Metformin, an antidiabetic drug, reduces neurodegeneration in rat hippocampus by disrupting adenosine receptor signalling
Bibliographic record
Abstract
Adenosine signalling has been implicated in the pathophysiology of CNS disorders, such as stroke, epilepsy and Parkinson’s disease (PD). Recent reports suggest that prolonged activation of adenosine A1 and A2A receptors during stroke increases hippocampal neurodegeneration. Epidemiological studies suggested that the anti-diabetic drug metformin could promote neuroprotection in stroke patients, but the precise mechanism of this neuroprotective property remains unclear, and current literature was often conflicting. Based on pilot studies carried out initially in ex vivo rat hippocampal brain slices, we investigated our hypothesis that metformin binds to adenosine receptors to mediate neuroprotection. Using in vivo administration of adenosine A1 receptor agonist N(6)cyclopentyladenosine (CPA), with or without the A1R antagonist dipropylcyclopentylxanthine (DPCPX), and elevation of endogenous adenosine in our ex-vivo hypoxia-reperfusion model, we aimed to characterize the effects of metformin co-treatments on the electrophysiological, biochemical, and morphological changes in rat hippocampus and correlated these with behavioral outcomes. Results indicated that metformin treatments prevented synaptic depression induced by CPA administration or hypoxia treatments. Moreover, metformin reduced adenosine A1 receptor-mediated hippocampal neurodegeneration and behavioral deficits. Finally, radioligand binding studies revealed a potential binding affinity of metformin to A1Rs from hippocampal membranes. In conclusion, the clinically approved metformin was effective in preventing A1R-mediated hippocampal neuronal damage, synaptic depression and accompanying behavioral abnormalities. Metformin, with partial binding affinity to at least the A1R, exhibits neuroprotective properties by acting to antagonize the effects of endogenous adenosine during ischemic conditions. This study provides support that chronic A1R stimulation promotes neurodegeneration and behavioral deficits that can be partially inhibited by the clinically approved and putative A1R antagonist metformin.
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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) | 0.001 | 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".