contributions in development in that it demonstrated an Epo/EpoR requirement for embryonic neural development, adult neurogenesis, and neuron regeneration after injury. High doses of exogenous erythropoietin could demonstrate a neuroprotective role by binding to a receptor that contains the common beta receptor but lacks EpoR. These types of studies into Epo and EpoR null animals have seen and are further elucidating the neuroprotective role of Epo/EpoR in genetics and development.

Neuroregeneration

While the neuroprotective effects of Epo administration in models of brain injury and disease have been well described, the effects of Epo on Neuroregeneration are currently being investigated. Epo administration during optic nerve transaction was used to assess the neuroprotective properties in vivo as well as demonstrate the neuroregenerative capabilities. [25] The intravitreal injection of Epo increased retinal ganglion cell somata and axon survival after transaction. A small amount of axons penetrated the transaction site and regenerated up to 1 mm into the distal nerve. In a second experiment, Epo doubled the number of retinal ganglion cell axons regenerating along a length of nerve grafted onto the retrobulbar optic nerve. This evidence of Epo as a neuroprotective and neuroregenerative agent is extremely promising for Epo as therapy in central nerve injury and repair.

Research directions

Erythropoietin has shown to have a neuroprotective role in both the central and peripheral nervous system through pathways that inhibit apoptosis. It has been successful in demonstrating neuroprotective effects in many models of brain injury and in some experiments. It is also capable of influencing neuron stimulation and promoting peripheral nerve regeneration. Epo has a lot of potential uses and could provide a therapeutic answer for nervous system injury. However, more studies need to be conducted to determine the optimal time and dosage for Epo treatment.

Glaucoma

Neuroprotection is also a concept used in ophthalmology regarding glaucoma. The only neuroprotection currently proven in glaucoma is intraocular pressure reduction. However, there are theories that there are other possible areas of neuroprotection, such as protecting from the toxicity induced by degenerating nerve fibres from glaucoma. Cell culture models show that retinal ganglion cells can be prevented from dying by certain pharmacological treatments. Intraperitoneal injection of Epo in DBA/2J mice protected / slowed down the degeneration of Retinal ganglion cell (RGC). [26] Overexpression of Epo and Epo mutants in the eye via, viral vectors is toxic to the retina.

See also

Related Research Articles

<span class="mw-page-title-main">Neuron</span> Electrically excitable cell found in the nervous system of animals

Within a nervous system, a neuron, neurone, or nerve cell is an electrically excitable cell that fires electric signals called action potentials across a neural network. Neurons communicate with other cells via synapses, which are specialized connections that commonly use minute amounts of chemical neurotransmitters to pass the electric signal from the presynaptic neuron to the target cell through the synaptic gap.

<span class="mw-page-title-main">Nervous system</span> Part of an animal that coordinates actions and senses

In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes that impact the body, then works in tandem with the endocrine system to respond to such events. Nervous tissue first arose in wormlike organisms about 550 to 600 million years ago. In vertebrates, it consists of two main parts, the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and spinal cord. The PNS consists mainly of nerves, which are enclosed bundles of the long fibers, or axons, that connect the CNS to every other part of the body. Nerves that transmit signals from the brain are called motor nerves or efferent nerves, while those nerves that transmit information from the body to the CNS are called sensory nerves or afferent. Spinal nerves are mixed nerves that serve both functions. The PNS is divided into three separate subsystems, the somatic, autonomic, and enteric nervous systems. Somatic nerves mediate voluntary movement. The autonomic nervous system is further subdivided into the sympathetic and the parasympathetic nervous systems. The sympathetic nervous system is activated in cases of emergencies to mobilize energy, while the parasympathetic nervous system is activated when organisms are in a relaxed state. The enteric nervous system functions to control the gastrointestinal system. Both autonomic and enteric nervous systems function involuntarily. Nerves that exit from the cranium are called cranial nerves while those exiting from the spinal cord are called spinal nerves.

<span class="mw-page-title-main">Schwann cell</span> Glial cell type

Schwann cells or neurolemmocytes are the principal glia of the peripheral nervous system (PNS). Glial cells function to support neurons and in the PNS, also include satellite cells, olfactory ensheathing cells, enteric glia and glia that reside at sensory nerve endings, such as the Pacinian corpuscle. The two types of Schwann cells are myelinating and nonmyelinating. Myelinating Schwann cells wrap around axons of motor and sensory neurons to form the myelin sheath. The Schwann cell promoter is present in the downstream region of the human dystrophin gene that gives shortened transcript that are again synthesized in a tissue-specific manner.

<span class="mw-page-title-main">Erythropoietin</span> Protein that stimulates red blood cell production

Erythropoietin, also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO include any anemia, and hypoxemia due to chronic lung disease and mouth disease.

<span class="mw-page-title-main">Nervous tissue</span> Main component of the nervous system

Nervous tissue, also called neural tissue, is the main tissue component of the nervous system. The nervous system regulates and controls body functions and activity. It consists of two parts: the central nervous system (CNS) comprising the brain and spinal cord, and the peripheral nervous system (PNS) comprising the branching peripheral nerves. It is composed of neurons, also known as nerve cells, which receive and transmit impulses, and neuroglia, also known as glial cells or glia, which assist the propagation of the nerve impulse as well as provide nutrients to the neurons.

<span class="mw-page-title-main">Oligodendrocyte</span> Neural cell type

Oligodendrocytes, also known as oligodendroglia, are a type of neuroglia whose main functions are to provide support and insulation to axons within the central nervous system (CNS) of jawed vertebrates. Their function is similar to that of Schwann cells, which perform the same task in the peripheral nervous system (PNS). Oligodendrocytes accomplish this by forming the myelin sheath around axons. Unlike Schwann cells, a single oligodendrocyte can extend its processes to cover around 50 axons, with each axon being wrapped in approximately 1 μm of myelin sheath. Furthermore, an oligodendrocyte can provide myelin segments for multiple adjacent axons.

<span class="mw-page-title-main">Wallerian degeneration</span> Biological process of axonal degeneration

Wallerian degeneration is an active process of degeneration that results when a nerve fiber is cut or crushed and the part of the axon distal to the injury degenerates. A related process of dying back or retrograde degeneration known as 'Wallerian-like degeneration' occurs in many neurodegenerative diseases, especially those where axonal transport is impaired such as ALS and Alzheimer's disease. Primary culture studies suggest that a failure to deliver sufficient quantities of the essential axonal protein NMNAT2 is a key initiating event.

<span class="mw-page-title-main">Neurotrophin</span> Family of proteins

Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.

<span class="mw-page-title-main">Dorsal root ganglion</span> Cluster of neurons in a dorsal root of a spinal nerve

A dorsal root ganglion is a cluster of neurons in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the dorsal root ganglia.

<span class="mw-page-title-main">Peripherin</span> Protein-coding gene in the species Homo sapiens

Peripherin is a type III intermediate filament protein expressed mainly in neurons of the peripheral nervous system. It is also found in neurons of the central nervous system that have projections toward peripheral structures, such as spinal motor neurons. Its size, structure, and sequence/location of protein motifs is similar to other type III intermediate filament proteins such as desmin, vimentin and glial fibrillary acidic protein. Like these proteins, peripherin can self-assemble to form homopolymeric filamentous networks, but it can also heteropolymerize with neurofilaments in several neuronal types. This protein in humans is encoded by the PRPH gene. Peripherin is thought to play a role in neurite elongation during development and axonal regeneration after injury, but its exact function is unknown. It is also associated with some of the major neuropathologies that characterize amyotropic lateral sclerosis (ALS), but despite extensive research into how neurofilaments and peripherin contribute to ALS, their role in this disease is still unidentified.

<span class="mw-page-title-main">Neuroprotection</span> Relative preservation of neuronal structure and/or function

Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.

<span class="mw-page-title-main">Neuroimmune system</span>

The neuroimmune system is a system of structures and processes involving the biochemical and electrophysiological interactions between the nervous system and immune system which protect neurons from pathogens. It serves to protect neurons against disease by maintaining selectively permeable barriers, mediating neuroinflammation and wound healing in damaged neurons, and mobilizing host defenses against pathogens.

<span class="mw-page-title-main">Low-affinity nerve growth factor receptor</span> Human protein-coding gene

The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic factor receptor. Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor, Neurotrophin-3, Brain-derived neurotrophic factor, and Neurotrophin-4. All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR is involved in pathways that promote neuronal survival and neuronal death.

<span class="mw-page-title-main">Galanin</span>

Galanin is a neuropeptide encoded by the GAL gene, that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors.

<span class="mw-page-title-main">Satellite glial cell</span> SINGLE CELL SOMATA

Satellite glial cells, formerly called amphicytes, are glial cells that cover the surface of neuron cell bodies in ganglia of the peripheral nervous system. Thus, they are found in sensory, sympathetic, and parasympathetic ganglia. Both satellite glial cells (SGCs) and Schwann cells are derived from the neural crest of the embryo during development. SGCs have been found to play a variety of roles, including control over the microenvironment of sympathetic ganglia. They are thought to have a similar role to astrocytes in the central nervous system (CNS). They supply nutrients to the surrounding neurons and also have some structural function. Satellite cells also act as protective, cushioning cells. Additionally, they express a variety of receptors that allow for a range of interactions with neuroactive chemicals. Many of these receptors and other ion channels have recently been implicated in health issues including chronic pain and herpes simplex. There is much more to be learned about these cells, and research surrounding additional properties and roles of the SGCs is ongoing.

<span class="mw-page-title-main">Nerve injury</span> Damage to nervous tissue

Nerve injury is an injury to a nerve. There is no single classification system that can describe all the many variations of nerve injuries. In 1941, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve. Usually, however, nerve injuries are classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved.

Neuroregeneration involves the regrowth or repair of nervous tissues, cells or cell products. Neuroregenerative 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 involved, especially in the extent and speed of repair. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.

Protective autoimmunity is a condition in which cells of the adaptive immune system contribute to maintenance of the functional integrity of a tissue, or facilitate its repair following an insult. The term ‘protective autoimmunity’ was coined by Prof. Michal Schwartz of the Weizmann Institute of Science (Israel), whose pioneering studies were the first to demonstrate that autoimmune T lymphocytes can have a beneficial role in repair, following an injury to the central nervous system (CNS). Most of the studies on the phenomenon of protective autoimmunity were conducted in experimental settings of various CNS pathologies and thus reside within the scientific discipline of neuroimmunology.

<span class="mw-page-title-main">Olfactory ensheathing cell</span> Type of macroglia that ensheath unmyelinated olfactory neurons

Olfactory ensheathing cells (OECs), also known as olfactory ensheathing glia or olfactory ensheathing glial cells, are a type of macroglia found in the nervous system. They are also known as olfactory Schwann cells, because they ensheath the non-myelinated axons of olfactory neurons in a similar way to which Schwann cells ensheath non-myelinated peripheral neurons. They also share the property of assisting axonal regeneration.

<span class="mw-page-title-main">Outline of the human nervous system</span> Overview of and topical guide to the human nervous system

The following diagram is provided as an overview of and topical guide to the human nervous system:

References

  1. ↑ Juul SE, Anderson DK, Li Y, Christensen RD (January 1998). "Erythropoietin and erythropoietin receptor in the developing human central nervous system". Pediatr. Res. 43 (1): 40–9. doi: 10.1203/00006450-199804001-00243 . PMID   9432111.
  2. 1 2 Grimm C, Wenzel A, Groszer M, Mayser H, Seeliger M, Samardzija M, Bauer C, Gassmann M, Remé CE (July 2002). "HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration". Nat. Med. 8 (7): 718–24. doi:10.1038/nm723. PMID   12068288. S2CID   1595426.
  3. ↑ Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R (January 1997). "Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death". Neuroscience. 76 (1): 105–16. doi:10.1016/S0306-4522(96)00306-5. PMID   8971763. S2CID   41374229.
  4. ↑ Celik M, Gökmen N, Erbayraktar S, Akhisaroglu M, Konakc S, Ulukus C, Genc S, Genc K, Sagiroglu E, Cerami A, Brines M (February 2002). "Erythropoietin prevents motor neuron apoptosis and neurologic disability in experimental spinal cord ischemic injury". Proc. Natl. Acad. Sci. U.S.A. 99 (4): 2258–63. Bibcode:2002PNAS...99.2258C. doi: 10.1073/pnas.042693799 . PMC   122352 . PMID   11854521.
  5. ↑ Yu X, Shacka JJ, Eells JB, Suarez-Quian C, Przygodzki RM, Beleslin-Cokic B, Lin CS, Nikodem VM, Hempstead B, Flanders KC, Costantini F, Noguchi CT (January 2002). "Erythropoietin receptor signalling is required for normal brain development". Development. 129 (2): 505–16. doi:10.1242/dev.129.2.505. PMID   11807041.
  6. ↑ Suzuki N, Ohneda O, Takahashi S, Higuchi M, Mukai HY, Nakahata T, Imagawa S, Yamamoto M (October 2002). "Erythroid-specific expression of the erythropoietin receptor rescued its null mutant mice from lethality". Blood. 100 (7): 2279–88. doi:10.1182/blood-2002-01-0124. hdl: 2241/1805 . PMID   12239135. S2CID   35004292.
  7. ↑ Yuan, R.; Wang, B.; Lu, W.; Maeda, Y.; Dowling, P. (2015). "A Distinct Region in Erythropoietin that Induces Immuno/Inflammatory Modulation and Tissue Protection". Neurotherapeutics. 12 (4): 850–861. doi:10.1007/s13311-015-0379-1. PMC   4604189 . PMID   26271954.
  8. ↑ "Short Stabilized EPO-Peptide as Side-Effect-Free Therapeutic Agents for Multiple Sclerosis and Acute Brain Trauma". National Center for Advancing Translational Science (NCATS). 2015-03-12.
  9. ↑ Campana WM, Myers RR (August 2001). "Erythropoietin and erythropoietin receptors in the peripheral nervous system: changes after nerve injury". FASEB J. 15 (10): 1804–6. doi: 10.1096/fj.00-0857fje . PMID   11481236. S2CID   11803744.
  10. ↑ Bernaudin M, Bellail A, Marti HH, Yvon A, Vivien D, Duchatelle I, Mackenzie ET, Petit E (May 2000). "Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain". Glia. 30 (3): 271–8. doi:10.1002/(sici)1098-1136(200005)30:3<271::aid-glia6>3.0.co;2-h. PMID   10756076. S2CID   10131344.
  11. 1 2 3 4 5 Lykissas MG, Korompilias AV, Vekris MD, Mitsionis GI, Sakellariou E, Beris AE (October 2007). "The role of erythropoietin in central and peripheral nerve injury". Clin Neurol Neurosurg. 109 (8): 639–44. doi:10.1016/j.clineuro.2007.05.013. PMID   17624659. S2CID   22990605.
  12. ↑ Keswani SC, Buldanlioglu U, Fischer A, Reed N, Polley M, Liang H, Zhou C, Jack C, Leitz GJ, Hoke A (December 2004). "A novel endogenous erythropoietin mediated pathway prevents axonal degeneration". Ann. Neurol. 56 (6): 815–26. doi:10.1002/ana.20285. PMID   15470751. S2CID   22025115.
  13. ↑ Springborg JB, Ma X, Rochat P, Knudsen GM, Amtorp O, Paulson OB, Juhler M, Olsen NV (February 2002). "A single subcutaneous bolus of erythropoietin normalizes cerebral blood flow autoregulation after subarachnoid haemorrhage in rats". Br. J. Pharmacol. 135 (3): 823–9. doi:10.1038/sj.bjp.0704521. PMC   1573185 . PMID   11834631.
  14. ↑ Chong ZZ, Kang JQ, Maiese K (May 2002). "Hematopoietic factor erythropoietin fosters neuroprotection through novel signal transduction cascades". J. Cereb. Blood Flow Metab. 22 (5): 503–14. doi: 10.1097/00004647-200205000-00001 . PMID   11973422.
  15. ↑ Sirén AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A, Mennini T, Heumann R, Cerami A, Ehrenreich H, Ghezzi P (March 2001). "Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress". Proc. Natl. Acad. Sci. U.S.A. 98 (7): 4044–9. Bibcode:2001PNAS...98.4044S. doi: 10.1073/pnas.051606598 . PMC   31176 . PMID   11259643.
  16. ↑ Digicaylioglu M, Lipton SA (August 2001). "Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades". Nature. 412 (6847): 641–7. Bibcode:2001Natur.412..641D. doi:10.1038/35088074. PMID   11493922. S2CID   4346187.
  17. ↑ Yamamoto Y, Gaynor RB (July 2001). "Role of the NF-kappaB pathway in the pathogenesis of human disease states". Curr. Mol. Med. 1 (3): 287–96. doi:10.2174/1566524013363816. PMID   11899077.
  18. ↑ Campana WM, Myers RR (September 2003). "Exogenous erythropoietin protects against dorsal root ganglion apoptosis and pain following peripheral nerve injury". Eur. J. Neurosci. 18 (6): 1497–506. doi:10.1046/j.1460-9568.2003.02875.x. PMID   14511329. S2CID   8533004.
  19. 1 2 McPherson RJ, Juul SE (February 2008). "Recent trends in erythropoietin-mediated neuroprotection". Int. J. Dev. Neurosci. 26 (1): 103–11. doi:10.1016/j.ijdevneu.2007.08.012. PMC   2312376 . PMID   17936539.
  20. ↑ Gonzalez FF, McQuillen P, Mu D, Chang Y, Wendland M, Vexler Z, Ferriero DM (2007). "Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke". Dev. Neurosci. 29 (4–5): 321–30. doi: 10.1159/000105473 . PMID   17762200.
  21. ↑ Mogensen J, Jensen C, Kingod SC, Hansen A, Larsen JA, Malá H (January 2008). "Erythropoietin improves spatial delayed alternation in a T-maze in fimbria-fornix transected rats". Behav. Brain Res. 186 (2): 215–21. doi:10.1016/j.bbr.2007.08.009. PMID   17888525. S2CID   22974206.
  22. ↑ Xue YQ, Zhao LR, Guo WP, Duan WM (May 2007). "Intrastriatal administration of erythropoietin protects dopaminergic neurons and improves neurobehavioral outcome in a rat model of Parkinson's disease". Neuroscience. 146 (3): 1245–58. doi:10.1016/j.neuroscience.2007.02.004. PMID   17363174. S2CID   10775364.
  23. 1 2 Brines M (September 2002). "What evidence supports use of erythropoietin as a novel neurotherapeutic?". Oncology (Williston Park, N.Y.). 16 (9 Suppl 10): 79–89. PMID   12380958.
  24. ↑ Tsai PT, Ohab JJ, Kertesz N, Groszer M, Matter C, Gao J, Liu X, Wu H, Carmichael ST (2006). "A critical role of erythropoietin receptor in neurogenesis and post-stroke recovery". J. Neurosci. 26 (4): 1269–74. doi:10.1523/JNEUROSCI.4480-05.2006. PMC   6674578 . PMID   16436614.
  25. ↑ King CE, Rodger J, Bartlett C, Esmaili T, Dunlop SA, Beazley LD (May 2007). "Erythropoietin is both neuroprotective and neuroregenerative following optic nerve transection". Exp. Neurol. 205 (1): 48–55. doi:10.1016/j.expneurol.2007.01.017. PMID   17328893. S2CID   43344936.
  26. ↑ Zhong L, Bradley J, Schubert W, Ahmed E, Adamis AP, Shima DT, Robinson GS, Ng YS (March 2007). "Erythropoietin promotes survival of retinal ganglion cells in DBA/2J glaucoma mice". Invest. Ophthalmol. Vis. Sci. 48 (3): 1212–8. doi:10.1167/iovs.06-0757. PMID   17325165. Erythropioetin is a very potent molecule (One Unit ~ 10 ng)and is known to be extremely toxic in higher doses. Since, such a tight control of expression is impossible, genetherapy with viral vectors is not an option
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