Mitochondrial Dysfunction and Oxidative Stress Promote Apoptotic Cell Death in the Striatum via Cytochrome c/ Caspase-3 Signaling Cascade Following Chronic Rotenone Intoxication in Rats

Tsu-Kung Lin,Chia-Wei Liou,Ching-Hsiao Cheng,Chi-Ren Huang,Yao-Chung Chuang,Shang-Der Chen

doi:10.3390/ijms13078722

Abstract

Parkinson’s disease (PD) is a progressive neurological disorder marked by nigrostriatal dopaminergic degeneration. Evidence suggests that mitochondrial dysfunction may be linked to PD through a variety of different pathways, including free-radical generation and dysfunction of the mitochondrial Complex I activity. In Lewis rats, chronic systemic administration of a specific mitochondrial Complex I inhibitor, rotenone (3 mg/kg/day) produced parkinsonism-like symptoms. Increased oxidized proteins and peroxynitrite, and mitochondrial or cytosol translocation of Bim, Bax or cytochrome c in the striatum was observed after 2–4 weeks of rotenone infusion. After 28 days of systemic rotenone exposure, imunohistochemical staining for tyrosine hydroxylase indicated nigrostriatal dopaminergic neuronal cell degeneration. Characteristic histochemical (TUNEL or activated caspase-3 staining) or ultrastructural (electron microscopy) features of apoptotic cell death were present in the striatal neuronal cell after chronic rotenone intoxication. We conclude that chronic rotenone intoxication may enhance oxidative and nitrosative stress that induces mitochondrial dysfunction and ultrastructural damage, resulting in translocation of Bim and Bax from cytosol to mitochondria that contributes to apoptotic cell death in the striatum via cytochrome c/caspase-3 signaling cascade.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, affecting about 1% of adults older than 60 years [1]
47% of rotenone-infused rats exhibited Parkinsonism-like symptoms that included reduced mobility, flexed posture and rigidity
The present study took advantage of an animal model of chronic systemic rotenone intoxication that closely resembles PD. Based on this animal model, the present study revealed that the repertoire of cellular events after inhibition of mitochondrial respiratory chain enzyme Complex I activity with chronic systemic rotenone infusion caused degeneration of the striatal neurons

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, affecting about 1% of adults older than 60 years [1]. PD is a chronic, progressive disease caused by degeneration of specific neuronal population in the brain, notably the dopaminergic neurons of the substantia nigra pas compacta [1,2]. With the increasing age of the general population, the prevalence of PD will rise steadily in the future [1]. The impact of this disease indicates that PD patients have a two to five-fold higher risk of mortality than the general population [3,4]. Increasing evidence suggests that mitochondrial dysfunction may be linked to PD through a variety of pathways, including free-radical generation, inflammation, deficiency of the activity of mitochondrial respiratory chain enzyme Complex I [5,6,7].

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Conclusion