Protective effect of bexarotene against apoptosis of substantia nigra neurons in Parkinson rats and role of mTOR/AKT/GSK-3β pathway

Xuemei TANG; Xuehua JIANG; Lu XU

doi:10.16016/j.1000-5404.201709207

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Protective effect of bexarotene against apoptosis of substantia nigra neurons in Parkinson rats and role of mTOR/AKT/GSK-3β pathway

更新时间：2026-03-02

- Protective effect of bexarotene against apoptosis of substantia nigra neurons in Parkinson rats and role of mTOR/AKT/GSK-3β pathway
- Journal of Third Military Medical University Vol. 40, Issue 4, Pages: 328-333(2018)
- 作者机构：
  
  1..610041 成都，四川大学华西药学院West China School of Pharmacy, Sichuan University, Chengdu, Sichuan Province, 610041
  2..610021 成都，四川省第四人民医院药剂科Fourth People's Hospital of Sichuan Province, Chengdu, Sichuan Province, 610021
  3..401331 重庆，重庆医药高等专科学校Chongqing Medical and Pharmaceutical College, Chongqing, 401331, China
- 作者简介：
- 基金信息：
  
  the Science and Technology Project of Chongqing Municipal Education Commission(KJ1600235);the Basic and Frontier Project of Chongqing Science and Technology Commission(CSTC2016jcyjA0268)
- DOI：10.16016/j.1000-5404.201709207
  CLC： R742.5; R969; R971.5
- Received：28 September 2017，
  
  Published：28 February 2018
- 稿件说明：
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Xuemei TANG, Xuehua JIANG, Lu XU. Protective effect of bexarotene against apoptosis of substantia nigra neurons in Parkinson rats and role of mTOR/AKT/GSK-3β pathway[J]. Journal of Third Military Medical University, 2018, 40(4): 328-333.
DOI：

Xuemei TANG, Xuehua JIANG, Lu XU. Protective effect of bexarotene against apoptosis of substantia nigra neurons in Parkinson rats and role of mTOR/AKT/GSK-3β pathway[J]. Journal of Third Military Medical University, 2018, 40(4): 328-333. DOI： 10.16016/j.1000-5404.201709207.

摘要

目的

探讨贝沙罗汀对6-羟多巴胺诱导的帕金森大鼠黑质神经元凋亡及mTOR/AKT/GSK-3β通路的影响。

方法

选取50只健康雄性SD大鼠，按随机数字表法分为假手术组，帕金森模型组，贝沙罗汀高、中、低剂量组(分别为100、50、25 mg/kg，1次/d，连续4周)，每组10只。向帕金森模型组及贝沙罗汀高、中、低剂量组大鼠的右侧大脑纹状体注射6-羟多巴胺，建立帕金森大鼠模型；假手术组仅注射生理盐水。观察大鼠转圈数、速度和左前肢使用率；TUNEL染色法检测黑质神经元凋亡情况；免疫组化法检测黑质部位α-SYN的表达；Western blot检测黑质部位mTOR、p-mTOR(Ser2448)、AKT、p-AKT(Ser473)、GSK-3β和p-GSK-3β(Ser9)蛋白的表达。

结果

与模型组相比，贝沙罗汀高、中、低剂量组旋转圈数、转速显著降低，左前肢使用率显著升高(

0.01)，凋亡神经元数量显著减少(

0.01)，黑质部位α-SYN的表达显著降低(

0.01)，mTOR、p-mTOR、AKT、p-AKT、GSK-3β和p-GSK-3β的表达明显上调(

0.01)。

结论

贝沙罗汀对6-羟多巴胺诱导的帕金森大鼠的黑质神经元具有显著的抑制凋亡作用，其机制可能与激活mTOR/AKT/GSK-3β信号通路有关。

Abstract

Objective

To investigate the protective effect of bexarotene against apoptosis of substantia nigra neurons in a rat model of 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) and explore the role of mTOR/AKT/GSK-3β pathway in mediating this effect.

Methods

Fifty healthy male SD rats were randomized into control group

PD model group

and high-

medium-and low-dose bexarotene treatment groups. Rat models of PD were established in the model group and the 3 bexarotene treatment groups by injecting 6-OHDA into the right striatum; the rats in the control group received an injection with saline only. One day after 6-OHDA injection

the rats in high-

medium-and low-dose bexarotene group were subjected to intragastric administration of 100

and 25 mg/kg bexarotene

respectively

once daily for 4 consecutive weeks. The rats were observed for the number of rotations

rotating speed and left forelimb usage; neuronal apoptosis was detected with TUNEL assay

and immunohistochemistry was performed to detect the expression of α-SYN in the substantia nigra. Western blotting was used to detect the expression levels of mTOR

p-mTOR (Ser2448)

AKT

p-AKT (Ser473)

GSK-3β and p-GSK-3β (Ser9) in the substantia nigra.

Results

Compared with those in the model group

the rats in high-

medium-and low-dose bexarotene groups showed significantly reduced number of rotations

lowered rotating speed

and significantly increased left forelimb usage (

0.01). Bexarotene treatment significantly reduced neuronal apoptosis

decreased α-SYN expression (

0.01)

and lowered the expression of mTOR

p-mTOR

AKT

p-AKT

GSK-3β and p-GSK-3β proteins (

0.01) in the substantia nigra of the Parkinsonian rats.

Conclusion

Bexarotene can reduce neuronal apoptosis in the substantia nigra of rats with 6-OHDA-induced PD

the mechanism of which may involve the activation of mTOR/AKT/GSK-3β signaling pathway.

关键词

Keywords

references

LAZZARINI M, MARTIN S, MITKOVSKI M, et al . Doxycycline restrains glia and confers neuroprotection in a 6-OHDA Parkinson model[J ] . Glia, 2013, 61(7):1084-1100. DOI: 10.1002/glia.22496.

MANOHAR S G, HUSAIN M. Reduced pupillary reward sensitivity in Parkinson's disease[J]. NPJ Parkinsons Dis, 2015, 1: 15026. DOI: 10.1038/npjparkd.2015.26.

CRAMER P E, CIRRITO J R, WESSON D W, et al . ApoE-directed therapeutics rapidly clearβ-amyloidand reverse deficits in AD mouse models[J ] . Science, 2012, 335(6075): 1503-1506. DOI: 10.1126/science.1217697.

MCFARLAND K, SPALDING T A, HUBBARD D, et al . Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson's disease[J ] . ACS Chem Neurosci, 2013, 4(11): 1430-1438. DOI: 10.1021/cn400100f.

ALMEIDA L, AHMED B, WALZ R, et al . Symptoms are frequent in atypical parkinsonian disorders[J ] . Mov Disord Clin Pract, 2017, 4(2): 191-197. DOI: 10.1002/mdc3.12382.

MASTRANGELO L.The Genetics of Parkinson disease[J]. Adv Genet, 2017, 98: 43-62. DOI: 10. 1016/bs. adgen.2017.08.001.

THIELE S L, WARRE R, NASH J E. Development of a unilaterally-lesioned 6-OHDA mouse model of parkinson's disease[J]. J Vis Exp, 2012, 60(60): e3234-e3234. DOI: 10.3791/3234

ARIZA D, LOPES FNC, CRESTANI C C, et al . Chemoreflex and baroreflex alterations in Parkinsonism induced by 6-OHDA in unanesthetized rats[J ] . Neurosci Lett, 2015, 607: 77-82. DOI: 10.1016/j.neulet.2015.09.024.

MOLLENHAUER B, TRAUTMANN E, OTTE B, et al . α-Synuclein in human cerebrospinal fluid is principally derived from neurons of the central nervous system[J ] . J Neural Transm(Vienna), 2012, 119(7):739-746. DOI: 10.1007/s00702-012-0784-0.

KALIA L V, KALIA S K. α-Synuclein and Lewy pathology in Parkinson's disease[J]. Curr Opin Neurol, 2015, 28(4): 375-381. DOI: 10.1097/WCO.0000000000000215.

HERAS-SANDOVAL D, P REZ-ROJAS J M, HERN NDEZ-DAMI N J, et al . The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration[J ] . Cell Signal, 2014, 26(12): 2694-2701. DOI: 10.1016/j.cellsig.2014.08.019.

SADOWSKI K, KOTULSKA-JÓŹWIAK K, JÓŹWIAK S. Role of mTOR inhibitors in epilepsy treatment[J]. Pharmacol Rep, 2015, 67(3): 636-646. DOI: 10.1016/j.pharep.2014.12.017.

PRUSINER S B, WOERMAN A L, MORDES D A, et al . Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism[J ] . Proc Natl Acad Sci USA, 2015, 112(38): E5308-E5317. DOI: 10.1073/pnas.1514475112.

CHUNG J Y, LEE S J, LEE S H, et al . Direct interaction of α-synuclein and AKT regulates IGF-1 signaling: implication of Parkinson disease[J ] . Neurosignals, 2011, 19(2): 86-96.DOI: 10.1159/000325028.

HERAS-SANDOVAL D, P REZ-ROJAS J M, HER N NDEZ-DAMI N J, et al . The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration[J ] . Cell Signal, 2014, 26(12): 2694-2701. DOI: 10.1016/j.cellsig.2014.08.019.

KHWANRAJ K, MADLAH S, GRATAITONG K, et al . Comparative mRNA expression of eEF1A isoforms and a PI3K/AKT/mTOR pathway in a cellular model of parkinson's disease[J ] . Parkinsons Dis, 2016, 2016: 8716016. DOI: 10.1155/2016/8716016.

MORALES-GARC A J A, SUS N C, ALONSO-GIL S, et al . Glycogen synthase kinase-3 inhibitors as potent therapeutic agents for the treatment of Parkinson disease[J ] . ACS Chemical Neuroscience, 2013, 4(2): 350-360. DOI: 10.1021/cn300182g.

ARMENTERO M T, SINFORIANI E, GHEZZI C, et al . Peripheral expression of key regulatory kinases in Alzheimer's disease and Parkinson's disease[J ] . Neurobiol Aging, 2011, 32(12): 2142-2151. DOI: 10.1016/j.neurobiolaging.2010.01.004.

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