丙戊酸对大鼠臂丛根性撕脱伤后脊髓神经元存活和再生的影响
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摘要
臂丛根性撕脱伤是临床最严重的周围神经损伤类型，常见于交通事故或产瘫，它导致上肢感觉的完全丧失和所有肌群的麻痹，给病人带来严重的身心障碍外，也带来沉重的社会负担。与其它类型的神经损伤(如钳夹、切断等)相比，根性撕脱伤由于最靠近脊髓的神经元胞体，会引起大量神经元细胞死亡。而周围神经损伤后，只有神经元细胞体存活，神经才能再生，如果神经损伤后相应的神经元细胞体死亡，那么神经再生将成为不可能。大量脊髓神经元的死亡大大限制了臂丛撕脱伤外科修复后神经的再生和功能的恢复，导致临床治疗效果非常差。因此，对于臂丛撕脱伤，寻找能既能保护脊髓神经元而减少其死亡，同时又可以促进残存神经元再生的药物或方法是非常有价值的。传统的神经生长因子家族，虽然已被证实有明确的神经保护和促进再生作用，但由于其属于肽类物质，难以通过血脑及血神经屏障进入脊髓，而且由于其生物半衰期短，临床长期大量给药容易引起副作用，因此目前临床应用还有许多问题需要解决。
丙戊酸（valproic acid，VPA）神经保护作用的发现给这一难题带来希望。由于其属于小分子无机化合物，易于通过血脑屏障，且不容易被酶降解，因此相对于神经生长因子具有较大优势。VPA在临床用于抗癫痫治疗30余年，1995年又被FDA批准用于抑郁症，安全性已得到广泛验证。现已证实VPA对坐骨神经切断伤导致的脊髓运动神经元损伤具有保护作用，而且能促进切断的坐骨神经再生和功能恢复。但对于导致大量神经元死亡的臂丛撕脱伤，VPA是否能一样发挥神经保护和促进神经再生作用呢？为了明确这一问题，本研究设计了大鼠臂丛根性撕脱伤的动物模型，通过对大鼠口服给予VPA，观察VPA对脊髓神经元的影响，以明确VPA是否可以对臂丛撕脱伤后的脊髓神经元起到保护和促进再生作用，并对其神经保护作用的机制进行探讨。
研究证实神经型一氧化氮合酶(neuronal NOS, nNOS)与神经根撕脱后脊髓前角运动神经元的死亡密切相关，根性撕脱伤后nNOS的大量表达会导致神经元的死亡。而已经明确的是在神经损伤导致的神经元死亡中，细胞内Ca~（2+）超载是主要机制之一。nNOS发挥活性依赖于细胞内Ca~（2+），但同时nNOS自身的表达也受到细胞内Ca~（2+）的调控。因此，在臂丛撕脱伤导致的脊髓神经元死亡过程中，nNOS以及细胞内Ca~（2+）的变化起到了至关重要的作用。生长相关蛋白(Growth Associated Protein,GAP-43)是目前研究神经元再生能力的理想指标，神经元内GAP-43表达的升高即提示神经元再生能力的增强。
因此，本研究通过TUNEL法检测确定VPA对臂丛撕脱伤后脊髓神经元具有保护作用后，进一步通过检测VPA对脊髓神经元内nNOS以及细胞内Ca~(2+)的影响来探索VPA发挥神经保护作用的机制。另外，通过检测脊髓神经元内GAP-43的变化，来明确VPA对撕脱伤后的神经元是否有促进再生的作用。
本试验建立Wistar大鼠臂丛根性撕脱伤的动物模型，随机分为空白组（仅暴露臂丛，不做神经损伤），对照组（行臂丛撕脱）和VPA组（撕脱伤后口服给予VPA）。三组动物在D1、D2、D3、D7、D14、D28（D表示天）6个时间点进行脊髓中运动神经元凋亡、nNOS表达、细胞内Ca~(2+)浓度、GAP-43四个指标的检测。对脊髓运动神经元凋亡的检测采用TUNEL法，对nNOS的检测采用Real-time PCR、Western blot法和免疫组化染色法，对细胞内Ca~(2+)浓度采用荧光指示剂Fura-2/AM检测，对GAP-43的检测采用Real-time PCR和Western blot法。实验结果显示：1.空白组没有神经元的凋亡出现。空白组大鼠脊髓中nNOS、GAP-43在整个实验中均呈低水平表稳态表达，细胞内Ca~(2+)浓度无明显变化。2.对照组在撕脱伤后的28天内，凋亡神经元的比例、脊髓中nNOS的表达和细胞内Ca~(2+)浓度、以及GAP-43的表达均出现先升高后下降的过程，其中凋亡神经元峰值出现在D7，nNOS峰值出现在D2，细胞内Ca~(2+)浓度峰值出现在D2，GAP43峰值出现在D14。3.与空白组相比，VPA组在撕脱伤后，凋亡神经元的比例、nNOS表达、细胞内Ca~(2+)浓度和GAP-43的变化趋势及峰值时间同对照组类似。但相对于对照组，VPA在D3、7时明显减少了凋亡神经元的数目，在D1、2、3、7时明显下调了nNOS的表达，在D2、3、7时明显降低了细胞内Ca~(2+)浓度，且在D2~D28明显上调了GAP-43的表达。
分析以上结果，可以得出结论：1.大鼠臂丛根性撕脱伤后，口服VPA可以减少脊髓神经元的凋亡，对神经元产生保护作用。2.大鼠臂丛根性撕脱伤后，VPA可以通过下调脊髓神经元中nNOS的表达对神经元产生保护作用。3.大鼠臂丛根性撕脱伤后，VPA可以通过降低脊髓神经元内Ca~(2+)浓度对神经元产生保护作用。另外，VPA对nNOS表达的下调可能是通过降低神经元内Ca~(2+)浓度来实现的。4.大鼠臂丛根性撕脱伤后，VPA可以通过上调脊髓神经元中GAP-43表达来促进受损神经元的再生。该结论为在临床应用VPA治疗神经损伤提供了更丰富的理论支持。
Brachial plexus root avulsion is the most serious type of peripheral nerve injury. It isencountered commonly in victims of traffic accident and children after obstetriccomplications, leads to totally paralysis of the corresponding muscle groups and severesensory deficits in the arm on the lesion side. Compared with other types of nerve damage(such as clamping, cutting, etc.), root avulsion cause a large number of neuronal death as thedamage site is closer to the neuronal cell bodies in the spinal cord. After peripheral nerveinjury, the survival of motoneurons is an essential prerequisite of nerve regeneration andfunction recovery. The loss of neurons may significantly restrict the achievement of themuscle reinnervation after a surgical repair of the ventral root connection. Therefore, aneffective agent to reduce the neuronal death and promote the survival neuron to regeneratewill be very important and valuable for brachial plexus root avulsion. An increasing numberof neurotrophic factors have been found to support the motoneuron survival and enhanceaxonal regrowth in a variety of experimental paradigms.However, as the neurotrophinsbelong to peptide, their benefits are largely limited by the poor ability to cross theblood-nerve and blood-brain barrier and by enzymatic degradation. Besides, a long time andfrequent administration with high-dose neurotrophic factor may have unexpected side effects.There is still a long way to go before the neurotrophin can be effectively used in clinicalpatients.
The discovery of the neuroprotective effects of valproic acid brings hope to this problem.Since VPA is an inorganic compound with small molecules allowing easily penetrating theblood-brain barrier, and is not easily degraded by enzymes, it has a great advantage relative toneurotrophic factors. The security of VPA has been widely validated because it has been usedfor antiepileptic therapy clinically for more than30years, and approved by the FDA in1995for antidepressant. Clinical studies have found that VPA can protect neurons against death inthe sciatic nerve transection model in rats. However, as to the brachial plexus root avulsion, which induces much more neuronal injury and death, whether the VPAcan exert its protectiveeffect on the neuron? In order to clarify this problem, we designed this study.
In the present study, after the brachial plexus root avulsions of rats were made, the ratswere orally administrated with water containing VPA. First, we detected the neuronalapoptosis in the spinal cord to verify the neuronal protection role of VPA. Then we detectedthe expression of nNOS and Ca~(2+)concentration in the spinal cord neurons to explore theprotective mechanism of VPA. Besides, we want to know whether VPA can enhance theneural regeneration by detecting the GAP-43expression in spinal cord.
Rats were randomly divided to sham group (exposure the brachial plexus root withoutinjury), control group (brachial plexus root avulsion) and VPAgroup (administered with VPAafter avulsion). At different time points, the apoptosis of neurons, expression of nNOS,intracellular Ca~(2+)concentration and GAP-43expression were investigated. Apoptosis ofneurons was inspected by TUNEL method. Detection of nNOS used Real-time PCR, Westernblot method and immunohistochemical staining and GAP-43was by the Real-time PCR andWestern blot method. The intracellular Ca~(2+)concentration were tested by Fura-2/AM method.
Results were showed as follows. In the sham group, there was no neuron apoptosis,expression of nNOS and GAP-43in spinal cord are in low level, and intracellular Ca~(2+)concentration has no obvious change at all time points. In the control group, within28daysafter injury, the proportion of apoptosis neurons, the expression of nNOS in the spinal cordand intracellular Ca~(2+)concentration, as well as the expression of GAP43-all appear to dropafter rising first. The process of apoptosis of neuron spikes at D7; nNOS expression waspeaked at D2; intracellular Ca~(2+)concentration peak appeared at D2, and GAP-43peakappeared at D14. The four indicators in the VPA group had similar changes and peak time asin the sham group. But relative to the control group, the VPA significantly reduced thenumber of apoptotic neurons at D3, significantly lowered the expression of nNOS at D1, D2,D3, and D7, significantly reduced intracellular Ca~(2+)concentration at D2, D3, and D7, andobviously up-regulated the expression of GAP-43between D2and D28.
The results indicated four conclusions as follows. First, VPA is able to protect neuronsagainst cell death induced by brachial plexus root avulsion in rats. Second, VPA may exertneuronal protection through decreasing the nNOS expression. Third, VPA may down regulate the intracellular Ca~(2+)concentration to protect neurons. The down regulation of nNOS may beattributed to the decrease of intracellular Ca~(2+)concentration induced by VPA. Four, VPA canpromote neural regeneration by up regulate the expression of GAP-43. The conclusionsprovide theory supports for the clinical application of VPAto treat nerve injury.
丙戊酸（valproic acid，VPA）神经保护作用的发现给这一难题带来希望。由于其属于小分子无机化合物，易于通过血脑屏障，且不容易被酶降解，因此相对于神经生长因子具有较大优势。VPA在临床用于抗癫痫治疗30余年，1995年又被FDA批准用于抑郁症，安全性已得到广泛验证。现已证实VPA对坐骨神经切断伤导致的脊髓运动神经元损伤具有保护作用，而且能促进切断的坐骨神经再生和功能恢复。但对于导致大量神经元死亡的臂丛撕脱伤，VPA是否能一样发挥神经保护和促进神经再生作用呢？为了明确这一问题，本研究设计了大鼠臂丛根性撕脱伤的动物模型，通过对大鼠口服给予VPA，观察VPA对脊髓神经元的影响，以明确VPA是否可以对臂丛撕脱伤后的脊髓神经元起到保护和促进再生作用，并对其神经保护作用的机制进行探讨。
研究证实神经型一氧化氮合酶(neuronal NOS, nNOS)与神经根撕脱后脊髓前角运动神经元的死亡密切相关，根性撕脱伤后nNOS的大量表达会导致神经元的死亡。而已经明确的是在神经损伤导致的神经元死亡中，细胞内Ca~（2+）超载是主要机制之一。nNOS发挥活性依赖于细胞内Ca~（2+），但同时nNOS自身的表达也受到细胞内Ca~（2+）的调控。因此，在臂丛撕脱伤导致的脊髓神经元死亡过程中，nNOS以及细胞内Ca~（2+）的变化起到了至关重要的作用。生长相关蛋白(Growth Associated Protein,GAP-43)是目前研究神经元再生能力的理想指标，神经元内GAP-43表达的升高即提示神经元再生能力的增强。
因此，本研究通过TUNEL法检测确定VPA对臂丛撕脱伤后脊髓神经元具有保护作用后，进一步通过检测VPA对脊髓神经元内nNOS以及细胞内Ca~(2+)的影响来探索VPA发挥神经保护作用的机制。另外，通过检测脊髓神经元内GAP-43的变化，来明确VPA对撕脱伤后的神经元是否有促进再生的作用。
本试验建立Wistar大鼠臂丛根性撕脱伤的动物模型，随机分为空白组（仅暴露臂丛，不做神经损伤），对照组（行臂丛撕脱）和VPA组（撕脱伤后口服给予VPA）。三组动物在D1、D2、D3、D7、D14、D28（D表示天）6个时间点进行脊髓中运动神经元凋亡、nNOS表达、细胞内Ca~(2+)浓度、GAP-43四个指标的检测。对脊髓运动神经元凋亡的检测采用TUNEL法，对nNOS的检测采用Real-time PCR、Western blot法和免疫组化染色法，对细胞内Ca~(2+)浓度采用荧光指示剂Fura-2/AM检测，对GAP-43的检测采用Real-time PCR和Western blot法。实验结果显示：1.空白组没有神经元的凋亡出现。空白组大鼠脊髓中nNOS、GAP-43在整个实验中均呈低水平表稳态表达，细胞内Ca~(2+)浓度无明显变化。2.对照组在撕脱伤后的28天内，凋亡神经元的比例、脊髓中nNOS的表达和细胞内Ca~(2+)浓度、以及GAP-43的表达均出现先升高后下降的过程，其中凋亡神经元峰值出现在D7，nNOS峰值出现在D2，细胞内Ca~(2+)浓度峰值出现在D2，GAP43峰值出现在D14。3.与空白组相比，VPA组在撕脱伤后，凋亡神经元的比例、nNOS表达、细胞内Ca~(2+)浓度和GAP-43的变化趋势及峰值时间同对照组类似。但相对于对照组，VPA在D3、7时明显减少了凋亡神经元的数目，在D1、2、3、7时明显下调了nNOS的表达，在D2、3、7时明显降低了细胞内Ca~(2+)浓度，且在D2~D28明显上调了GAP-43的表达。
分析以上结果，可以得出结论：1.大鼠臂丛根性撕脱伤后，口服VPA可以减少脊髓神经元的凋亡，对神经元产生保护作用。2.大鼠臂丛根性撕脱伤后，VPA可以通过下调脊髓神经元中nNOS的表达对神经元产生保护作用。3.大鼠臂丛根性撕脱伤后，VPA可以通过降低脊髓神经元内Ca~(2+)浓度对神经元产生保护作用。另外，VPA对nNOS表达的下调可能是通过降低神经元内Ca~(2+)浓度来实现的。4.大鼠臂丛根性撕脱伤后，VPA可以通过上调脊髓神经元中GAP-43表达来促进受损神经元的再生。该结论为在临床应用VPA治疗神经损伤提供了更丰富的理论支持。
Brachial plexus root avulsion is the most serious type of peripheral nerve injury. It isencountered commonly in victims of traffic accident and children after obstetriccomplications, leads to totally paralysis of the corresponding muscle groups and severesensory deficits in the arm on the lesion side. Compared with other types of nerve damage(such as clamping, cutting, etc.), root avulsion cause a large number of neuronal death as thedamage site is closer to the neuronal cell bodies in the spinal cord. After peripheral nerveinjury, the survival of motoneurons is an essential prerequisite of nerve regeneration andfunction recovery. The loss of neurons may significantly restrict the achievement of themuscle reinnervation after a surgical repair of the ventral root connection. Therefore, aneffective agent to reduce the neuronal death and promote the survival neuron to regeneratewill be very important and valuable for brachial plexus root avulsion. An increasing numberof neurotrophic factors have been found to support the motoneuron survival and enhanceaxonal regrowth in a variety of experimental paradigms.However, as the neurotrophinsbelong to peptide, their benefits are largely limited by the poor ability to cross theblood-nerve and blood-brain barrier and by enzymatic degradation. Besides, a long time andfrequent administration with high-dose neurotrophic factor may have unexpected side effects.There is still a long way to go before the neurotrophin can be effectively used in clinicalpatients.
The discovery of the neuroprotective effects of valproic acid brings hope to this problem.Since VPA is an inorganic compound with small molecules allowing easily penetrating theblood-brain barrier, and is not easily degraded by enzymes, it has a great advantage relative toneurotrophic factors. The security of VPA has been widely validated because it has been usedfor antiepileptic therapy clinically for more than30years, and approved by the FDA in1995for antidepressant. Clinical studies have found that VPA can protect neurons against death inthe sciatic nerve transection model in rats. However, as to the brachial plexus root avulsion, which induces much more neuronal injury and death, whether the VPAcan exert its protectiveeffect on the neuron? In order to clarify this problem, we designed this study.
In the present study, after the brachial plexus root avulsions of rats were made, the ratswere orally administrated with water containing VPA. First, we detected the neuronalapoptosis in the spinal cord to verify the neuronal protection role of VPA. Then we detectedthe expression of nNOS and Ca~(2+)concentration in the spinal cord neurons to explore theprotective mechanism of VPA. Besides, we want to know whether VPA can enhance theneural regeneration by detecting the GAP-43expression in spinal cord.
Rats were randomly divided to sham group (exposure the brachial plexus root withoutinjury), control group (brachial plexus root avulsion) and VPAgroup (administered with VPAafter avulsion). At different time points, the apoptosis of neurons, expression of nNOS,intracellular Ca~(2+)concentration and GAP-43expression were investigated. Apoptosis ofneurons was inspected by TUNEL method. Detection of nNOS used Real-time PCR, Westernblot method and immunohistochemical staining and GAP-43was by the Real-time PCR andWestern blot method. The intracellular Ca~(2+)concentration were tested by Fura-2/AM method.
Results were showed as follows. In the sham group, there was no neuron apoptosis,expression of nNOS and GAP-43in spinal cord are in low level, and intracellular Ca~(2+)concentration has no obvious change at all time points. In the control group, within28daysafter injury, the proportion of apoptosis neurons, the expression of nNOS in the spinal cordand intracellular Ca~(2+)concentration, as well as the expression of GAP43-all appear to dropafter rising first. The process of apoptosis of neuron spikes at D7; nNOS expression waspeaked at D2; intracellular Ca~(2+)concentration peak appeared at D2, and GAP-43peakappeared at D14. The four indicators in the VPA group had similar changes and peak time asin the sham group. But relative to the control group, the VPA significantly reduced thenumber of apoptotic neurons at D3, significantly lowered the expression of nNOS at D1, D2,D3, and D7, significantly reduced intracellular Ca~(2+)concentration at D2, D3, and D7, andobviously up-regulated the expression of GAP-43between D2and D28.
The results indicated four conclusions as follows. First, VPA is able to protect neuronsagainst cell death induced by brachial plexus root avulsion in rats. Second, VPA may exertneuronal protection through decreasing the nNOS expression. Third, VPA may down regulate the intracellular Ca~(2+)concentration to protect neurons. The down regulation of nNOS may beattributed to the decrease of intracellular Ca~(2+)concentration induced by VPA. Four, VPA canpromote neural regeneration by up regulate the expression of GAP-43. The conclusionsprovide theory supports for the clinical application of VPAto treat nerve injury.
引文
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