Upregulation of Protease-Activated Receptor-1 in Astrocytes in Parkinson Disease: Astrocyte-Mediated Neuroprotection Through Increased Levels of Glutathione Peroxidase
Bibliographic record
Abstract
In the present study, we investigated the expression of protease-activated receptors (PARs), receptors for thrombin, in substantia nigra pars compacta (SNpc) of Parkinson disease (PD) brains and cultures of human neurons, astrocytes, oligodendrocytes, and microglia as determined by immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of PAR-1 was demonstrated only in glial fibrillary acidic protein-positive astrocytes in SNpc, and the number of astrocytes expressing PAR-1 increased in SNpc of PD as compared with nonneurologic control brain. Immunoreactivity for thrombin and prothrombin was stronger in astrocytes and the vessel walls in SNpc of PD brains. PAR-1 was expressed in human astrocytes and neurons, but not in oligodendrocytes or microglia as determined by RT-PCR. We investigated thrombin-mediated activation of human astrocytes. Thrombin treatment activates human astrocytes and induces morphologic change and a marked increase in proliferation of astrocytes. Increased expression of glial cell line-derived growth factor and glutathione peroxidase (GPx) but no change in the expression of nerve growth factor and inflammatory cytokines/chemokine (IL-1beta, IL-6, IL-8, MCP-1) was found in thrombin/PAR-activated astrocytes. Next, we studied the neuroprotective effect exerted by thrombin-activated astrocytes in human cerebral neuron x human neuroblastoma hybrid neurons. Although thrombin showed neurotoxicity against human hybrid neurons in a dose-dependent manner, the conditioned media derived from thrombin-pretreated astrocyte cultures promoted the survival of human hybrid neurons. The protective effect was completely inhibited with a GPx inhibitor, mercaptosuccinic acid, indicating that GPx released from thrombin/PAR-activated astrocytes is responsible for neuroprotection of hybrid neurons against thrombin cytotoxicity. The present study suggests that the increased expression of PAR-1 in astrocytes in SNpc of PD brain is the restorative move taken by the brain to provide neuroprotection against neuronal degeneration and cell death of dopaminergic neurons caused by noxious insults during the progression of PD pathology.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".