Nigrostriatal neuronal death following chronic dichlorvos exposure: crosstalk between mitochondrial impairments, α synuclein aggregation, oxidative damage and behavioral changes.

B K Binukumar,Ramesh J L Kandimalla,Kiran Dip Gill,Amanjit Bal

doi:10.1186/1756-6606-3-35

B K Binukumar, Ramesh J L Kandimalla + Show 2 more

Open Access

https://doi.org/10.1186/1756-6606-3-35

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Abstract

BackgroundIn recent years, several lines of evidence have shown an increase in Parkinson's disease prevalence in rural environments where pesticides are heavily used. Although, the underlying mechanism for neuronal degeneration in sporadic PD remains unknown, mitochondrial dysfunction, oxidative stress and proteasomal dysfunction are proposed as contributing factors. In this study rats were chronically and continuously exposed to the pesticide, dichlorvos to identify the molecular mechanism of nigrostaital neuronal degeneration.ResultChronic dichlorvos exposure (2.50 mg/kg b.wt.s.c/daily for 12 weeks) caused nigrostriatal dopaminergic degeneration. The degenerative changes were accompanied by a loss of 60-80% of the nigral dopamine neurons and 60-70% reduction in striatal dopamine and tyrosine hydroxylase levels. Dichlorvos exposed animals also showed α -synuclein and ubiquitin positive inclusions along with swollen, dystrophic neurites and mitochondrial abnormalities like decreased complex I&IV activities, increased mitochondrial size, axonal degeneration and presence of electron dense perinuclear cytoplasmic inclusions in the substantia nigra of rats. These animals also showed evidence of oxidative stress, including increased mitochondrial ROS levels, decreased MnSOD activity and increased lipid peroxidation. Measurable impairments in neurobehavioral indices were also observed. Notable exacerbations in motor impairments, open field and catalepsy were also evident in dichlorvos exposed animals.ConclusionAll these findings taken together indicate that chronic dichlorvos exposure may cause nigrostaital neurodegenaration and significant behavioral impairments.

Highlights

In recent years, several lines of evidence have shown an increase in Parkinson’s disease prevalence in rural environments where pesticides are heavily used
Its main neuropathological feature is the loss of the nigrostriatal dopamine containing neurons, whose cell bodies are in the substantia nigra pars compacta (SNpc) and nerve terminals in the striatum
The underlying mechanism for neuronal degeneration in sporadic Parkinson’s disease (PD) remains unknown, mitochondrial dysfunction, oxidative stress and proteasomal dysfunction are proposed as contributing factors

Summary

Result

Male albino rats (Wistar strain) were administrated dichlorvos (2.5 mg/kg, sc. dissolved in corn oil over a period of 12 weeks systemically on a daily basis). In the case of HVA, dichlorvos treated animal showed 72.5% (SN) and 44% (CS) reduction when compared to controls (Figure 2E) These results indicate that dichlorvos administration may cause significant decrease in the levels of dopamine and its metabolites in SN and CS region of rat brain. As shown in additional file 3, no significant change in the Monoamine oxidase enzyme activity was observed in any of the brain regions studied after chronic dichlorvos administration as compared to control This indicates that chronic dichlorvos exposure is not affecting the degradative pathway. Following chronic (2.5 mg/kg b.wt./day for 12 weeks, sc) dichlorvos exposure it was observed that there was no significant decrease (Additional file 4) in the activity of brain acetyl cholinesterase in treated rats as compared to controls At this dose regime cholinergic neurons are not affected. In contrast to changes in a-synuclein protein levels, b actin and synaptophysin protein levels remained unchanged in the SN after chronic dichlorvos administration (Figure 8I, J)

Background

Discussion

Materials and methods

50. Wills ED

Findings

59. Kulkarni SK