Antioxidant and anti-inflammatory effects of dexrazoxane on dopaminergic neuron degeneration in rodent models of Parkinson's disease

NEUROPHARMACOLOGY

卷:160

Article

Mei, Meng²  Zhou, Yuanzhang¹  Liu, Mengdi¹  Zhao, Fangfang¹  Wang, Cong¹  Ding, Jianhua¹  Lu, Ming^1,3  Hu, Gang^1,2 

[1] Nanjing Med Univ, Dept Pharmacol, Jiangsu Key Lab Neurodegenerat, 101 Longmian Ave, Nanjing 211166, Jiangsu, Peoples R China

[2] Nanjing Univ Chinese Med, Dept Pharmacol, 138 Xianlin Ave, Nanjing 210023, Jiangsu, Peoples R China

[3] Nanjing Med Univ, Dept Pharmacol, Neuroprotect Drug Discovery Key Lab, 101 Longmian Ave, Nanjing 211166, Jiangsu, Peoples R China

关键词: Dexrazoxane;    Systemic inflammation;    Oxidative stress;    ER stress;    PD;   

DOI  :  10.1016/j.neuropharm.2019.107758

来源: Elsevier

【 摘 要 】

Emerging evidence has demonstrated that the integrity and the function of blood-brain barrier (BBB) are gradually impaired in the processes of aging and nervous system disorders, including neurodegenerative diseases (e.g. Parkinson's disease, PD). The leakage of BBB contributes to the infiltration of peripheral immune cells and harmful mediators into brain parenchyma, even the drugs that can not cross BBB under physiological conditions. Therefore, PD has been regarded as not only a neurodegenerative disease, but also a systemic disorder. In the present study, we demonstrate for the first time that Dexrazoxane (Dex), a drug clinically used to reduce doxorubicin-induced cardiotoxicity in chemotherapy, can enter into midbrain and striatum through broken BBB in 6-hydroxydopamine (6-OHDA)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced rodent models of PD. Unexpectedly, Dex (1.5, 5, 15 mg/kg, i.p.) administration for 3-week significantly ameliorates apomorphine-induced contralateral rotation behavior in 6-OHDA-treated rats and Dex (10 mg/kg, i.p.) treatment for 5-week improves MPTP-induced mouse motor dysfunctions. We find that Dex administration protects dopaminergic neurons against neurotoxin-induced degeneration in SNc, accompanied by the attenuated glial cell activation. Further study indicates that suppression of oxidative stress and endoplasmic reticulum stress, as well as the inhibition of systemic inflammation in both peripheral tissues and brain, contribute to the neuroprotective effects of Dex in PD models. Our study implies that Dex may serve as an effective neuroprotectant to treat neurodegeneration and has potential clinical value in term of PD therapeutics.

【 授权许可】

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