Ketamine Does Not Exert Protective Properties on Dopaminergic Neurons in the Lactacystin Mouse Model of Parkinson's Disease.

Lauren Deneyer,Ann Massie,Eduard Bentea

doi:10.3389/fnbeh.2018.00219

Lauren Deneyer, Ann Massie + Show 1 more

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https://doi.org/10.3389/fnbeh.2018.00219

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Abstract

Parkinson’s disease (PD) is an age-related neurodegenerative condition characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). A loss of proteasome function participates to the pathogenesis of PD, leading to the development of rodent models in which a proteasome inhibitor is applied to the nigrostriatal pathway. We recently characterized the intranigral lactacystin (LAC) mouse model, leading to nigrostriatal degeneration, motor dysfunction and alpha-synuclein accumulation. In the present study, we compared the effect of two commonly used anesthetics for generating animal models of PD—i.e., ketamine (KET) and isoflurane (ISO)—on the vulnerability of mouse dopaminergic neurons to proteasome inhibition-induced degeneration. Both anesthetics have the potential to affect the susceptibility of the nigrostriatal pathway for toxin-induced degeneration, and are known to modulate dopamine (DA) homeostasis. Yet, their impact on nigrostriatal degeneration in the proteasome inhibition model has not been evaluated. Unilateral injection with LAC in the SNpc of mice induced motor impairment and significantly reduced the number of dopaminergic cells to ~55%, irrespective of the anesthetic used. However, LAC-induced striatal DA depletion was slightly affected by the choice of anesthetic, resulting in a significant increase in DA turnover in the ISO- but not in KET-treated mice. These results suggest that the extent of nigrostriatal dopaminergic neural loss caused by LAC is not influenced by the choice of anesthetic, and that compared to other PD models, KET is not neuroprotective in the LAC model.

Highlights

The main pathological hallmark of Parkinson’s disease (PD), an age-related chronic and progressive neurodegenerative disorder, is the loss of dopaminergic cells in the substantia nigra pars compacta (SNpc) and the reduction in striatal dopamine (DA) content
LAC infusion into the left SNpc significantly reduced the mean number of dopaminergic cells compared to sham-treatment (F(1,20) = 19.88, p < 0.001; Figures 1A–C), with no influence of anesthetics on the outcome (F(1,20) = 0.002, p > 0.05) or interaction effect (F(1,20) = 0.03, p > 0.05)
We examined for the first time the vulnerability of the nigrostriatal pathway to proteasome inhibition-induced degeneration caused by LAC in mice that were anesthetized with either KET or ISO

Summary

Introduction

The main pathological hallmark of Parkinson’s disease (PD), an age-related chronic and progressive neurodegenerative disorder, is the loss of dopaminergic cells in the substantia nigra pars compacta (SNpc) and the reduction in striatal dopamine (DA) content. Administration of Anesthetics and Lactacystin-Induced Neurodegeneration lactacystin (LAC), a selective proteasome inhibitor, leads to dopaminergic cell death when applied to the nigrostriatal pathway of rodents (Mackey et al, 2013; Savolainen et al, 2017). We recently reported that intranigral administration of LAC—reflecting PD pathology where proteasome dysfunction is limited to the SN (McNaught et al, 2003)—leads to acute and non-progressive dopaminergic cell loss in mice (Bentea et al, 2015). The present study aimed at comparing the susceptibility of the nigrostriatal pathway for proteasome inhibition-induced degeneration in mice that were anesthetized using either the commonly used injectable anesthetic ketamine (KET) or the volatile anesthetic isoflurane (ISO). In addition to the effects on GABAA receptors, the volatile anesthetics depress excitatory synaptic transmission presynaptically, where their principal action appears to be a reduction in glutamate release (Hemmings et al, 2005)

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