PPARγ激动剂吡格列酮对创伤性脑损伤保护作用的实验研究
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摘要
目的:过氧化物酶体增殖物激活受体γ(Peroxisomeproliferator-activated receptor-γ,PPARγ)是配体活化的核转录因子,属Ⅱ型核受体超家族成员。该受体在糖代谢、脂代谢和细胞的增殖与分化中扮演了重要角色[1]。近年来,大量的研究已显示PPARγ被其激动剂(配体)激活后对外周器官和中枢神经系统急慢性疾病的炎症反应具有抑制作用。噻唑烷二酮类药物(TZDs)吡格列酮、罗格列酮是PPARγ受体激动剂,动物实验已证实对脑缺血、脊髓损伤和神经退行性疾病(如Parkinson's病、Alzheimer's病)等有神经保护作用[2,3,4,5]。本实验用PPARγ激动剂(配体)吡格列酮治疗创伤性脑损伤(traumatic brain injury,TBI)大鼠模型,观察其神经功能变化、脑水肿程度、迟发性神经元死亡情况、神经细胞凋亡程度以及细胞间粘附分子-1(ICAM-1)的表达等,探讨PPARγ激动剂吡格列酮激活PPARγ后对TBI的神经保护作用,希望为治疗TBI提供一些新的理论基础和实验依据。
方法:将SD大鼠随机分为假致伤组、对照组、吡格列酮治疗组,对照组和吡格列酮治疗组采用改良的Feeney氏法制作TBI模型,治疗组在致伤前0.5h、致伤后6h、12h、24h采用吡格列酮(10mg/kg)灌胃,假致伤组和对照组在相同时间点用等量生理盐水灌胃。TBI后6h、48h、5d行大鼠神经功能评分,了解神经功能缺失改善情况;TBI后24h用干湿重法进行脑组织含水量测定,了解脑水肿程度;TBI后48h进行HE、Nissl及TUNEL染色观察脑组织损伤程度、迟发性神经元死亡及神经细胞凋亡程度;TBI后24h用免疫组化方法测定脑组织ICAM-1的表达变化。
结果:
实验制作的TBI模型稳定性、重复性和可控性好,模型建立成功;
1. TBI后48h、5d,吡格列酮治疗组的神经功能评分明显优于对照组(P<0.05);
2. TBI后24h吡格列酮治疗组与对照组脑组织含水量差异无统计学意义(P>0.05);
3. TBI后48h,吡格列酮治疗组迟发性神经元死亡和神经细胞凋亡数明显低于对照组(P<0.05);
4. TBI后48h,吡格列酮治疗组脑组织ICAM-1的表达显著低于对照组(P<0.05)
结论:实验成功建立了创伤性脑损伤模型;PPARγ激动剂吡格列酮能明显抑制大鼠创伤性脑损伤后的迟发性神经元死亡和神经细胞凋亡,改善神经功能缺失;同时,PPARγ激动剂吡格列酮能抑制大鼠创伤性脑损伤后ICAM-1的表达,提示PPARγ激动剂吡格列酮可能对创伤性脑损伤后炎症反应有抑制作用。
Objective:Peroxisome proliferator-activated receptor gamma(PPARγ) is a ligand-activated transcription factor of nuclear hormone receptor superfamily. It plays an important role in glucose and lipid metabolism and cell proliferation and differentiation[1]. More recently, much of the research has focused on the anti-inflammatory effects of PPARγactivation by its agonists(ligands) on peripheral organs and the CNS after acute and chronic insults. Thiazolidinedione pioglitazone is a potent agonist of PPARγwhich was shown to induce neuroprotection in animal models of focal ischemia ,spinal cord injury and chronic CNS injuries like Parkinson's disease, Alzheimer's disease[2,3,4,5]. To explored the neuroprotection of PPARγagonist Pioglitazone following traumatic brain injury(TBI) in rats, We treated rats with Pioglitazone following traumatic brain injury. The neurological function, brain oedema, delayed neuronal death and apoptosis of neurocytes were observed. Meanwhile, the expression of ICAM-1 in brain tissue was evaluated. This study provided both rationale and experiment evidences for neuroprotection after TBI.
Methods: The rat models were established by Feeney’s free falling method.The male Sprague-Dawley rats were randomly divided into 3 groups: Pioglitazone treatment group(treated with Pioglitazone 10mg/kg gastric perfusion once at 30mins before TBI and 6h,12h,24h after TBI),control group(treated with the same volume saline gastric perfusion at the same times),sham operation group(treated with the same volume saline gastric perfusion at the same times).The neural deficit scores were tested at 6h,48h,5d after TBI respectively in order to evaluate neurological function. Brain water content(BWC) was estimated by dry-wet weighing method at 24h after TBI in order to evaluate brain oedema. HE, TUNEL and Nissl's staining were employed at 48h after TBI in order to observe injured cerebral cortex, delayed neuronal death and apoptosis of neurocytes. Immunohistochemistry of ICAM-1 was employed at 48h after TBI.
Results:
1.The TBI rat models were steady,repeatable and controllable. So the establishment of rat models were successful.
2. The neural deficit scores in Pioglitazone treatment group were superior to control group at 48h,5d after TBI(P<0.05).
3. The BWC was no significant difference between Pioglitazone treatment group and control group at 48h after TBI(P>0.05).
4. The delayed dead and apoptotic neurocyte numbers in Pioglitazone treatment group were significantly lower than those in control group at 48h after TBI(P<0.05).
5. The expression of ICAM-1 in Pioglitazone treatment group was significantly lower than that in control group at 48h after TBI(P<0.05).
Conclusion: The experiment has established the TBI model in rat successfully. The PPARγagonist Pioglitazone significantly reduced the numbers of the delayed dead and apoptotic neurocyte,and improve the prognosis of TBI. Meanwhile,it prevented the expression of ICAM-1 in brain tissue of rat after TBI,which maybe induce the anti-inflammatory of Pioglitazone.
方法:将SD大鼠随机分为假致伤组、对照组、吡格列酮治疗组,对照组和吡格列酮治疗组采用改良的Feeney氏法制作TBI模型,治疗组在致伤前0.5h、致伤后6h、12h、24h采用吡格列酮(10mg/kg)灌胃,假致伤组和对照组在相同时间点用等量生理盐水灌胃。TBI后6h、48h、5d行大鼠神经功能评分,了解神经功能缺失改善情况;TBI后24h用干湿重法进行脑组织含水量测定,了解脑水肿程度;TBI后48h进行HE、Nissl及TUNEL染色观察脑组织损伤程度、迟发性神经元死亡及神经细胞凋亡程度;TBI后24h用免疫组化方法测定脑组织ICAM-1的表达变化。
结果:
实验制作的TBI模型稳定性、重复性和可控性好,模型建立成功;
1. TBI后48h、5d,吡格列酮治疗组的神经功能评分明显优于对照组(P<0.05);
2. TBI后24h吡格列酮治疗组与对照组脑组织含水量差异无统计学意义(P>0.05);
3. TBI后48h,吡格列酮治疗组迟发性神经元死亡和神经细胞凋亡数明显低于对照组(P<0.05);
4. TBI后48h,吡格列酮治疗组脑组织ICAM-1的表达显著低于对照组(P<0.05)
结论:实验成功建立了创伤性脑损伤模型;PPARγ激动剂吡格列酮能明显抑制大鼠创伤性脑损伤后的迟发性神经元死亡和神经细胞凋亡,改善神经功能缺失;同时,PPARγ激动剂吡格列酮能抑制大鼠创伤性脑损伤后ICAM-1的表达,提示PPARγ激动剂吡格列酮可能对创伤性脑损伤后炎症反应有抑制作用。
Objective:Peroxisome proliferator-activated receptor gamma(PPARγ) is a ligand-activated transcription factor of nuclear hormone receptor superfamily. It plays an important role in glucose and lipid metabolism and cell proliferation and differentiation[1]. More recently, much of the research has focused on the anti-inflammatory effects of PPARγactivation by its agonists(ligands) on peripheral organs and the CNS after acute and chronic insults. Thiazolidinedione pioglitazone is a potent agonist of PPARγwhich was shown to induce neuroprotection in animal models of focal ischemia ,spinal cord injury and chronic CNS injuries like Parkinson's disease, Alzheimer's disease[2,3,4,5]. To explored the neuroprotection of PPARγagonist Pioglitazone following traumatic brain injury(TBI) in rats, We treated rats with Pioglitazone following traumatic brain injury. The neurological function, brain oedema, delayed neuronal death and apoptosis of neurocytes were observed. Meanwhile, the expression of ICAM-1 in brain tissue was evaluated. This study provided both rationale and experiment evidences for neuroprotection after TBI.
Methods: The rat models were established by Feeney’s free falling method.The male Sprague-Dawley rats were randomly divided into 3 groups: Pioglitazone treatment group(treated with Pioglitazone 10mg/kg gastric perfusion once at 30mins before TBI and 6h,12h,24h after TBI),control group(treated with the same volume saline gastric perfusion at the same times),sham operation group(treated with the same volume saline gastric perfusion at the same times).The neural deficit scores were tested at 6h,48h,5d after TBI respectively in order to evaluate neurological function. Brain water content(BWC) was estimated by dry-wet weighing method at 24h after TBI in order to evaluate brain oedema. HE, TUNEL and Nissl's staining were employed at 48h after TBI in order to observe injured cerebral cortex, delayed neuronal death and apoptosis of neurocytes. Immunohistochemistry of ICAM-1 was employed at 48h after TBI.
Results:
1.The TBI rat models were steady,repeatable and controllable. So the establishment of rat models were successful.
2. The neural deficit scores in Pioglitazone treatment group were superior to control group at 48h,5d after TBI(P<0.05).
3. The BWC was no significant difference between Pioglitazone treatment group and control group at 48h after TBI(P>0.05).
4. The delayed dead and apoptotic neurocyte numbers in Pioglitazone treatment group were significantly lower than those in control group at 48h after TBI(P<0.05).
5. The expression of ICAM-1 in Pioglitazone treatment group was significantly lower than that in control group at 48h after TBI(P<0.05).
Conclusion: The experiment has established the TBI model in rat successfully. The PPARγagonist Pioglitazone significantly reduced the numbers of the delayed dead and apoptotic neurocyte,and improve the prognosis of TBI. Meanwhile,it prevented the expression of ICAM-1 in brain tissue of rat after TBI,which maybe induce the anti-inflammatory of Pioglitazone.
引文
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[2] Pedersen WA, McMillan PJ, Kulstad JJ,et al. Rosiglitazone attenuates learningand memory deficits in Tg2576 Alzheimer mice[J].Exp Neurol, 2006, 199:265-273.
[3] Collino M, Aragno M, Mastrocola R,et al. Modulation of the oxidative stress and inflammatory response by PPAR-gamma agonists in the hippocampus of rats exposed to cerebral ischemia/reperfusion[J].Eur J Pharamacol, 2006,530(1):70–80.
[4] McTigue DM, Tripathi R, Wei P, et al. The PPAR gamma agonist pioglitazone improves anatomical and locomotor recovery after rodent spinal cord injury[J]. Exp Neurol, 2007,205:396–406.
[5] Park SW, Yi JH, Miranpuri G, et al. Thiazolidinedione class of peroxisome proliferator-activated receptor-gamma agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain and inflammation after spinal cord injury in adult rats[J]. J Pharm Exp Therap, 2007,320:1002–1012.
[6] Jennings JS, Gerber AM, Vallano ML. Pharmacological strategies for neuroprotection in traumatic brain injury[J].Mini Rev.Med.Chem,2008,8(7): 689-701.
[7] Onyszchuk G, He YY, Berman NE,et al. Detrimental effects of aging on out come from traumatic brain injury:a behavioral,magnetic resonance imaging,and histological study in mice[J]. Neurotrauma,2008,25:153-171
[8] Sundararajan S,Gamboa J L,Victor N A,et al.. Peroxisome proliferator-activated receptor-gamma ligands reduce inflammation and infarction size in transient focal ischemia[J].Neuroscience,2005,130:685–696.
[9] Tureyen K, Kapadia R, Bowen K,et al. Peroxisome proliferator activated receptor-gamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents[J]. Neurochem ,2007,101(1): 41-56.
[10] Bordet R, Ouk T, Petrault O,et al. PPAR:a new pharmacological target for neuroprotection in stroke and neurodegenerative diseases[ J]. Biochem Soc Trans, 2006,34:1341–1346.
[11] Schütz B, Reimann J, Dumitrescu-Ozimek L,et al. The oral antidiabetic pioglitazone protects from neurodegeneration and amyotrophic lateral sclerosis-like symptoms in superoxide dismutase-G93A transgenic mice[ J]. J Neurosci, 2005,25:7805–7812.
[12] Hong Sun , Yuangui Huang , Xin Yu,et al. Peroxisome proliferator-activated receptor gamma agonist,rosiglitazone, suppresses CD40 expression and attenuates inflammatory responses after lithium pilocarpine-induced status epilepticus in rats[ J]. Neuroscience, 2008,26 :505–515
[13] Xin Yu, Xiao-Guang Shao, Hong Sun,et al. Activation of cerebral peroxisome proliferator-activated receptors gamma exerts neuroprotection by inhibiting oxidative stress following pilocarpine-induced status epilepticus[ J]. Brain Research1, 2008,200:146-158.
[14] Magdalena Sastre , Thomas Klockgether , Michael T, et al. Contribution of inflammatory processes to Alzheimer’s disease: molecular mechanisms[ J]. Neuroscience, 2006,24:167–176
[15] Huang Z,Huang P L,Panahian N,et al. Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase[J].Science,1994,265(5180):1883-1885.
[16]李力仙,王天佑,钟震宇,等.自由落体和液压致大鼠脑损伤的对比研究[J].中华实验外科杂志,1999,16(5):447-448.
[17]尹延庆,陈兵.创伤性脑损伤模型的研究进展[J].广东医学院学报,2008,26(6):648-651.
[18] Feeney DM,Boyeson MG,Linn RT,et al. Methodology and local effects of contusion in the rat[J].Brain Res.1981;211(1):67-77
[19] Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS disease and injury[ J]. Br J Pharmacol, 2006,147:232–240
[20] Iadecola C, Alexander M. Cerebral ischemia and inflammation[ J]. Curr OpinNeurol, 2001,14:89–94.
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