| Popis: |
Parkinson’s disease (PD) is an age-related neurodegenerative disorder that primarily targets the dopaminergic nigrostriatal pathway resulting in motor deficits. Degeneration of this pathway is also associated with a-synuclein inclusions (Lewy bodies) and neuroinflammation. In addition to the pathology and motor symptoms, there is a high association of non-motor symptoms with the disease, including depression. Aging, inflammation and depression are linked to each other independently of, and within, PD. Understanding these separate, yet interconnected, mechanisms may help influence preventative and post-diagnosis treatments. In the present work, we hypothesized that proteins related to stress-induced depression, inflammation and PD would be altered in the aged midbrain, and that inhibiting inflammation would ameliorate and increasing glucocorticoid signaling would exacerbate behavioral dysfunction and dopaminergic neuronal loss in neurotoxin models of PD.As PD is an age-associated disease, we first explored age-dependent changes in stress-, inflammation- and PD-related proteins in male Sprague Dawley rats. Compared to young rats, we found an age-associated decrease in glucocorticoid receptor (GR) expression and an increase in a-synuclein expression in the ventral midbrain. Morphological and unbiased stereological analyses of the substantia nigra pars compacta (SNpc) revealed a significant increase in the number of microglia with age, accompanied by an inflammatory morphology. The second study examined the effect of anti-inflammatory treatment in the 6-hydroxydopamine (6-OHDA) neurotoxin model of PD. Increased inflammation is reported in PD brains and animal models, and chronic anti-inflammatory treatment is associated with a decreased risk for developing PD. Here, animals received the anti-inflammatory drug, minocycline, flanking the neurotoxin lesion. Motor behavior was assessed using the forelimb asymmetry test and dopaminergic neuron survival in the SNpc was evaluated via immunohistochemical labeling of tyrosine hydroxylase (TH, the catecholamine biosynthetic enzyme) and unbiased stereology. Results revealed a treatment x lesion interaction trend for both behavior and TH+ cell counts, suggesting that anti-inflammatory treatment had positive effects on the outcome measures and implicating microglial activation in the mechanism of neurotoxin-mediated dopaminergic degeneration. In the third study, we expanded upon previous work showing that chronic stress combined with 6-OHDA exacerbated behavioral dysfunction and cellular degeneration in a combined chronic variable stress (CVS)/PD model. We tested the hypothesis that increased GR signaling in the SNpc, in the CVS/PD paradigm, would further exacerbate behavioral deficits and cell loss. A lentivirus-packaged GR overexpression vector was used to upregulate GR expression in nigral dopaminergic neurons prior to exposing rats to the dual model. We found that GR overexpression did not affect the behavioral deficits or neuronal degeneration in the combined model, however there was a stress x lesion interaction, supporting previous findings and suggesting that neuronal GR signaling may not be the primary mechanism of enhanced degeneration in the CVS/6-OHDA model.Overall, the major findings from this work show an altered inflammatory environment in the aged ventral midbrain, and a role for pro-inflammatory processes in exacerbated behavioral deficits and dopaminergic cell degeneration in the 6-OHDA model of PD. The results suggest that modulation of inflammatory processes may be a promising preventative measure to reduce common age-associated neuropathologies. |
