Non-invasive evaluation of nigrostriatal neuropathology in a proteasome inhibitor rodent model of Parkinson's disease.
BACKGROUND
Predominantly, magnetic resonance imaging (MRI) studies in animal models of Parkinson's disease (PD) have focused on alterations in T2 water 1H relaxation or 1H MR spectroscopy (MRS), whilst potential morphological changes and their relationship to histological or behavioural outcomes have not been appropriately addressed. Therefore, in this study we have utilised MRI to scan in vivo brains from rodents bearing a nigrostriatal lesion induced by intranigral injection of the proteasome inhibitor lactacystin.


RESULTS
Lactacystin induced parkinsonian-like behaviour, characterised by impaired contralateral forelimb grip strength and increased contralateral circling in response to apomorphine. T2-weighted MRI, 3-weeks post-lesion, revealed significant morphological changes in PD-relevant brain areas, including the striatum and ventral midbrain in addition to a decrease in T2 water 1H relaxation in the substantia nigra (SN), but not the striatum. Post-mortem histological analyses revealed extensive dopaminergic neuronal degeneration and alpha-synuclein aggregation in the SN. However, extensive neuronal loss could also be observed in extra-nigral areas, suggesting non-specific toxicity of lactacystin. Iron accumulation could also be observed throughout the midbrain reflecting changes in T2. Importantly, morphological, but not T2 relaxivity changes, were significantly associated with both behavioural and histological outcomes in this model.


CONCLUSIONS
A pattern of morphological changes in lactacystin-lesioned animals has been identified, as well as alterations in nigral T2 relaxivity. The significant relationship of morphological changes with behavioural and histological outcomes in this model raises the possibility that these may be useful non-invasive surrogate markers of nigrostriatal degeneration in vivo.
Vernon
Anthony C
AC
Department of Neuroscience, Kings College London, The James Black Centre, UK.
Johansson
Saga M
SM
Modo
Michel M
MM
D000111:Acetylcysteine / Q000031:analogs & derivatives; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D015853:Cysteine Proteinase Inhibitors; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D007501:Iron / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology*; D051844:alpha-Synuclein / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D018491:Dopamine Agonists; D051844:alpha-Synuclein; C067713:lactacystin; D007501:Iron; D001058:Apomorphine; D004298:Dopamine; D000111:Acetylcysteine