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MicroRNA cerebrospinal fluid profile during the early brain injury period as a biomarker in subarachnoid hemorrhage patients

ABSTRACT: Delayed cerebral ischemia (DCI) is a dreadful complication present in up to 30% of patients with spontaneous subarachnoid hemorrhage (SAH). Indeed, DCI is one of the main causes of long-term disability in SAH, yet its prediction and prevention are troublesome in poor-grade SAH cases. In this prospective study, we explored the potential role of micro ribonucleic acid (microRNA, abbreviated miRNAs), – small non-coding RNAs involved in clue gene regulation at the post-transcriptional level – as biomarkers of neurological outcomes in SAH patients. We analyzed the expression of several miRNAs present in the cerebrospinal fluid (CSF) of SAH patients during the early stage of the disease (third-day post-hemorrhage). NanoString Technologies were used for the characterization of the CSF samples. We found an overexpression of miRNAs in the acute stage of 57 SAH in comparison with 10 non-SAH controls. Moreover, a differential expression of specific miRNAs was detected according to the severity of clinical onset, but also regarding the development of DCI and the midterm functional outcomes. These observations reinforce the potential utility of miRNAs as prognostic and diagnostic biomarkers in SAH patients. In addition, the identification of specific miRNAs related to SAH evolution might provide insights into their regulatory functions of pathophysiological pathways, such as the TGF-β inflammatory pathway and blood-brain barrier disruption

ORGANISM(S): Homo sapiens

PROVIDER: GSE211002 | GEO | 2022/08/13

REPOSITORIES: GEO

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Project description:Purpose: Subarachnoid hemorrhage (SAH) is fatal in approximately 40% of cases. However, among survivors up to 95% experience permanent disabilities: post-SAH syndrome, which include impaired memory, executive functions, emotional and cognitive disturbances. Up to 45% of SAH patients are unable to continue with their professional activities. The long-term cognitive deficits result from morphological brain damage, including atrophy of the temporomesial/hippocampal area, which correlates with decreased neurocognitive scores. The mechanisms of the remote brain damage following SAH remain unknown, which hinders the progress in identifying new therapeutic targets. To unveil the leading mechanisms of permanent cognitive abnormalities following SAH and origin of atrophy of the temporomesial/hippocampal area, we analyzed SAH-induced specific hippocampal genomic pathways, which may lead to long term morphological damage. methods: Hippocampal RNA of SAH and Control groups, obtained 4 days after SAH induced by perforation of the circle of Willis in mice, was processed and sequenced. Using the next-generation RNA sequencing we determined differentially expressed genes in the bilateral whole hippocampus remote from SAH and applied different functional analyses and clustering tools to determine the main molecular pathways. Results: Differential gene expression analysis detected 642 upregulated and 398 down-regulated genes (false discovery rate <0.10) in SAH compared to Control group. Functional analyses using IPA suite, Gene Ontology terms, REACTOME pathways, and MsigDB Hallmark gene set collections revealed suppression of oligodendrocytes/myelin related genes, and overexpression of genes related to complement system along with genes related to innate and adaptive immunity, and extracellular matrix reorganization. Interferon regulatory factors, TGF-β1 and BMP, were identified as major orchestrating elements in the hippocampal tissue response. The MEME-Suite identified binding motifs of Krüppel-like factors, zinc finger transcription factors, and interferon regulatory factors as overrepresented DNA promoter motifs. Conclusion: Our findings suggest that damage of the entorhinal cortex by the subarachnoid blood remotely triggers specific hippocampal response, which may include suppression of oligodendrocytes functioning due to anterograde degeneration of hippocampal afferents accompanied. Identification of the prominent molecular hippocampal pathways may lead to the development of new therapeutic approaches for the treatment of long-term SAH consequences.

Project description:Numerous studies have elucidated the neuroprotective effect of 6-gingerol in central nervous system diseases. However, the potential role and mechanism of 6-gingerol on early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains poorly understood. Here, we report that 6-gingerol exerts a neuroprotective effect on SAH-induced EBI through the GBP2/PI3K/AKT pathway. A SAH rat model was established by injecting femoral artery blood into the cisterna magna. 6-gingerol or vehicle was injected intraperitoneally one hour post-SAH induction. We found that the neurological function score and brain edema of SAH rats were significantly improved after 6-gingerol treatment, as well as neuronal apoptosis was attenuated in SAH rats by Nissl staining assay and TUNEL assay. To further explore potential molecular mechanisms associated with 6-gingerol, RNA sequencing was implemented to investigate the differences in transcriptomes between SAH rats with and without 6-gingerol treatment; and found that the expression of guanylate-binding protein 2 (GBP2) evidently was suppressed with 6-gingerol treatment compared to vehicle group. In addition, dual immunofluorescence was also employed to investigate changes in neurons, astrocytes, and microglia after 6-gingerol treatment. The results showed that GBP2 was expressed in neurons but not astrocytes or microglia. Western blotting analysis results demonstrated that the PI3K/AKT pathway was activated in the SAH rats treated with 6-gingerol. Furthermore, recombinant GBP2 protein and LY294002 (PI3K inhibitor) treatment reversed the effects of 6-gingerol treatment in SAH rats. These results indicate that 6-gingerol suppressed the expression of GBP2 to activate the PI3K/AKT pathway, improve neurologic outcomes, reduce brain edema and neuronal apoptosis. In summary, our findings suggest that 6-gingerol could attenuate EBI post-SAH in rats, and 6-gingerol may serve as a novel candidate neuroprotective drug for SAH-induced EBI.

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MicroRNA cerebrospinal fluid profile during the early brain injury period as a biomarker in subarachnoid hemorrhage patients

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