Melatonin combined with chondroitin sulfate ABC promotes nerve regeneration after root-avulsion brachial plexus injury
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摘要
After nerve-root avulsion injury of the brachial plexus, oxidative damage, inflammatory reaction, and glial scar formation can affect nerve regeneration and functional recovery. Melatonin(MT) has been shown to have good anti-inflammatory, antioxidant, and neuroprotective effects. Chondroitin sulfate ABC(ChABC) has been shown to metabolize chondroitin sulfate proteoglycans and can reduce colloidal scar formation. However, the effect of any of these drugs alone in the recovery of nerve function after injury is not completely satisfactory. Therefore, this experiment aimed to explore the effect and mechanism of combined application of melatonin and chondroitin sulfate ABC on nerve regeneration and functional recovery after nerve-root avulsion of the brachial plexus. Fifty-two Sprague-Dawley rats were selected and their C5–7 nerve roots were avulsed. Then, the C6 nerve roots were replanted to construct the brachial plexus nerve-root avulsion model. After successful modeling, the injured rats were randomly divided into four groups. The first group(injury) did not receive any drug treatment, but was treated with a pure gel-sponge carrier nerve-root implantation and an ethanol-saline solution via intraperitoneal(i.p.) injection. The second group(melatonin) was treated with melatonin via i.p. injection. The third group(chondroitin sulfate ABC) was treated with chondroitin sulfate ABC through local administration. The fourth group(melatonin + chondroitin sulfate ABC) was treated with melatonin through i.p. injection and chondroitin sulfate ABC through local administration. The upper limb Terzis grooming test was used 2–6 weeks after injury to evaluate motor function. Inflammation and oxidative damage within 24 hours of injury were evaluated by spectrophotometry. Immunofluorescence and neuroelectrophysiology were used to evaluate glial scar, neuronal protection, and nerve regeneration. The results showed that the Terzis grooming-test scores of the three groups that received treatment were better than those of the injury only group. Additionally, these three groups showed lower levels of C5–7 intramedullary peroxidase and malondialdehyde. Further, glial scar tissue in the C6 spinal segment was smaller and the number of motor neurons was greater. The endplate area of the biceps muscle was larger and the structure was clear. The latency of the compound potential of the myocutaneous nerve-biceps muscle was shorter. All these indexes were even greater in the melatonin + chondroitin sulfate ABC group than in the melatonin only or chondroitin sulfate ABC only groups. Thus, the results showed that melatonin combined with chondroitin sulfate ABC can promote nerve regeneration after nerve-root avulsion injury of the brachial plexus, which may be achieved by reducing oxidative damage and inflammatory reaction in the injury area and inhibiting glial scar formation.
After nerve-root avulsion injury of the brachial plexus, oxidative damage, inflammatory reaction, and glial scar formation can affect nerve regeneration and functional recovery. Melatonin(MT) has been shown to have good anti-inflammatory, antioxidant, and neuroprotective effects. Chondroitin sulfate ABC(ChABC) has been shown to metabolize chondroitin sulfate proteoglycans and can reduce colloidal scar formation. However, the effect of any of these drugs alone in the recovery of nerve function after injury is not completely satisfactory. Therefore, this experiment aimed to explore the effect and mechanism of combined application of melatonin and chondroitin sulfate ABC on nerve regeneration and functional recovery after nerve-root avulsion of the brachial plexus. Fifty-two Sprague-Dawley rats were selected and their C5–7 nerve roots were avulsed. Then, the C6 nerve roots were replanted to construct the brachial plexus nerve-root avulsion model. After successful modeling, the injured rats were randomly divided into four groups. The first group(injury) did not receive any drug treatment, but was treated with a pure gel-sponge carrier nerve-root implantation and an ethanol-saline solution via intraperitoneal(i.p.) injection. The second group(melatonin) was treated with melatonin via i.p. injection. The third group(chondroitin sulfate ABC) was treated with chondroitin sulfate ABC through local administration. The fourth group(melatonin + chondroitin sulfate ABC) was treated with melatonin through i.p. injection and chondroitin sulfate ABC through local administration. The upper limb Terzis grooming test was used 2–6 weeks after injury to evaluate motor function. Inflammation and oxidative damage within 24 hours of injury were evaluated by spectrophotometry. Immunofluorescence and neuroelectrophysiology were used to evaluate glial scar, neuronal protection, and nerve regeneration. The results showed that the Terzis grooming-test scores of the three groups that received treatment were better than those of the injury only group. Additionally, these three groups showed lower levels of C5–7 intramedullary peroxidase and malondialdehyde. Further, glial scar tissue in the C6 spinal segment was smaller and the number of motor neurons was greater. The endplate area of the biceps muscle was larger and the structure was clear. The latency of the compound potential of the myocutaneous nerve-biceps muscle was shorter. All these indexes were even greater in the melatonin + chondroitin sulfate ABC group than in the melatonin only or chondroitin sulfate ABC only groups. Thus, the results showed that melatonin combined with chondroitin sulfate ABC can promote nerve regeneration after nerve-root avulsion injury of the brachial plexus, which may be achieved by reducing oxidative damage and inflammatory reaction in the injury area and inhibiting glial scar formation.
After nerve-root avulsion injury of the brachial plexus, oxidative damage, inflammatory reaction, and glial scar formation can affect nerve regeneration and functional recovery. Melatonin(MT) has been shown to have good anti-inflammatory, antioxidant, and neuroprotective effects. Chondroitin sulfate ABC(ChABC) has been shown to metabolize chondroitin sulfate proteoglycans and can reduce colloidal scar formation. However, the effect of any of these drugs alone in the recovery of nerve function after injury is not completely satisfactory. Therefore, this experiment aimed to explore the effect and mechanism of combined application of melatonin and chondroitin sulfate ABC on nerve regeneration and functional recovery after nerve-root avulsion of the brachial plexus. Fifty-two Sprague-Dawley rats were selected and their C5–7 nerve roots were avulsed. Then, the C6 nerve roots were replanted to construct the brachial plexus nerve-root avulsion model. After successful modeling, the injured rats were randomly divided into four groups. The first group(injury) did not receive any drug treatment, but was treated with a pure gel-sponge carrier nerve-root implantation and an ethanol-saline solution via intraperitoneal(i.p.) injection. The second group(melatonin) was treated with melatonin via i.p. injection. The third group(chondroitin sulfate ABC) was treated with chondroitin sulfate ABC through local administration. The fourth group(melatonin + chondroitin sulfate ABC) was treated with melatonin through i.p. injection and chondroitin sulfate ABC through local administration. The upper limb Terzis grooming test was used 2–6 weeks after injury to evaluate motor function. Inflammation and oxidative damage within 24 hours of injury were evaluated by spectrophotometry. Immunofluorescence and neuroelectrophysiology were used to evaluate glial scar, neuronal protection, and nerve regeneration. The results showed that the Terzis grooming-test scores of the three groups that received treatment were better than those of the injury only group. Additionally, these three groups showed lower levels of C5–7 intramedullary peroxidase and malondialdehyde. Further, glial scar tissue in the C6 spinal segment was smaller and the number of motor neurons was greater. The endplate area of the biceps muscle was larger and the structure was clear. The latency of the compound potential of the myocutaneous nerve-biceps muscle was shorter. All these indexes were even greater in the melatonin + chondroitin sulfate ABC group than in the melatonin only or chondroitin sulfate ABC only groups. Thus, the results showed that melatonin combined with chondroitin sulfate ABC can promote nerve regeneration after nerve-root avulsion injury of the brachial plexus, which may be achieved by reducing oxidative damage and inflammatory reaction in the injury area and inhibiting glial scar formation.
引文
Bai F,Peng H,Etlinger JD,Zeman RJ(2010)Partial functional recovery after complete spinal cord transection by combined chondroitinase and clenbuterol treatment.Pflugers Arch 460:657-666.
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Cafferty WBJ,Bradbury EJ,Lidierth M,Jones M,Duffy PJ,Pezet S,Mcmahon SB(2008)Chondroitinase ABC-mediated plasticity of spinal sensory function.J Neurosci 28:11998-12009.
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Chen H,Chen T,Lee M,Chen S,Hsu Y,Kuo Y,Chang G,Wu T,Lee E(2006)Melatonin decreases neurovascular oxidative/nitrosative damage and protects against early increases in the blood-brain barrier permeability after transient focal cerebral ischemia in mice.JPineal Res 41:175-182.
Chen H,Hung Y,Chen T,Huang S,Wang Y,Lee W,Wu T,Lee E(2009)Melatonin improves presynaptic protein,SNAP-25,expression and dendritic spine density and enhances functional and electrophysiological recovery following transient focal cerebral ischemia in rats.JPineal Res 47:260-270.
Chern CM,Liao JF,Wang YH,Shen YC(2012)Melatonin ameliorates neural function by promoting endogenous neurogenesis through the MT2 melatonin receptor in ischemic-stroke mice.Free Radic Biol Med 52:1634-1647.
Dickendesher TL,Baldwin KT,Mironova YA,Koriyama Y,Raiker SJ,Askew KL,Wood A,Geoffroy CG,Zheng B,Liepmann CD(2012)NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans.Nat Neurosci 15:703-712.
Didangelos A,Iberl M,Vinsland E,Bartus K,Bradbury EJ(2014)Regulation of IL-10 by chondroitinase ABC promotes a distinct immune response following spinal cord injury.J Neurosci 34:16424-16432.
Erol FS,Kaplan M,Tiftikci M,Yakar H,Ozercan I,Ilhan N,Topsakal C(2008)Comparison of the effects of octreotide and melatonin in preventing nerve injury in rats with experimental spinal cord injury.J Clin Neurosci 15:784-790.
Esposito E,Genovese T,Caminiti R,Bramanti P,Meli R,Cuzzocrea S(2010a)Melatonin reduces stress-activated/mitogen-activated protein kinases in spinal cord injury.J Pineal Res 46:79-86.
Esposito E,Genovese T,Caminiti R,Bramanti P,Meli R,Cuzzocrea S(2010b)Melatonin regulates matrix metalloproteinases after traumatic experimental spinal cord injury.J Pineal Res 45:149-156.
Fisher D,Xing B,Dill J,Li H,Hoang HH,Zhao Z,Yang XL,Bachoo R,Cannon S,Longo FM,Sheng M,Silver J,Li S(2011)Leukocyte common antigen-related phosphatase is a functional receptor for chondroitin sulfate proteoglycan axon growth inhibitors.J Neurosci 31:14051-14066.
Fraher JP(1999)The transitional zone and CNS regeneration.J Anat194:161.
Francois RM,Hiroyuki K,Takeshi I,Akio I,Masahiko M,Akimasa Y,Satoshi N,Yo M,Hirobumi T,Shinsuke S(2011)Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition.EMBO Mol Med 3:682-696.
Genovese T,Mazzon E,Crisafulli C,Esposito E,Di Paola R,MuiàC,Di Bella P,Bramanti P,Cuzzocrea S(2007)Effects of combination of melatonin and dexamethasone on secondary injury in an experimental mice model of spinal cord trauma.J Pineal Res 43:140-153.
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