P‐192: Tramiprosate decreases amyloid‐β induced ERK1/2 activity in primary rat neurons by a GABA‐independent pathway
Bibliographic record
Abstract
The mitogen-activated protein kinase (MAPK) family members, including extracellular signal regulated kinase (ERK1/2), are involved in neuronal cell death mediated by amyloid-β (Aβ). Aβ has been shown to induce activation of ERK1/2 in primary neurons (Rapoport. J Neurochem 2000, 74:125). Treatment of organotypic hippocampal cultures (OHC) with soluble oligomeric Aβ has been reported to result in ERK1/2 activation and contribute to cell death (Chong. J Biol Chem 2006:281). Tramiprosate (3-amino-1-propanesulfonic acid), presently in phase III trials for Alzheimer's disease, is neuroprotective against Aβ42-mediated toxicity in rat primary neurons and OHC. This study assessed the role of MAPK in this neuroprotective activity. Rat primary cortical/hippocampal neurons were treated with soluble Aβ42, and ERK1/2 phosphorylation and caspase 3/7 activity were assessed. OHC were treated with soluble Aβ42 ± U0126 (MEK1 inhibitor). Cellular mortality was assessed by propidium iodide uptake. Treatment of rat primary neurons with Aβ42 induced ERK1/2 phosphorylation, while coincubation with tramiprosate significantly reduced this effect. Tramiprosate preferentially inhibits ERK1/2 activation induced by an Aβ42 preparation that is predominantly in a β-sheet conformation rather than random coil. U0126 completely blocked Aβ42-induced ERK1/2 phosphorylation while muscimol, a potent GABAA receptor agonist, was inactive. Together these results demonstrate the GABAA-independent activity of tramiprosate on ERK1/2. Treatment of OHC with Aβ42 induced ERK1/2 phosphorylation in all hippocampal regions while U0126 was completely protective against Aβ42-induced cell death. The effect of tramiprosate on Aβ42-mediated ERK1/2 activation in OHC is under investigation. Tramiprosate is neuroprotective in rat primary neurons at least in part via inhibition of Aβ42-induced activation of ERK1/2 by a GABAA-independent mechanism. Interestingly, tramiprosate binds to the GABAA receptor with high affinity and inhibits Aβ42-induced caspase-3/7 activation in rat primary neurons through a GABAA-dependent mechanism (See Galarneau et al., poster presentation at this meeting). Because muscimol was inactive against Aβ42-induced ERK1/2 phosphorylation, and U0126 did not protect against Aβ42-induced caspase 3/7 activation, these results suggest that the neuroprotective activity of tramiprosate involves at least two potentially independent and complementary mechanisms, one GABAergic and the other non-GABAergic.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.004 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".