脊髓损伤的相关问题
作者：王廷华
单位：王廷华(昆明医学院神经科学研究所，昆明 650031)
关键词：脊髓损伤修复；神经营养因子；抑制因子；药物
昆明医学院学学报000104Many Questions on Spinal Cord Injury
WANG Ting-hua,MD Ph D
(Institute for Research on Neuroscience，Kunming Medical College,Kunming 650031)
Abstract：Spinal cord injury (SCI) is a commen desease in clinic. We mainly introduced some trends on research of SCI. Especially, some challenging questions were primarily discussed in this paper.
, 百拇医药
Key words：Spinal cord injury;Neurotrophins;Inhibitor;Drugs
CLC number：Q 189，Q 421 Document code：A Article ID：1003-4706(2000)01-0012-07
摘 要：脊髓损伤是临床常见多发病. 目前，脊髓损伤的修复治疗仍是临床所面临的一大难题. 笔者对脊髓损伤后的变化过程、研究现状、损伤修复中存在的问题及解决这些问题的方向进行了初步探讨.
The spinal cord is the lowest part of the central nervous system (CNS). It consists of centrally located gray matter containing nerve cell bodies，and surrounding white matter，which is made up of the extensions of the nerve cells. The neuronal extensions are called axons，i.e. the long，thin strings of nerve cell cytoplasm that carry electrical signals up and down the spinal cord. Axons of nerve cells with similar functions are organised in groups，or pathways. The so～called afferent fibers (or ascending pathways) carry sensory information of touch，temperature，pain，and body position from the entire body to the brain. The efferent fibers (or descending pathways) carry signals that control voluntary movements，from the brain to the entire body. Normally the bony vertebrae of the spinal column protect the spinal cord. However，the spinal cord can still be injured，with disastrous consequences. Spinal cord injury (SCI) is commonly encountered in clinical neurosurgery. According to statistics gathered in 1996 by the National Institutes of Health，it is estimated that every year 7 000 to 10 000 people in the United States sustain a SCI，resulting in a prevalence of more than 200 000 American children and adults now living with the sequel of a SCI. In China，the number of patients with SCI is significantly larger than in USA. It is easy to understand that the result of a SCI involves a lot of suffering，including living with permanent paralysis in arms and/or legs.
, 百拇医药
Recently many scientists have focused their interest on this field，and have acquired important new insights. The aim is to clarify the mechanism of SCI and to look for possible ways of treatment. This research has not only given us new information different aspects of SCI，but have also triggered many new questions. In this paper，we summarize the results from recent laboratory and clinical research on SCI.
1 What happens in the spinal cord following injury
, 百拇医药
Before going into the details of the pathophysiological events in the spinal cord following injury，it is necessary to point out that the term SCI includes many different types of injuries. Thus，a SCI do not always results in a complete cut through the cord; rather the result is often a partial crushing of the white matter the central gray matter. When occurring，a transection may be partial or complete. Different types of injury in spinal cord may bring out different clinical outcomes. In the following，we want primarily to discuss the common pathophysiological characteristics following different types of injury to the spinal cord.
, 百拇医药
It is clear that the pathophysiological events following a SCI are complex and that they occur in stages. Initially the normal blood flow is disrupted，with a resulting oxygen deprivation of some of the tissues of the spinal cord. In addition，bleeding into the injured area leads to swelling，which can further compress and damage spinal cord axons. Specifically，highly reactive molecule known as free radicals will be released resulting in the breaking up of cell membranes，thus killing cells that were not injured initially. These early events following a SCI may later lead to other kinds of damage. For example，an inflammatory reaction will be triggered. Blood cells called macrophages will invade the site of injury to clean up debris. As a result，some uninjured tissue may also be damaged. Within weeks or months，cysts often form at the site of injury and fill with cerebrospinal fluid. In severe cases large cavitities may be formed. Meanwhile，non～neuronal cells including astrocytes may be activated and participate in the formation of scar tissue，that will impedes the regrowth of injured nerve cell axons. On the other hand，astrocytes may secret glia derived neurotrophic factor (GDNF) that can promote neuron survival and neurite growth in vitro[1].
, http://www.100md.com
These different events often lead to a permantent discontinuation of different neuronal pathways，including the corticospinal tract controlling voluntary movement. Even nerve cell axons that were not initially damaged may often lose their myelin. The pathological processes described above will often be cumulative and progressive，with a resulting permanent loss of sensory and motor function. [2，3].
Usually，the different components in the process of SCI can not be clearly distinguished，since most processes occur simultaneously. However，it is probably useful to make a distinction between the initial，or primary injury，and the subsequent secondary injury. One important reason for this is that while the primary injury is irreversible and directly related to the traumatic impact，the secondary injury develops over time and may be influenced by different therapeutic interventions[4]. Over time，inflammation，wound healing mechanisms and tissue repair play a role in the outcome following a SCI. Therefore，in studying the spinal cord's response to injury，one must consider both the glia～neuronal interactions essential to neuronal growth and their regulation by the physiological activity of inflammatory cells. The most important among these cell types are the macrophages and lymphocytes，which have been shown to secrete a great variety of growth factors and cytokines that can，directly or indirectly，influence axonal growth. In additon，the neurotrophic factor secreted from the target of effective neurons have to be considered，since recent findings strongly support the view that neurotrophic factors are instrumental in promoting the repair following SCI.
, http://www.100md.com
2 Challenging questions regarding the cure of SCI
Successful regeneration following SCI is associated with several requirements. First，damaged nerve cells and supporting cells must survive or be replaced. Secondly，nerve cells must have the ability to navigate its axons to their targets. Thirdly，axons must be able to connect to the appropriate target cells，and to form new and functional synapsis for release of neurotransmitters or NTFs. Finally，new neuronal circuits may have to form in order to compensate for changes related to the SCI.
, http://www.100md.com
Obviously，it is not a simple matter for scientist to find ways to support these healing processes. For example，it has been demonstrated in vitro that axon regeneration is age dependent，i.e. that the intrinsic growth capacity is less in adult than in young animals. Addition of growth factors to cultured neurons only partially increased survival and growth，but is not sufficient to overcome the large decline in growth ability in older neurons.
In addition，it is known that environmental factors are very important for axonal growth[5，6]. Scientists have now identified a long list of molecules in the adult CNS that actively inhibit growth. For example，oligodendrocytes produce a myelin～associated growth inhibitor that may be one of the most important inhibitors of growth in the adult spinal cord. Other inhibitory factors include collapsin～1，tromblin，and many others. One way these inhibitors act is by making growth cones collapse. Some other inhibitors act by modifying the extracellular matrix to become "anti～adhesive"，thus preventing the growing axons from sticking to surrounding tissue，which is necessary for growth.
, 百拇医药
Finally，even if spinal cord axons can regrow up and down the spinal cord，they will have difficulties in finding their correct targets. And even if some axon make contact with their target，there may be problems establishing a functioning synaps. Thus，ideas for treatment of SCI would need to include measures to stimulate both axon regeneration and the formation of functional synapses with right target cells.
Among the present strategies for supporting axonal growth and functional synapse formation there are ideas about immunological and genetic manipulation in order block the action of inhibitory substances. Other possibilities include disturbance of second messenger systems by some toxin or drugs in order to block the action of inhibitory factors intracellularly，or in a similar fashion actively promote neurite growth. Yet another approach is to stimulate growth～stimulating factors such as NTFs，so that the positive stimulation may be sufficient to overcome inhibition.
, 百拇医药
3 Current focus of research on SCI
3.1 Neurotrophic factors
Neurotrophic factors are low molecular weight proteins，which are synthesized and secreted from target cells in order to promote neuronal survival and neurite growth during the period when neurons specialize and begin to connect with their target. Since the nervous system produces many more cells than the adult nervous system needs，and the supply of trophic factors is very limit，a large proportion of developing neurons will die，in a process called apoptosis. Only the neurons stimulated by NTFs can survive and grow.
, http://www.100md.com
Many different NTFs have now been identified，including nerve growth factor (NGF)[7]，brain derived factor (BDNF)[8]，neurotrophin～3，4/5，6 (NT-3，4/5，6[9～12]，glia derived neurotrophic factor (GDNF)[1]，ciliary neurotrophic factor (CNTF)[13]，and so on. Many studies have confined the presence of NTFs in the spinal cord. For example，NGF and its mRNA are widely distributed in the spinal cord while the distribution of BDNF and NT-3 appears more limited.
, http://www.100md.com
There are strong indications that some NTFs play an important role in the pathophysiological processes following a SCI. For example，administration of NT-3 can promote the sprouting of injured axons[14]，BDNF can ameliorate synapse plasticity[15，16] and NGF can induce the sprouting of primary afferent fibers in the spinal cord[17]. Recent studies have also shown that the effect of NTFs are modified by other factors，e.g. by the levels of second messengers. Neuronal activity and signals from other cells will stimulate second messenger systems，and it should be kept in mind that such activities will be drastically altered distal to the site of spinal cord injury.
, 百拇医药
Another issue is that although administration of trophic factors，and/or optimizing the conditions for their positive action may promote nerve cell survival in the damaged spinal cord，such interference may have serious side effects. How to control these side effects is another problem that needs to be resolved.
3.2 Transplants
One approach for repairing a damaged spinal cord is to transplant cells or whole tissue. Scientists are using animal models for transplantion of cells or pieces of peripheral nerves that will produce substances that create an improved environment for axons to grow. Since the environment of the peripheral nervous system (PNS) supports axon regeneration，re～creating this environment in the spinal cord might allow CNS axons to regrow after an injury. Many experiments with PNS transplants in rat models of SCI have shown that it is possible to achieve axon elongation and cell body changes associated with regrowth. Transplants from the PNS also seem to reduce the scarring that may impede regrowth. Transplanted Schwann cells have been shown to stimulte myelination of axons，a key element for the achievment of normal function following SCI.
, 百拇医药
Although the experimental data is promising，it is not clear if the results would be similar in humans.
3.3 Drugs
Many drugs have been reported as having the capacity of promoting neurite growth following SCI. Among them are FK506，an immuno～suppressant used for prevention of allografte rejection. The effect of FK506 in promoting regeneration of different types of neurons have been established by a series of studies from the American scientist Bruce G，Gold indicating that FK506 will be important for treatment of SCI in the future[18].
, 百拇医药
3.4 Influencing gene controlling programes
As previous mentioned，adult neurons are difficult to regrow because it is an age～dependent process. Assuming that the capacity of neuronal growth is related to intrinsic program controlled by specific genes，a strategy trying to influence this program may be useful.
4 Reasons for hope
4.1 Basic theories for the cure of SCI
, 百拇医药
The present therapeutic approaches for cure of SCI can be summarized by three terms: rejuvenation，regeneration and/or replacement.Rejuvenation:The idea behind the rejuvenation approach is that since the spinal cord is rarely completely severed，the connections in the cord are there but are not working because they have lost their natural insulation. Under these circumstances，drugs like IN～1，4～AP，andNT-4can be used. These types of drugs all acts in a similar way，i.e. by promoting the repair of lost connections or the repair of the insulation of the physically intact but non～functioning axons.Regeneration:The basic concept behind the regeneration approach is that the cord tries to repair itself at first，but that this process is inhibited by other biochemical reactions. Thus，the idea is to control the inhibiting process，and by doing this allowing the natural healing processes to continue undisturbed. It is a simple idea，but the human CNS is very complex. Nevertheless，scientists are making important progress in this area. There are many drugs，(such as NGF，NT-3 and L～1 that either keep the inhibiting processes at bay or promote growth in spite of the inhibiting factors. Such drugs are either used alone or in combination with other drugs. Time will show which is the optimal combination.Replacement:Replacement is probably the least popular of the concepts here discussed，but it is still being investigated as a possibility. The idea behind this approach is that the injured cells of the spinal cord can be replaced by fetal tissue or by genetically engineered cells. The use of human fetal cells for transplantion is not only technically difficult but also raises difficult ethical and political questions. Even if it can be done，most of the transplanted cells die soon after the operation，partly due to host～vs～graft rejection. Genetic engineering is still in an infantile stage and it is likely that decades will pass before it can be put to actual clinical use. One problem common to all three of these approaches is that following SCI the scar formed at the site of the injury will not permit any growth at all. Although some researchers question the significance and validity of this problem，many research groups are trying to solve the problem of scar formation，so that，once ready，the different therapeutic approaches can be put into practice.
, http://www.100md.com
4.2 Some current methods for treatment of SCI
Immediate administration of methyl prednisolone: Methylprednisolone，which is a synthetic steroid，suppresses immune responses throughout the body. This can be beneficial for patients with SCI，since the inflammatory responses at the site of injury may worsen its consequences. In addition，methylprednisolone can block the formation of free radicals，which can disrupt the membranes of cells that were not initially injured. However，it should be kept in mind that methyl～prednisolone will also cause unwanted side effects，such as hyperglycemia or an exaggerated immune suppression throughout the body.
, http://www.100md.com
Removal of bone fragments that is compressing the spinal cord: As previously mentioned，in most cases of SCI the spinal cord is compressed，not cut. Thus，surgical decompression of the spinal cord may be necessary in order to minimize mechanical damage，as well as to prevent disturbances in the supply of blood and oxygen.
Stabilize the spine: The third step in present treatment of SCI is to stabilize the spine. Stabilization should prevent further compression or twisting of the spinal cord and it should also allow the injured person to be hoisted upright in a specialized bed frame as soon as possible.
, 百拇医药
Consideration of experimental therapies like implantation of Schwann cell，or administration of NTFs and other drugs:First，Schwann cells can supply nourishing chemical factors that encourage regeneration，and allow the normal functioning of undamaged or regenerated axons. Specifically，transplanted Schwann cells should help maintain the myelin wrapping that is so essential for the normal function of nerve cells. Usually，following a SCI the myelin wrapping around the axons of spinal cord nerve cells becomes very thin，which makes the axons incapable of transmitting nerve impulses fast enough to accomplish their normal functions. Therefore，if another source of myelin from transplanted Schwann cells could be supplied，the intact and regenerating nerve cells might function more normally.
, 百拇医药
Secondly，there is certainly a potential use of NTF for the treatment of SCI. Recently，some scientists reported that neurotrophin administration including BDNF，NT-3，NT～4，and GDNF leds to increases in the extent of serotonergic，noradrenergic，and corticospinal axonal ingrowth within the transplants，following spinal cord hemisection and transplants of E14 fetal spinal cord tissue in adult rats.
Thirdly，some drugs promoting neurite growth，like FK506，should be considered for clinical use.
, 百拇医药
Begin rehabilitation as soon as possible: Rehabilitation therapy for patients with spinal cord injuries is very important，and there are now a wide varitey of techniques available. Authorities in the field have repeatedly emphasized the important role of active rehabililation therapy in the care of patients with SCI.
In summary，SCI is a complex process，and it is therefore presently difficult for us to master it completely. We hope that many people will join the discussion and research regarding the treatment of SCI. With increased knowledge and continuing development of laboratory and clinical research，we believe some therapies may some day be available.
, http://www.100md.com
Acknowledgements I thank Dr. Pekka Mellergard for his suppurting on this paper.■
作者简介：王廷华(1966-)，男，云南宣威人, 讲师, 博士, 研究方向：脊髓损伤及修复.
References：
[1] LEU-FEN H L，DANLEL H D，JACK D L. GDNF: A glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons[J]. Nature, 1991，354: 411
[2] SCHWAB M E,BARTHOLDI D.Degeneration and regeneration of axons in the lesioned spinal cord[J].Physiol Rev, 1996，76 (2): 319
, http://www.100md.com
[3] SCHWAB M E.Bridging the gap in spinal cord regeneration[J].Nature Med, 1996，2 (9): 976
[4] ZHANG Z Y. Experimental spinal cord injury: Wallerian degeneration in the dorsal column is followed by revascularization glial proliferation and nerve regeneration[J]. Experimental Neurology, 1997，147:159
[5] BAHR M，BONHOEFFER F. Perspectives on axonal regeneration in the mammalian CNS[J]. TINS, 1994，17:473
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[6] BJORKLUND.A question of making it works[J]. Nature, 1994，367(1):112
[7] ANGELETTI R H，BRAD SHAW P A. Nerve growth factor from the mouse submaxillary glands: amino acid sequence[J]. Proc Natl Alad Sci USA, 1971，68:2417
[8] LEIBROCK J，LOTTSPEICH F，HOHN A. Molecular cloning and expression of BDNF[J]. Nature, 1989, 341:149
[9] MAISONPIERRE P C. Human and rat brain-derived neurotrophic factor and neurotrophin-3: gene structure，distribution and Chr omosomal localization[J]. Geromics，1991，10:558
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[10] HALLBOOK F，IBANEZ C F，PERSSON H.Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary[J]. Neuron, 1991, 6:845
[11] KOLIATSOS V E.Neurotrophin-4/5 is a trophic factor for mammalian facial motor neurons[J]. Proc Natl Acad Sci USA, 1994，91:3304
[12] GOTZ R，KOSTER R，WINKLER C，et al.. Neurotrophin-6 is a new member of the nerve growth factor family[J]. Nature，1994，372(17):266
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[13] ADLER R，LANDA K B，MANTHORPE M. Cholinergic neurotrophic factors: intraocular distribution of trophic activity for ciliary neurons[J]. Science, 1979, 204:1434
[14] SCHNEL L，SCHNEIDER R，KOLBELK R. Neurotrin-3 enhances sprouting of corticospinal tract during development and after adult spinal cord lesion[J]. Nature, 1994，367:170
[15] LO D C.Neurotrophic factors and synapticplasticity[J]. Neuron, 1995，15: 979
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[16] THOENEN H: Neurotrophins and neuronal plasticity[J]. Science, 1995, 270:593
[17] ERIKSSON N P. Effects of NGF，BDNF and NT-3 on the laminar distribution of transganglionically transported choleragenoid in the spinal cord dorsal horn following transection of the sciatic nerve in the adult rat[J]. Neurosci, 1997，78(3):863
[18] GOLD B G，KATOH K，STORM-DICKERSON T. The immunosuppressant FK506 increase the rate of axonal regeneration in rat sciatic nerve[J]. The J of Neurosci,1995，15(11):7509
收稿日期：2000-01-05, http://www.100md.com
单位：王廷华(昆明医学院神经科学研究所，昆明 650031)
关键词：脊髓损伤修复；神经营养因子；抑制因子；药物
昆明医学院学学报000104Many Questions on Spinal Cord Injury
WANG Ting-hua,MD Ph D
(Institute for Research on Neuroscience，Kunming Medical College,Kunming 650031)
Abstract：Spinal cord injury (SCI) is a commen desease in clinic. We mainly introduced some trends on research of SCI. Especially, some challenging questions were primarily discussed in this paper.
, 百拇医药
Key words：Spinal cord injury;Neurotrophins;Inhibitor;Drugs
CLC number：Q 189，Q 421 Document code：A Article ID：1003-4706(2000)01-0012-07
摘 要：脊髓损伤是临床常见多发病. 目前，脊髓损伤的修复治疗仍是临床所面临的一大难题. 笔者对脊髓损伤后的变化过程、研究现状、损伤修复中存在的问题及解决这些问题的方向进行了初步探讨.
The spinal cord is the lowest part of the central nervous system (CNS). It consists of centrally located gray matter containing nerve cell bodies，and surrounding white matter，which is made up of the extensions of the nerve cells. The neuronal extensions are called axons，i.e. the long，thin strings of nerve cell cytoplasm that carry electrical signals up and down the spinal cord. Axons of nerve cells with similar functions are organised in groups，or pathways. The so～called afferent fibers (or ascending pathways) carry sensory information of touch，temperature，pain，and body position from the entire body to the brain. The efferent fibers (or descending pathways) carry signals that control voluntary movements，from the brain to the entire body. Normally the bony vertebrae of the spinal column protect the spinal cord. However，the spinal cord can still be injured，with disastrous consequences. Spinal cord injury (SCI) is commonly encountered in clinical neurosurgery. According to statistics gathered in 1996 by the National Institutes of Health，it is estimated that every year 7 000 to 10 000 people in the United States sustain a SCI，resulting in a prevalence of more than 200 000 American children and adults now living with the sequel of a SCI. In China，the number of patients with SCI is significantly larger than in USA. It is easy to understand that the result of a SCI involves a lot of suffering，including living with permanent paralysis in arms and/or legs.
, 百拇医药
Recently many scientists have focused their interest on this field，and have acquired important new insights. The aim is to clarify the mechanism of SCI and to look for possible ways of treatment. This research has not only given us new information different aspects of SCI，but have also triggered many new questions. In this paper，we summarize the results from recent laboratory and clinical research on SCI.
1 What happens in the spinal cord following injury
, 百拇医药
Before going into the details of the pathophysiological events in the spinal cord following injury，it is necessary to point out that the term SCI includes many different types of injuries. Thus，a SCI do not always results in a complete cut through the cord; rather the result is often a partial crushing of the white matter the central gray matter. When occurring，a transection may be partial or complete. Different types of injury in spinal cord may bring out different clinical outcomes. In the following，we want primarily to discuss the common pathophysiological characteristics following different types of injury to the spinal cord.
, 百拇医药
It is clear that the pathophysiological events following a SCI are complex and that they occur in stages. Initially the normal blood flow is disrupted，with a resulting oxygen deprivation of some of the tissues of the spinal cord. In addition，bleeding into the injured area leads to swelling，which can further compress and damage spinal cord axons. Specifically，highly reactive molecule known as free radicals will be released resulting in the breaking up of cell membranes，thus killing cells that were not injured initially. These early events following a SCI may later lead to other kinds of damage. For example，an inflammatory reaction will be triggered. Blood cells called macrophages will invade the site of injury to clean up debris. As a result，some uninjured tissue may also be damaged. Within weeks or months，cysts often form at the site of injury and fill with cerebrospinal fluid. In severe cases large cavitities may be formed. Meanwhile，non～neuronal cells including astrocytes may be activated and participate in the formation of scar tissue，that will impedes the regrowth of injured nerve cell axons. On the other hand，astrocytes may secret glia derived neurotrophic factor (GDNF) that can promote neuron survival and neurite growth in vitro[1].
, http://www.100md.com
These different events often lead to a permantent discontinuation of different neuronal pathways，including the corticospinal tract controlling voluntary movement. Even nerve cell axons that were not initially damaged may often lose their myelin. The pathological processes described above will often be cumulative and progressive，with a resulting permanent loss of sensory and motor function. [2，3].
Usually，the different components in the process of SCI can not be clearly distinguished，since most processes occur simultaneously. However，it is probably useful to make a distinction between the initial，or primary injury，and the subsequent secondary injury. One important reason for this is that while the primary injury is irreversible and directly related to the traumatic impact，the secondary injury develops over time and may be influenced by different therapeutic interventions[4]. Over time，inflammation，wound healing mechanisms and tissue repair play a role in the outcome following a SCI. Therefore，in studying the spinal cord's response to injury，one must consider both the glia～neuronal interactions essential to neuronal growth and their regulation by the physiological activity of inflammatory cells. The most important among these cell types are the macrophages and lymphocytes，which have been shown to secrete a great variety of growth factors and cytokines that can，directly or indirectly，influence axonal growth. In additon，the neurotrophic factor secreted from the target of effective neurons have to be considered，since recent findings strongly support the view that neurotrophic factors are instrumental in promoting the repair following SCI.
, http://www.100md.com
2 Challenging questions regarding the cure of SCI
Successful regeneration following SCI is associated with several requirements. First，damaged nerve cells and supporting cells must survive or be replaced. Secondly，nerve cells must have the ability to navigate its axons to their targets. Thirdly，axons must be able to connect to the appropriate target cells，and to form new and functional synapsis for release of neurotransmitters or NTFs. Finally，new neuronal circuits may have to form in order to compensate for changes related to the SCI.
, http://www.100md.com
Obviously，it is not a simple matter for scientist to find ways to support these healing processes. For example，it has been demonstrated in vitro that axon regeneration is age dependent，i.e. that the intrinsic growth capacity is less in adult than in young animals. Addition of growth factors to cultured neurons only partially increased survival and growth，but is not sufficient to overcome the large decline in growth ability in older neurons.
In addition，it is known that environmental factors are very important for axonal growth[5，6]. Scientists have now identified a long list of molecules in the adult CNS that actively inhibit growth. For example，oligodendrocytes produce a myelin～associated growth inhibitor that may be one of the most important inhibitors of growth in the adult spinal cord. Other inhibitory factors include collapsin～1，tromblin，and many others. One way these inhibitors act is by making growth cones collapse. Some other inhibitors act by modifying the extracellular matrix to become "anti～adhesive"，thus preventing the growing axons from sticking to surrounding tissue，which is necessary for growth.
, 百拇医药
Finally，even if spinal cord axons can regrow up and down the spinal cord，they will have difficulties in finding their correct targets. And even if some axon make contact with their target，there may be problems establishing a functioning synaps. Thus，ideas for treatment of SCI would need to include measures to stimulate both axon regeneration and the formation of functional synapses with right target cells.
Among the present strategies for supporting axonal growth and functional synapse formation there are ideas about immunological and genetic manipulation in order block the action of inhibitory substances. Other possibilities include disturbance of second messenger systems by some toxin or drugs in order to block the action of inhibitory factors intracellularly，or in a similar fashion actively promote neurite growth. Yet another approach is to stimulate growth～stimulating factors such as NTFs，so that the positive stimulation may be sufficient to overcome inhibition.
, 百拇医药
3 Current focus of research on SCI
3.1 Neurotrophic factors
Neurotrophic factors are low molecular weight proteins，which are synthesized and secreted from target cells in order to promote neuronal survival and neurite growth during the period when neurons specialize and begin to connect with their target. Since the nervous system produces many more cells than the adult nervous system needs，and the supply of trophic factors is very limit，a large proportion of developing neurons will die，in a process called apoptosis. Only the neurons stimulated by NTFs can survive and grow.
, http://www.100md.com
Many different NTFs have now been identified，including nerve growth factor (NGF)[7]，brain derived factor (BDNF)[8]，neurotrophin～3，4/5，6 (NT-3，4/5，6[9～12]，glia derived neurotrophic factor (GDNF)[1]，ciliary neurotrophic factor (CNTF)[13]，and so on. Many studies have confined the presence of NTFs in the spinal cord. For example，NGF and its mRNA are widely distributed in the spinal cord while the distribution of BDNF and NT-3 appears more limited.
, http://www.100md.com
There are strong indications that some NTFs play an important role in the pathophysiological processes following a SCI. For example，administration of NT-3 can promote the sprouting of injured axons[14]，BDNF can ameliorate synapse plasticity[15，16] and NGF can induce the sprouting of primary afferent fibers in the spinal cord[17]. Recent studies have also shown that the effect of NTFs are modified by other factors，e.g. by the levels of second messengers. Neuronal activity and signals from other cells will stimulate second messenger systems，and it should be kept in mind that such activities will be drastically altered distal to the site of spinal cord injury.
, 百拇医药
Another issue is that although administration of trophic factors，and/or optimizing the conditions for their positive action may promote nerve cell survival in the damaged spinal cord，such interference may have serious side effects. How to control these side effects is another problem that needs to be resolved.
3.2 Transplants
One approach for repairing a damaged spinal cord is to transplant cells or whole tissue. Scientists are using animal models for transplantion of cells or pieces of peripheral nerves that will produce substances that create an improved environment for axons to grow. Since the environment of the peripheral nervous system (PNS) supports axon regeneration，re～creating this environment in the spinal cord might allow CNS axons to regrow after an injury. Many experiments with PNS transplants in rat models of SCI have shown that it is possible to achieve axon elongation and cell body changes associated with regrowth. Transplants from the PNS also seem to reduce the scarring that may impede regrowth. Transplanted Schwann cells have been shown to stimulte myelination of axons，a key element for the achievment of normal function following SCI.
, 百拇医药
Although the experimental data is promising，it is not clear if the results would be similar in humans.
3.3 Drugs
Many drugs have been reported as having the capacity of promoting neurite growth following SCI. Among them are FK506，an immuno～suppressant used for prevention of allografte rejection. The effect of FK506 in promoting regeneration of different types of neurons have been established by a series of studies from the American scientist Bruce G，Gold indicating that FK506 will be important for treatment of SCI in the future[18].
, 百拇医药
3.4 Influencing gene controlling programes
As previous mentioned，adult neurons are difficult to regrow because it is an age～dependent process. Assuming that the capacity of neuronal growth is related to intrinsic program controlled by specific genes，a strategy trying to influence this program may be useful.
4 Reasons for hope
4.1 Basic theories for the cure of SCI
, 百拇医药
The present therapeutic approaches for cure of SCI can be summarized by three terms: rejuvenation，regeneration and/or replacement.Rejuvenation:The idea behind the rejuvenation approach is that since the spinal cord is rarely completely severed，the connections in the cord are there but are not working because they have lost their natural insulation. Under these circumstances，drugs like IN～1，4～AP，andNT-4can be used. These types of drugs all acts in a similar way，i.e. by promoting the repair of lost connections or the repair of the insulation of the physically intact but non～functioning axons.Regeneration:The basic concept behind the regeneration approach is that the cord tries to repair itself at first，but that this process is inhibited by other biochemical reactions. Thus，the idea is to control the inhibiting process，and by doing this allowing the natural healing processes to continue undisturbed. It is a simple idea，but the human CNS is very complex. Nevertheless，scientists are making important progress in this area. There are many drugs，(such as NGF，NT-3 and L～1 that either keep the inhibiting processes at bay or promote growth in spite of the inhibiting factors. Such drugs are either used alone or in combination with other drugs. Time will show which is the optimal combination.Replacement:Replacement is probably the least popular of the concepts here discussed，but it is still being investigated as a possibility. The idea behind this approach is that the injured cells of the spinal cord can be replaced by fetal tissue or by genetically engineered cells. The use of human fetal cells for transplantion is not only technically difficult but also raises difficult ethical and political questions. Even if it can be done，most of the transplanted cells die soon after the operation，partly due to host～vs～graft rejection. Genetic engineering is still in an infantile stage and it is likely that decades will pass before it can be put to actual clinical use. One problem common to all three of these approaches is that following SCI the scar formed at the site of the injury will not permit any growth at all. Although some researchers question the significance and validity of this problem，many research groups are trying to solve the problem of scar formation，so that，once ready，the different therapeutic approaches can be put into practice.
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4.2 Some current methods for treatment of SCI
Immediate administration of methyl prednisolone: Methylprednisolone，which is a synthetic steroid，suppresses immune responses throughout the body. This can be beneficial for patients with SCI，since the inflammatory responses at the site of injury may worsen its consequences. In addition，methylprednisolone can block the formation of free radicals，which can disrupt the membranes of cells that were not initially injured. However，it should be kept in mind that methyl～prednisolone will also cause unwanted side effects，such as hyperglycemia or an exaggerated immune suppression throughout the body.
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Removal of bone fragments that is compressing the spinal cord: As previously mentioned，in most cases of SCI the spinal cord is compressed，not cut. Thus，surgical decompression of the spinal cord may be necessary in order to minimize mechanical damage，as well as to prevent disturbances in the supply of blood and oxygen.
Stabilize the spine: The third step in present treatment of SCI is to stabilize the spine. Stabilization should prevent further compression or twisting of the spinal cord and it should also allow the injured person to be hoisted upright in a specialized bed frame as soon as possible.
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Consideration of experimental therapies like implantation of Schwann cell，or administration of NTFs and other drugs:First，Schwann cells can supply nourishing chemical factors that encourage regeneration，and allow the normal functioning of undamaged or regenerated axons. Specifically，transplanted Schwann cells should help maintain the myelin wrapping that is so essential for the normal function of nerve cells. Usually，following a SCI the myelin wrapping around the axons of spinal cord nerve cells becomes very thin，which makes the axons incapable of transmitting nerve impulses fast enough to accomplish their normal functions. Therefore，if another source of myelin from transplanted Schwann cells could be supplied，the intact and regenerating nerve cells might function more normally.
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Secondly，there is certainly a potential use of NTF for the treatment of SCI. Recently，some scientists reported that neurotrophin administration including BDNF，NT-3，NT～4，and GDNF leds to increases in the extent of serotonergic，noradrenergic，and corticospinal axonal ingrowth within the transplants，following spinal cord hemisection and transplants of E14 fetal spinal cord tissue in adult rats.
Thirdly，some drugs promoting neurite growth，like FK506，should be considered for clinical use.
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Begin rehabilitation as soon as possible: Rehabilitation therapy for patients with spinal cord injuries is very important，and there are now a wide varitey of techniques available. Authorities in the field have repeatedly emphasized the important role of active rehabililation therapy in the care of patients with SCI.
In summary，SCI is a complex process，and it is therefore presently difficult for us to master it completely. We hope that many people will join the discussion and research regarding the treatment of SCI. With increased knowledge and continuing development of laboratory and clinical research，we believe some therapies may some day be available.
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Acknowledgements I thank Dr. Pekka Mellergard for his suppurting on this paper.■
作者简介：王廷华(1966-)，男，云南宣威人, 讲师, 博士, 研究方向：脊髓损伤及修复.
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收稿日期：2000-01-05, http://www.100md.com