Antipsychotics Prevent Psychosine Induced Toxicity in Glial Cells.
Bibliographic record
Abstract
Glial cells are implicated in the neuropathophysiology of schizophrenia and other neuropsychiatric disorders. Also, the role of altered myelin in the onset and development of schizophrenia and changes in myelin due to antipsychotics remains unclear. There is growing interest in the effects of antipsychotics on glial cells, to explore the ways these drugs may act via non-neuronal mechanisms. To investigate if antipsychotic drugs modulate glial cell dysfunction, human astrocytes were treated with the toxin psychosine, with or without antipsychotics (chapter 3). MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and LDH (Lactate Dehydrogenase) assays showed that psychosine decreased cell viability and induced cell toxicity in human astrocytes. This was returned to almost control levels by antipsychotics. Immunocytochemical analysis showed that psychosine impaired astrocyte morphology which was reversed significantly by antipsychotics. Selective D2 and 5HT2A receptor antagonists were found to attenuate psychosine-induced decrease in cell viability, toxic effects, and reductions in astrocyte processes with advantage of dopamine over serotonin antagonism (Results, chapter 3). The effects of the antipsychotics, haloperidol and clozapine, on levels of myelin using mouse organotypic cerebellar slices treated with the demyelinating agent psychosine was also investigated (Chapter 4). Psychosine induced a concentration-dependent loss of myelin. Importantly, both haloperidol and clozapine, reduced this psychosine-induced loss. Similarly, these drugs attenuated psychosine-induced loss of astrocyte markers. Psychosine also induced a decrease in nonphosphorylated neurofilament levels, which were restored by both haloperidol and clozapine, indicating neuroprotective and neurorestorative processes (Results, chapter 4). Having shown that antipsychotics prevented psychosine toxicity to human astrocytes in-vitro and ameliorated psychosine induced demyelination in mouse organotypic cerebellar slice cultures ex-vivo. Another study aimed to examine if these findings would translate into improved survival, mobility, and behavioural metrics in an in-vivo model of psychosine toxicity i.e., the twitcher mouse model of Krabbe Disease (Chapter 5). The antipsychotic haloperidol increased survival, improved mobility, and positively influenced behaviours in twitcher mice (Results, chapter 5). Overall, this work suggests that antipsychotics may regulate astrocyte cell damage and exert a protective effect on oligodendrocytes. Also, this suggests that antipsychotics or agents with similar pharmacology, namely D2/5HT2A receptor antagonists, may be a potential novel treatment for KD, a leukodystrophy that leads to the accumulation of the toxin psychosine.
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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) | 0.000 | 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".