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1、Int.J.Biol.Sci.2020,Vol.16 http:/ 116 International Journal of Biological Sciences 2020;16(1):116-134.doi:10.7150/ijbs.35653 Review Current Status of Therapeutic Approaches against Peripheral Nerve Injuries:A Detailed Story from Injury to Recovery Ghulam Hussain1,Jing Wang2,Azhar Rasul3,Haseeb Anwar

2、1,Muhammad Qasim4,Shamaila Zafar1,Nimra Aziz1,Aroona Razzaq1,Rashad Hussain5,Jose-Luis Gonzalez de Aguilar6,7 and Tao Sun2 1.Neurochemicalbiology and Genetics Laboratory(NGL),Department of Physiology,Faculty of Life Sciences,Government College University,Faisalabad,38000 Pakistan.2.Center for Precis

3、ion Medicine,School of Medicine and School of Biomedical Sciences,Huaqiao University,Xiamen,Fujian Province,361021 China 3.Department of Zoology,Faculty of Life Sciences,Government College University,Faisalabad,38000 Pakistan 4.Department of Bioinformatics and Biotechnology,Government College Univer

4、sity,Faisalabad,38000 Pakistan 5.Department of Neurosurgery,Center for Translational Neuromedicine(SMD),School of Medicine and Dentistry,University of Rochester Medical Center,601 Elmwood Ave,Box 645,Rochester,NY 14642,USA 6.Universit de Strasbourg,UMR_S 1118,Strasbourg,France 7.INSERM,U1118,Mcanism

5、es Centraux et Pripheriques de la Neurodgnrescence,Strasbourg,France Corresponding authors:Ghulam Hussain(gh_,ghulamhussaingcuf.edu.pk)and Tao Sun()The author(s).This is an open access article distributed under the terms of the Creative Commons Attribution License(https:/creativecommons.org/licenses

6、/by/4.0/).See http:/ for full terms and conditions.Received:2019.04.11;Accepted:2019.06.22;Published:2020.01.01 Abstract Peripheral nerve injury is a complex condition with a variety of signs and symptoms such as numbness,tingling,jabbing,throbbing,burning or sharp pain.Peripheral nerves are fragile

7、 in nature and can easily get damaged due to acute compression or trauma which may lead to the sensory and motor functions deficits and even lifelong disability.After lesion,the neuronal cell body becomes disconnected from the axons distal portion to the injury site leading to the axonal degeneratio

8、n and dismantlement of neuromuscular junctions of targeted muscles.In spite of extensive research on this aspect,complete functional recovery still remains a challenge to be resolved.This review highlights detailed pathophysiological events after an injury to a peripheral nerve and the associated fa

9、ctors that can either hinder or promote the regenerative machinery.In addition,it throws light on the available therapeutic strategies including supporting therapies,surgical and non-surgical interventions to ameliorate the axonal regeneration,neuronal survival,and reinnervation of peripheral target

10、s.Despite the availability of various treatment options,we are still lacking the optimal treatments for a perfect and complete functional regain.The need for the present age is to discover or design such potent compounds that would be able to execute the complete functional retrieval.In this regard,

11、plant-derived compounds are getting more attention and several recent reports validate their remedial effects.A plethora of plants and plant-derived phytochemicals have been suggested with curative effects against a number of diseases in general and neuronal injury in particular.They can be a ray of

12、 hope for the suffering individuals.Key words:Peripheral Nerve Injury,Pathophysiology,Surgical interventions,Non-surgical intervention,Plant-derived compounds Introduction The nervous system is a complex network of nerves which coordinates its activities by the transmission of signals to and from di

13、fferent body regions.It senses the changes in the environment which influence the body 1 and is classified into two portions,the central nervous system(CNS)and peripheral nervous system(PNS).The CNS is comprised of spinal cord and brain,whereas nerves make the PNS which are the constrained bundles o

14、f prolonged fibers or axons and functionally integrate Ivyspring International Publisher Int.J.Biol.Sci.2020,Vol.16 http:/ 117 different parts of the body with CNS 2.The PNS includes several types of nerve fibers such as spinal and cranial nerve fibers which build up a communication pathway between

15、CNS and peripheral areas of the body.Sensory signals of our body are conveyed to the CNS with the help of sensory nerve fibers of PNS whereas;the generated response is delivered by motor nerve fibers of PNS to the target end 3.Thus,for physiological regulation of the entire living system,the continu

16、ity of this communication is pivotal.Peripheral nerve fibers,the most delicate and fragile structure of our body,are prone to get damaged easily by crush,compression,or trauma.Their damage manifests as abnormalities in the brains communication with the target organs and muscles 4.Peripheral nerve in

17、juries(PNIs)fall amongst the most pivotal issue regarding the health status because of their higher prevalence.These injuries affect motor activity and also cause the loss of sensation in the respective part of the body 5.Thus the PNIs adversely affect the brains functions and communication with the

18、 target organs or muscles.These injuries affect behavior,mobility,perception,consciousness,sensations of skin and joints and most often result in a life-long disability for the affected individual 6,7.These injuries are difficult to treat because of various underlying factors like location,intensity

19、 and type of nerve injury 8.Although,in this aspect,different strategies and medicinal interventions have been acquired and practiced.The future of PNI treatment depends on exploiting a recovery of sensory and motor function after injury to the nerve.Approach for the sustenance of neuromuscular junc

20、tions is significant for allowing re-innervation of muscles after persistent denervation of muscles and reducing injury to cell body as well 9.The present review will strive to delineate the series of pathophysiological changes at the site of nerve injury in a comprehensive and coherent manner.This

21、can lead to the adoption of innovative approaches with regard to the treatment of PNIs.The aim of this review is to enhance the understanding of PNIs,consequences,and pathophysiology of PNIs.At present,the available surgical and non-surgical remedies for PNIs have been brought to light.The literatur

22、e was searched via several e-sites,including PubMed,Springer Link,Science Direct Scopus,Elsevier,and some other pertinent medical journals,highlighting the informs in this field for surgeons and clinical practitioners.Keywords used for the literature search are“Peripheral Nerve Injuries”,“Consequenc

23、es and pathophysiology”,“Surgical Remedies”,and“Non-Surgical Remedies”.Classification of peripheral nerve injuries and their consequences Peripheral nerve injuries(PNIs)have been classified by scientists into different grades depending upon the severity.This classification scheme helps scientists an

24、d physicians to discuss effectively the nerve pathophysiology and to determine the appropriate treatment.The PNIs were classified by Sir Sydney Sunderland and Sir Herbert Seddon.Seddon classified the PNIs into 3 grades on the basis of the presence of demyelination and the extent of damage to the axo

25、ns and the connective tissue of the nerve.Sunderland then gave further subdivision on the basis of discontinuity of several layers of connective tissues in peripheral nerve 27.1.Seddons classification of nerve injuries In 1943,the injuries of peripheral nerves were classified into three main grades

26、by Seddon,termed as Seddons classification.These include neuropraxia,axonotmesis and neurotmesis 3.The brief description of these injuries with their consequences is given in table 1.Table 1.Seddons Classification-General Features Neuropraxia Axonotmesis Neurotmesis There is an occurrence of paralys

27、is but the peripheral degradation is absent 11.In this kind of damage,the action potential spreading capability of the nerve becomes partially or completely lost,but the essential axonal continuation remains entirely preserved.This situation is connected with the demyelination of the nerve fibers se

28、gmentally 12.The motor neuronal fibers are most susceptible to this injury and they lose their functioning capability at first and re-gain at last.The example of neuropraxia is“Saturday night palsy”in which pressure occurs on nerve while sleeping.This condition generally improves in 12 weeks with no

29、 intervention 30.The second grade of injury is axonotmesis in which the nerve fibers get severely damaged and leads to the intact peripheral deterioration 14,15.In this type of injury,the layers of connective tissue and the closely linked structures with nerve fibers remain conserved to some point s

30、o that the internal structures remain conserved suitably 33.Here,the entire Wallerian degeneration and axonal re-growth take place and the retrieval is good and spontaneous but not as worthy as neuropraxia.In this,the surgical intervention is generally not needed 17.The 3rd grade of nerve injury is

31、neurotmesis which results in the injury of neural connective tissue constituents and effects perineurium epineurium,and/or endoneurium.The nerve fiber is entirely divided into two ends and leads towards whole paralysis 18.The Wallerian degeneration and axonal re-growth is a distinct property of this

32、 injury.In this,the regeneration process is restricted by intraneural damaging,axonal misdirection,and loss of blood-brain barrier.The injuries leading to the damage of epineurium and perineurium mean that surgical intervention becomes inevitable for recovery 17,19.Int.J.Biol.Sci.2020,Vol.16 http:/

33、118 Table 2.Seddon and Sunderland classification of nerve injuries Seddon classification Neuropraxia Axonotmesis Axonotmesis Axonotmesis Neurotmesis Sunderland classification Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 6(According to MacKinnon)Causes Local ischemia,traction,mild crush,compression

34、Nerve crush Nerve crush Nerve crush Nerve laceration and transection Stab or gunshot wounds,closed traction damage Recovery Complete-hours up to a few weeks Complete-weeks to months Incomplete and variable-months Incomplete and variable-depending on injury and treatment months to years Incomplete-mo

35、nths to years Incomplete-months to years Pathophysiology Connective tissues and axons in continuity,nerve conduction block Division of axons but all layers of connective tissues remain intact Myelin sheath&endoneurial layer are disconnected.Axon with myelin sheath,endoneurium and perineurium disconn

36、ected Axon with myelin sheath,endoneurium,perineurium,and epineurium disconnected Mixed injuries,all grades involved Surgical Intercessions Typically not Typically not Typically not Typically required;procedure depends upon findings Required;Early nerve healing or reconstruction Surgical investigati

37、on&intraoperative electro-diagnostic techniques;nerve re-construction or nerve transferring 2.Sunderlands classification of nerve injuries In 1951,Sunderland expanded this scheme of classification to five grades to distinguish the extent of damage in connective tissues.As it is explained that neurop

38、raxia is the condition which involves the slight crush of nerve fiber or compression which also harms the myelin sheath,leads to the blockage of impulse conduction.The other grade of injury is axonotmesis that was first introduced by Seddon and it was further divided into three grades by Sunderland.

39、The grade 2 damage(Sunderland division)indicates the damage in which axon and the myelin sheath become disconnected but connective tissues continuity remain conserved 20.Thus,this leads to the denervation of targeted areas and causes the disturbance of sensory/motor function.It may take several week

40、s to several months for complete functional retrieval subsequently the axonal regeneration is essential,but this type of injury does not require any surgical intermediation 27.In grade 3 damage,the axon and axonal sheath become disconnected along-with the endoneurial layer,whereas the layers of conn

41、ective tissues remain intact and the functional retrieval is more difficult.In grade 4 injury,there is only continuity of epineurium whereas all the other layers and axonal sheath become disconnected.Thus the grade four damage(Sunderland division)is much more severe 21.The grade 5 Sunderland classif

42、ication of injury is termed as neurotmesis(Sometimes grade 4 can also be termed as neurotmesis),indicates that all the three layers(endoneurium,perineurium,epineurium)and axonal myelin sheath become disconnected 39.These types of whole nerve laceration/transection injuries require mandatory and prom

43、pt surgical intermediation for the achievement of complete functional retrieval 19.In few situations,the term grade 6 injuries might be used and entitles the injury with the mixed type of injury such as due to a gunshot,stabbed wound,or closed traction instigating partial nerves injuries called“a ne

44、uroma-in-continuity”.This represents a mixture of any of the previously described five grades of injury and is most challenging for surgeons to tackle 23.The summary of Seddon and Sunderland classification is described in table 2.Pathophysiology of peripheral nerve injury The peripheral nerve injury

45、 elicits a cascade of changes in physiological as well as the metabolic level at the injured site and several changes also happen in the soma of injured neuron 24.A neuron is divided into two segments as distal and proximal to the site of injury and both are significantly different from each other 4

46、8.The distal part suffers the Wallerian degeneration(WD)while the proximal part goes through the retrograde degenerative changes as well as instigates the process of regeneration.The process of WD initiates within 24-48 hours following injury and emerges at the distal end of the abrasion in case of

47、severe nerve injury 26,27.It was first described by Waller in 1850.It involves invasion by myelomonocytic cells that destroy myelin and initiate Int.J.Biol.Sci.2020,Vol.16 http:/ 119 mitosis in Schwann cells 28.When there is continuous disconnection of axons,a sequence of alterations occurs at dista

48、l and proximal sites of injury.The ends of the discontinued axons stamp themselves and become swollen within a few hours of injury.The site of individual axon becomes degenerated which is proximal to the subsequent node of Ranvier.Moreover,the disintegration of neurofilaments and cytoskeleton also t

49、akes place 29-31.1.Degenerative changes at the distal end On the injured site,the distal part of axon swells and Schwann cells allow the calcium influx which triggers the proteases discharge.This event causes a decrease in impulse transmission and leads to the breakdown of myelin 32.The activation o

50、f proteases leads to the degradation of neurofilaments,mitochondria,endoplasmic reticulum,and cytoskeleton of the axon 33.The shrinkage of nerves skeleton happens at the end of the Wallerian degeneration with retraction of axon terminals from the target.Initiation of the inflammatory process and ede