title: Associated degeneration of ventral tegmental area dopaminergic neurons in the rat nigrostriatal lactacystin model of parkinsonism and their neuroprotection by valproate.
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.
authors.affiliation: UCL Centre for Advanced Biomedical Imaging, Division of Medicine, University College London, 72 Huntley Street, London WC1E 6DD, UK; Parkinson's Disease Research Group, Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK. Electronic address: ian.harrison@ucl.ac.uk.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Harrison
authors.affiliation: Parkinson's Disease Research Group, Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: Hiba K
authors.initials: HK
authors.lastname: Anis
authors.affiliation: Parkinson's Disease Research Group, Centre for Neuroinflammation and Neurodegeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
authors.forename: David T
authors.initials: DT
authors.lastname: Dexter
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control; D061988:Proteasome Inhibitors; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D061988:Proteasome Inhibitors; C067713:lactacystin; D014635:Valproic Acid; D000111:Acetylcysteine
keywords: Dopamine; Histone deacetylase inhibitor; Lactacystin; Parkinson’s disease; Substantia Nigra pars compacta; Valproate; Ventral tegmental area