神经生长因子经鼻脑靶向联合骨髓干细胞自体动员治疗重型颅脑损伤
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摘要
背景:经鼻脑靶向给药是一种新型给药方法,可以绕开血脑屏障,直接作用于中枢神经系统,不仅具有良好的脑靶向性,还具有无创、快捷的优点。研究表明神经生长因子联合骨髓干细胞动员治疗脑损伤有协同作用。目的:观察神经生长因子经鼻脑靶向联合自体骨髓干细胞动员及综合康复治疗重型颅脑损伤的疗效。方法:(1)选择河南省人民医院神经外科收治的资料完整的创伤性脑损伤患者78例,根据治疗方案不同分为2组:对照组39例采用神经生长因子肌肉注射,1次/d,持续28 d,联合自体骨髓干细胞动员治疗;观察组39例采用神经生长因子经鼻脑靶向滴入,1次/d,连续给药28 d,联合自体骨髓干细胞动员治疗;(2)自体骨髓干细胞动员治疗方案:在脑损伤1周后皮下注射重组人粒细胞集落刺激因子或重组人巨噬细胞集落刺激因子,每3 d 1次,2种交替,同时配合辛伐他汀片10 mg/d口服,连续28 d;(3)出院后2组患者继续行神经生长因子治疗3个月。结果与结论:(1)患者治疗28 d时,观察组神经功能缺损评分略低于对照组,差异无显著性意义(t=0.429,P>0.05);(2)治疗3个月后NIHSS评分,观察组显著优于对照组(t=7.176,P<0.05);(3)格拉斯哥评分(GOS)观察组明显高于对照组(P<0.05);(4)两组患者治疗与随访期间均未出现明显不良反应。(5)结果说明,神经生长因子经鼻脑靶向联合自体骨髓干细胞动员及康复治疗能有效促进重型颅脑损伤的修复,显著改善患者神经功能。
BACKGROUND: Nasal administration is a new route of administration in which drugs can bypass the blood-brain barrier and act directly on the central nervous system. It not only has good brain targeting but also has the advantages of being non-invasive and convenient. Studies have shown that nerve growth factor(NGF) combined with bone marrow stem cell(BMSC) mobilization has a synergistic effect on brain injury. OBJECTIVE: To observe the therapeutic effect of NGF combined with autologous BMSC mobilization via nasal administration and comprehensive rehabilitation for severe craniocerebral injury. METHODS: Seventy-eight patients with traumatic brain injury from the Department of Neurosurgery of Henan Provincial People's Hospital were selected and treated with NGF intramuscular injection(once a day, for continuous 28 days) combined with BMSC mobilization and comprehensive rehabilitation therapy as control group(n=39) or treated with NGF through the nasal administration(once a day, for continuous 28 days) combined with BMSC and comprehensive rehabilitation treatment as observation group(n=39). Therapeutic schedule for autologous BMSC mobilization was as follows: subcutaneous injection of recombinant human granulocyte colony-stimulating factor or recombinant human macrophage colony-stimulating factor alternately at 1 week after brain injury, once every 3 days, and oral administration of simvastatin tablets, 10 mg per day, for continuous 28 days. Two groups of patients continued to be treated with NGF for 3 months after discharge. RESULTS AND CONCLUSION: At 28 days after treatment, the neurologic defect score in the observational group was slightly lower than that in the control group, but there was no significant difference between the two groups(t=0.429, P > 0.05). At 3 months after treatment, the score on the National Institutes of Health Stroke Scale was significantly better in the observational group than the control group(t=7.176, P < 0.05), and the score on the Glasgow Coma Scale Glasgow was also significantly higher in the observational group than the control group(P < 0.05). No obvious adverse event occurred in the two groups during the treatment and follow-up. To conclude, nasal administration of NGF combined with autologous BMSC mobilization and rehabilitation therapy can effectively promote the repair of severe craniocerebral injury and significantly improve the neurological function of the patients.
BACKGROUND: Nasal administration is a new route of administration in which drugs can bypass the blood-brain barrier and act directly on the central nervous system. It not only has good brain targeting but also has the advantages of being non-invasive and convenient. Studies have shown that nerve growth factor(NGF) combined with bone marrow stem cell(BMSC) mobilization has a synergistic effect on brain injury. OBJECTIVE: To observe the therapeutic effect of NGF combined with autologous BMSC mobilization via nasal administration and comprehensive rehabilitation for severe craniocerebral injury. METHODS: Seventy-eight patients with traumatic brain injury from the Department of Neurosurgery of Henan Provincial People's Hospital were selected and treated with NGF intramuscular injection(once a day, for continuous 28 days) combined with BMSC mobilization and comprehensive rehabilitation therapy as control group(n=39) or treated with NGF through the nasal administration(once a day, for continuous 28 days) combined with BMSC and comprehensive rehabilitation treatment as observation group(n=39). Therapeutic schedule for autologous BMSC mobilization was as follows: subcutaneous injection of recombinant human granulocyte colony-stimulating factor or recombinant human macrophage colony-stimulating factor alternately at 1 week after brain injury, once every 3 days, and oral administration of simvastatin tablets, 10 mg per day, for continuous 28 days. Two groups of patients continued to be treated with NGF for 3 months after discharge. RESULTS AND CONCLUSION: At 28 days after treatment, the neurologic defect score in the observational group was slightly lower than that in the control group, but there was no significant difference between the two groups(t=0.429, P > 0.05). At 3 months after treatment, the score on the National Institutes of Health Stroke Scale was significantly better in the observational group than the control group(t=7.176, P < 0.05), and the score on the Glasgow Coma Scale Glasgow was also significantly higher in the observational group than the control group(P < 0.05). No obvious adverse event occurred in the two groups during the treatment and follow-up. To conclude, nasal administration of NGF combined with autologous BMSC mobilization and rehabilitation therapy can effectively promote the repair of severe craniocerebral injury and significantly improve the neurological function of the patients.
引文
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[8]步星耀,赵红卫,钱宝延,等.自体骨髓间质干细胞移植联合神经营养因子及综合康复治疗脊髓损伤[J].中华实用诊断与治疗杂志,2009,23(4):329-331.
[9]Gao H.Progress and perspectives on targeting nanoparticles for brain drug delivery.Acta Pharm Sin B.2016;6(4):268-286
[10]Tian L,Guo R,Yue X,et al.Intranasal administration of nerve growth factor ameliorateβ-amyloid deposition after traumatic brain injury in rats.Brain Res.2012;1440:47-55.
[11]Song JN,Liu ZW,Sui L,et al.Dynamic expression of nerve growth factor and its receptor Trk A after subarachnoid hemorrhage in rat brain.Neural Regen Res.2016;11(8):1278-1284.
[12]Hui L,Yuan J,Ren Z,et al.Nerve growth factor reduces apoptotic cell death in rat facial motor neurons after facial nerve injury.Neurosciences(Riyadh).2015;20(1):65-68.
[13]缪一艇,童凌云,王勇,等.神经生长因子对重型颅脑损伤患者的治疗效果及血清MMP-2、NSE影响研究[J].中华全科医学,2016,14(12):2040-2041.
[14]朱骏,赵建华.神经节苷脂联合神经生长因子对小儿脑损伤患者神经行为功能及临床疗效的影响[J].临床和实验医学杂志,2017,16(1):82-85.
[15]Md S,Mustafa G,Baboota S,et al.Nanoneurotherapeutics approach intended for direct nose tobrain delivery,Drug Dev Ind Pharm.2015;41(12):1922-34 Drug Dev.Ind.Pharm.(2015)1-13.
[16]张慧,步星耀,杨冬谊,等.神经生长因子经鼻脑靶向联合腰大池外引流治疗外伤性蛛网膜下腔出血临床观察[J].中华实用诊断与治疗杂志,2015,29(12):1234-1236.
[17]Schaefer ML,B?ttger B,Silver WL,et al.Trigeminal collaterals in the nasal epithelium and olfactorybulb:a potential route for direct modulation of olfactory information by trigeminal stimuli.J Comp Neurol.2002;444(3):221-226.
[18]Illum L.Nasal drug delivery—possibilities,problems and solutions.J Control Release.2003;87(1-3):187-98.
[19]Hanson LR,Frey WH 2nd.Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease.BMC Neurosci.2008;9 Suppl 3:S5
[20]林彦琛,云晨,钟士江.经鼻给予不同剂量NGF对G93A—SOD1小鼠的治疗作用[J].武警后勤学院学报:医学版,2016(9):701-704.
[21]张慧,步星耀,杨冬谊,等.神经生长因子经鼻脑靶向联合腰大池外引流治疗外伤性蛛网膜下腔出血临床观察[J].中华实用诊断与治疗杂志,2015,29(12):1234-1236.
[22]Guo X,Bu X,Jiang J,et al.Enhanced neuroprotective effects of co-administration of G-CSF with simvastatin on intracerebral hemorrhage in rats.Turk Neurosurg.2012;22(6):732-739.
[23]Han X,Yang N,Cui Y,et al.Simvastatin mobilizes bone marrow stromal cells migrating to injured areas and promotes functional recovery after spinal cord injury in the rat.Neurosci Lett.2012;521(2):136-141.
[24]程培训,姜金豆,周长江,等.自体骨髓干细胞动员治疗持续植物状态临床研究[J].河南医学研究,2011,20(1):63-66
[25]李志营,夏云,郭晓鹤,等.自体骨髓干细胞动员联合醒脑静治疗脑损伤临床研究[J].中国实用神经疾病杂志,2016,19(7):71-73.
[26]Wojakowski W,Landmesser U,Bachowski R,et al.Mobilization of stem and progenitor cells in cardiovascular diseases.Leukemia.2012;26(1):23-33.
[27]Spaeth EL,Kidd S,Marini FC.Tracking inflammation-induced mobilization of mesenchymal stem cells.Methods Mol Biol.2012;904:173-190.
[28]翟亚萍,步星耀,王新军,等.自体骨髓干细胞动员移植联合神经营养因子和综合康复治疗持续植物状态[J].中华实用诊断与治疗杂志,2012,26(1):31-33.
[29]孙彦熙,步星耀,袁强,等.颅脑损伤术后带肌蒂颅骨成形联合干细胞动员及综合康复治疗临床分析[J].中华实用诊断与治疗杂志,2014,28(10):989-991.
[2]Davis T,Ings A.National Institute of Health and Care Excellence.Head injury:triage,assessment,investigation and early management of head injury in children,young people and adults(NICE guideline CG 176).Arch Dis Child Educ Pract Ed.2015;100(2):97-100.
[3]Davis-López de Carrizosa MA,Morado-Díaz CJ,Morcuende S,etal.Nerve growth factor regulates the firing patternasandsynaptic composition of motoneurons.J Neurosci.2010;30(24):8308-8319.
[4]Khan A R,Liu M,Khan M W,et al.Progress in brain targeting drug delivery system by nasal route.J Control Release.2017;268:364-389.
[5]步星耀,闫兆月,郭晓鹤,等.手术联合自体骨髓干细胞动员治疗重型颅脑损伤疗效观察[J].中华实用诊断与治疗杂志,2013,27(7):657-659.
[6]焦继超,袁强,步星耀,等.NGF联合自体骨髓干细胞动员治疗重型颅脑损伤疗效观察[J].中国实用神经疾病杂志,2015(2):4-6.
[7]姜金豆,步星耀,程培训,等.自体骨髓干细胞联合辛伐他汀治疗脊髓损伤[J].河南医学研究,2010,19(4):434-437.
[8]步星耀,赵红卫,钱宝延,等.自体骨髓间质干细胞移植联合神经营养因子及综合康复治疗脊髓损伤[J].中华实用诊断与治疗杂志,2009,23(4):329-331.
[9]Gao H.Progress and perspectives on targeting nanoparticles for brain drug delivery.Acta Pharm Sin B.2016;6(4):268-286
[10]Tian L,Guo R,Yue X,et al.Intranasal administration of nerve growth factor ameliorateβ-amyloid deposition after traumatic brain injury in rats.Brain Res.2012;1440:47-55.
[11]Song JN,Liu ZW,Sui L,et al.Dynamic expression of nerve growth factor and its receptor Trk A after subarachnoid hemorrhage in rat brain.Neural Regen Res.2016;11(8):1278-1284.
[12]Hui L,Yuan J,Ren Z,et al.Nerve growth factor reduces apoptotic cell death in rat facial motor neurons after facial nerve injury.Neurosciences(Riyadh).2015;20(1):65-68.
[13]缪一艇,童凌云,王勇,等.神经生长因子对重型颅脑损伤患者的治疗效果及血清MMP-2、NSE影响研究[J].中华全科医学,2016,14(12):2040-2041.
[14]朱骏,赵建华.神经节苷脂联合神经生长因子对小儿脑损伤患者神经行为功能及临床疗效的影响[J].临床和实验医学杂志,2017,16(1):82-85.
[15]Md S,Mustafa G,Baboota S,et al.Nanoneurotherapeutics approach intended for direct nose tobrain delivery,Drug Dev Ind Pharm.2015;41(12):1922-34 Drug Dev.Ind.Pharm.(2015)1-13.
[16]张慧,步星耀,杨冬谊,等.神经生长因子经鼻脑靶向联合腰大池外引流治疗外伤性蛛网膜下腔出血临床观察[J].中华实用诊断与治疗杂志,2015,29(12):1234-1236.
[17]Schaefer ML,B?ttger B,Silver WL,et al.Trigeminal collaterals in the nasal epithelium and olfactorybulb:a potential route for direct modulation of olfactory information by trigeminal stimuli.J Comp Neurol.2002;444(3):221-226.
[18]Illum L.Nasal drug delivery—possibilities,problems and solutions.J Control Release.2003;87(1-3):187-98.
[19]Hanson LR,Frey WH 2nd.Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease.BMC Neurosci.2008;9 Suppl 3:S5
[20]林彦琛,云晨,钟士江.经鼻给予不同剂量NGF对G93A—SOD1小鼠的治疗作用[J].武警后勤学院学报:医学版,2016(9):701-704.
[21]张慧,步星耀,杨冬谊,等.神经生长因子经鼻脑靶向联合腰大池外引流治疗外伤性蛛网膜下腔出血临床观察[J].中华实用诊断与治疗杂志,2015,29(12):1234-1236.
[22]Guo X,Bu X,Jiang J,et al.Enhanced neuroprotective effects of co-administration of G-CSF with simvastatin on intracerebral hemorrhage in rats.Turk Neurosurg.2012;22(6):732-739.
[23]Han X,Yang N,Cui Y,et al.Simvastatin mobilizes bone marrow stromal cells migrating to injured areas and promotes functional recovery after spinal cord injury in the rat.Neurosci Lett.2012;521(2):136-141.
[24]程培训,姜金豆,周长江,等.自体骨髓干细胞动员治疗持续植物状态临床研究[J].河南医学研究,2011,20(1):63-66
[25]李志营,夏云,郭晓鹤,等.自体骨髓干细胞动员联合醒脑静治疗脑损伤临床研究[J].中国实用神经疾病杂志,2016,19(7):71-73.
[26]Wojakowski W,Landmesser U,Bachowski R,et al.Mobilization of stem and progenitor cells in cardiovascular diseases.Leukemia.2012;26(1):23-33.
[27]Spaeth EL,Kidd S,Marini FC.Tracking inflammation-induced mobilization of mesenchymal stem cells.Methods Mol Biol.2012;904:173-190.
[28]翟亚萍,步星耀,王新军,等.自体骨髓干细胞动员移植联合神经营养因子和综合康复治疗持续植物状态[J].中华实用诊断与治疗杂志,2012,26(1):31-33.
[29]孙彦熙,步星耀,袁强,等.颅脑损伤术后带肌蒂颅骨成形联合干细胞动员及综合康复治疗临床分析[J].中华实用诊断与治疗杂志,2014,28(10):989-991.