Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate

David T Dexter,Hiba K Anis,Ian F Harrison

doi:10.1016/j.neulet.2015.12.052

David T Dexter, Hiba K Anis + Show 1 more

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https://doi.org/10.1016/j.neulet.2015.12.052

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Abstract

Parkinson’s disease (PD) manifests clinically as bradykinesia, rigidity, and development of a resting tremor, primarily due to degeneration of dopaminergic nigrostriatal pathways in the brain. Intranigral administration of the irreversible ubiquitin proteasome system inhibitor, lactacystin, has been used extensively to model nigrostriatal degeneration in rats, and study the effects of candidate neuroprotective agents on the integrity of the dopaminergic nigrostriatal system. Recently however, adjacent extra-nigral brain regions such as the ventral tegmental area (VTA) have been noted to also become affected in this model, yet their integrity in studies of candidate neuroprotective agents in the model have largely been overlooked. Here we quantify the extent and distribution of dopaminergic degeneration in the VTA of rats intranigrally lesioned with lactacystin, and quantify the extent of VTA dopaminergic neuroprotection after systemic treatment with an epigenetic therapeutic agent, valproate, shown previously to protect dopaminergic SNpc neurons in this model. We found that unilateral intranigral administration of lactacystin resulted in a 53.81% and 31.72% interhemispheric loss of dopaminergic SNpc and VTA neurons, respectively. Daily systemic treatment of lactacystin lesioned rats with valproate however resulted in dose-dependant neuroprotection of VTA neurons. Our findings demonstrate that not only is the VTA also affected in the intranigral lactacystin rat model of PD, but that this extra-nigral brain region is substrate for neuroprotection by valproate, an agent shown previously to induce neuroprotection and neurorestoration of SNpc dopaminergic neurons in this model. Our results therefore suggest that valproate is a candidate for extra-nigral as well as intra-nigral neuroprotection.

Highlights

The ventral tegmental area (VTA) exhibited only a subtle interhemispheric loss of dopaminergic neurons, 7 days post-lesion, (Fig. 2B and C, % interhemispheric loss in the VTA of tyrosine hydroxide (TH)+ and Nissl+ cells, week 1, 11.94 ± 2.12% and 12.83 ± 9.24%, respectively) which was markedly exacerbated 5 weeks post-lesion (TH+ and Nissl+ cells loss, 2.66 and 2.47 fold increase from week 1). This loss in the VTA at week 5 was far less than that observed in the Substantia Nigra pars compacta (SNpc) (Fig. 2B and C, % interhemispheric loss in the VTA of TH+ and Nissl+ cells, 22.10 and 23.25% less than that in the SNpc, respectively)
Like the dopaminergic neurons of the SNpc, as we have previously published [7], we show here that the lactacystin induced degeneration of dopaminergic neurons in the VTA is dose dependantly ablated upon systemic treatment with the histone deacetylase inhibitor (HDACI), valproate, suggesting that valproate is a candidate for both intra- and extra-nigral neuroprotection
We show here that intranigral injection of the irreversible proteasome inhibitor, lactacystin, causes neurodegeneration within the SNpc itself, and extensively within the nearby VTA, 5 weeks post-lesion

Summary

Introduction

Parkinson’s disease (PD) is a complex movement disorder classically characterised by clinical presentation of rigidity, tremor and bradykinesia, primarily resulting from degeneration of the dopaminergic nigrostriatal pathway [10]. Develops this ␣Syn pathology is thought to progressively spread rostrally throughout the brain, gradually affecting higher order centres with disease progression, bringing about dementia and neuropsychiatric symptoms which are synonymous with late stage PD [2]. Spread of ␣Syn pathology in the brain and the proximity of the SNpc to the VTA would suggest that this region is affected in PD. It has previously been shown that this is the case in PD: VTA neuron numbers being reduced in PD brains compared to control [9,28] thought, possibly to be related to duration or severity of depression in PD patients as these neurons normally function as part of the brain’s positive affect system, in reward or reinforcement processes [6]

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