Human Albumin Prevents 6-Hydroxydopamine-Induced Loss of Tyrosine Hydroxylase in In Vitro and In Vivo

Li-Juan Zhang,Qian-Jin Zhang,Chun Yang,Xiao-Min Wang,Yue-Qiang Xue,Ting-Yu Qu,Long Chen,Li-Ru Zhao,Wei-Ming Duan,Shile Huang,Wei-Hua Yang,David I Finkelstein

doi:10.1371/journal.pone.0041226

Abstract

Human albumin has recently been demonstrated to protect brain neurons from injury in rat ischemic brain. However, there is no information available about whether human albumin can prevent loss of tyrosine hydroxylase (TH) expression of dopaminergic (DA) neurons induced by 6-hydroxydopamine (6-OHDA) toxicity that is most commonly used to create a rat model of Parkinson's disease (PD). In the present study, two microliters of 1.25% human albumin were stereotaxically injected into the right striatum of rats one day before or 7 days after the 6-OHDA lesion in the same side. D-Amphetamine-induced rotational asymmetry was measured 7 days, 3 and 10 weeks after 6-OHDA lesion. We observed that intrastriatal administration of human albumin significantly reduced the degree of rotational asymmetry. The number of TH-immunoreactive neurons present in the substantia nigra was greater in 6-OHDA lesioned rats following human albumin-treatment than non-human albumin treatment. TH-immunoreactivity in the 6-OHDA-lesioned striatum was also significantly increased in the human albumin-treated rats. To examine the mechanisms underlying the effects of human albumin, we challenged PC12 cells with 6-OHDA as an in vitro model of PD. Incubation with human albumin prevented 6-OHDA-induced reduction of cell viability in PC12 cell cultures, as measured by MTT assay. Furthermore, human albumin reduced 6-OHDA-induced formation of reactive oxygen species (ROS) and apoptosis in cultured PC12 cells, as assessed by flow cytometry. Western blot analysis showed that human albumin inhibited 6-OHDA-induced activation of JNK, c-Jun, ERK, and p38 mitogen-activated protein kinases (MAPK) signaling in PC12 cultures challenged with 6-OHDA. Human albumin may protect against 6-OHDA toxicity by influencing MAPK pathway followed by anti-ROS formation and anti-apoptosis.

Highlights

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc)
Both pre- and post-treatment with human albumin resulted in a significant reduction of the number of d-amphetamine-induced rotations for hemiparkinsonian rats in the Albumin +6-OHDA group (261.0) and the 6-OHDA + Albumin group (662.5) 10 weeks after 6-OHDA lesion when compared with the Saline +6-OHDA group (1462.8) and the 6OHDA group (1362.3) (*P,0.01, # P,0.05)
The present study demonstrates that intrastriatal administration of 1.25% human albumin increases tyrosine hydroxylase (TH)-immunoreactivities in the 6-OHDA-injected striatum and enhances the number of THpositive DA neurons in the ispilateral SNc

Summary

Introduction

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Oral administration of levodopa remains the gold standard therapy for PD which is effective for symptomatic relief during early stage of PD. Long-term administration of levodopa is always associated with side effects and less effectiveness. There is a great need to develop a new therapy for PD. The mechanisms responsible for DA neuron death are not fully understood, accumulating evidence from both animal studies and human post-mortem studies suggests that oxidative stress plays the key role in initiating this cell death process [1,2,3,4]. The interventions into oxidative stress processes may potentially be developed into new therapeutic approaches for PD

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