Dolutegravir Disrupts Mouse Blood-Brain Barrier by Inducing Endoplasmic Reticulum Stress
Bibliographic record
Abstract
Abstract Background Dolutegravir (DTG) - based antiretroviral therapy is the contemporary first-line therapy to treat HIV infection. Despite its efficacy, mounting evidence has suggested a higher risk of neuropsychiatric adverse effect (NPAE) associated with DTG use with a limited understanding of the underlying mechanisms. Our laboratory has previously reported a toxic effect of DTG comparable to efavirenz in disrupting the blood-brain barrier (BBB) integrity in vitro and in vivo. The current study aimed to investigate, in vitro, the potential mechanisms involved in DTG toxicity. Methods Primary cultures of mouse brain microvascular endothelial cells were used as a robust rodent BBB cell model. The cells were treated with DTG at therapeutic relevant concentrations (2500, 3500, 5000 ng/ml) for 3–48 h with or without the presence of three endoplasmic reticulum (ER) sensor inhibitors (GSK2606414, 4µ8c, 4PBA). RNA-sequencing, qPCR, western blot analysis and cell stress assays (Ca2+ flux, H2DCFDA, TMRE, MTT) were performed. Results Our initial Gene Ontology (GO) analysis of RNA-Sequencing data revealed an enriched transcriptome signature of ER stress pathway in DTG treated cells. We further demonstrated that therapeutic concentrations of DTG significantly activated the ER stress sensor proteins (PERK, IRE1, p-IRE1) and downstream ER stress markers (eIF2α, p-eIF2α, Hspa5, Atf4, Ddit3, Ppp1r15a, Xbp1, spliced-Xbp1). In addition, DTG treatment resulted in a transient Ca2+ flux, an aberrant mitochondrial membrane potential, and a significant increase in reactive oxygen species in primary cultures of mouse brain microvascular endothelial cells. Furthermore, we found that prior cell treatment with 4PBA (a broad-spectrum ER stress inhibitor) significantly rescued DTG-induced downregulation of tight junction proteins (Zo-1, Ocln, Cldn5), whereas GSK2606414 (a PERK inhibitor) elicited the greatest protective effect on DTG-induced elevation of pro-inflammatory cytokines and chemokines (Il6, Il23a, Il12b, Cxcl1, Cxcl2). Conclusions The current study provides valuable insights into DTG toxicological cell mechanisms, which may serve as a potential explanation of DTG-associated NPAEs in the clinic.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".