Hypertonic saline improves brain edema resulting from traumatic brain injury by suppressing the NF‑&amp;kappa;B/IL‑1&amp;beta; signaling pathway and AQP4

Zhang, Hui; Li, Jun; Liu, Yunzhen; Su, Chunhai; Fan, Gaoyang; Lü, Wenpeng; Feng, Lei

doi:10.3892/etm.2020.9199

Cited by 7 publications

(3 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings are parallel to our observations in the Rs1 -KO mouse natural history and underscore the connection between the electrical function of the eye and the fluid homeostasis of the retina. Systemic infusions of hyperosmolar fluid have been shown to reduce edema in other organs, like the brain, in the setting of acute cerebral injury (25). With this precedent, strategies leveraging fluid exchange to promote the resolution of cysts in edematous retinal conditions merit further exploration.…”

Section: Discussionmentioning

confidence: 99%

An osmolarity dependent mechanism partially ameliorates retinal cysts and rescues cone function in a mouse model of X-linked Retinoschisis

Gehrke,

Thompson,

Kalmanek

et al. 2023

Preprint

View full text Add to dashboard Cite

Introduction X-linked retinoschisis (XLRS) is a vitreoretinal dystrophy caused by RS1 gene mutations which disrupt retinoschisin protein function. A vital protein for maintaining retinal architecture, the absence of functional retinoschisin leads to the development of intraretinal cysts. The preliminary goal of this study was to investigate a low dose gene therapy in Rs1 knockout (Rs1-KO) mice; however, our experiments revealed an unexpected therapeutic effect of a hypertonic buffer, which led to further exploration of this effect. Methods 10 Rs1-KO mice were subretinally injected with an AAV2/4 vector containing the RS1 gene driven by an Ef1a promoter. 16 Rs1-KO mice were subretinally injected with a hypertonic buffer (180 mM NaCl 0.001% F68/PBS (pH 7.4)) or an isotonic buffer (155.2 mM NaCl 0.001% F68/PBS, pH 7.0) as a sham control. Endpoints included electroretinogram (ERG), optical coherence tomography (OCT), and a visually guided swim assay (VGSA). An immunohistochemistry assay was used to quantify cone density in buffer injected and treatment-naive eyes. Results Unexpectedly, hypertonic buffer-injected eyes had significantly reduced cyst severity at 1 month post-injection (MPI) (p=<0.0001), significantly higher amplitudes in cone-dominant ERGs persisting to 5 months post-injection (5 Hz flicker; p=0.0018; 3.0 Flash; p=0.0060) and demonstrated improved navigational vision in the light compared to untreated Rs1-KO eyes (p<0.0001). To investigate the role of tonicity on this effect, an isotonic buffer-injected cohort was created (155.2 mM NaCl 0.001% F68/PBS, pH 7.0) (n=6). Surprisingly, hypertonic buffer-injected eyes exhibited a greater reduction in cyst severity and demonstrated improved cone-dominant ERG metrics over isotonic buffer-injected eyes. Using an immunohistochemistry assay, we demonstrated greater cone density in hypertonic buffer-injected eyes than untreated controls (p=0.0147), suggesting a possible cone preservation mechanism. Moreover, our findings reveal a negative correlation between the peak severity of cysts and long-term cone-dominant ERG metrics, implying that effectively managing cysts could yield enduring benefits for cone function. Discussion/Conclusion This study presents evidence that cyst resolution can be triggered through an osmosis-dependent pathway, and cyst resolution can have long term effects on cone signaling and survival, offering potential insights for the development of novel treatments for patients with XLRS.

show abstract

Section: Discussionmentioning

confidence: 99%

An osmolarity dependent mechanism partially ameliorates retinal cysts and rescues cone function in a mouse model of X-linked Retinoschisis

Gehrke,

Thompson,

Kalmanek

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Intraventricular injection of lipopolysaccharide (LPS) also induces overexpression of AQP4 [37]. Studies have found that both NF-kappa B signaling pathway and AQP4 are involved in the regulation of cerebral edema after TBI [38]. As a calmodulin blocker, TFP has regulatory relationship with NF-kappa B signaling pathway [39].…”

Section: Discussionmentioning

confidence: 99%

Trifluoperazine reduces apoptosis and inflammatory responses in traumatic brain injury by preventing the accumulation of Aquaporin4 on the surface of brain cells

Xing¹,

Cheng²,

Yu³

et al. 2023

Int. J. Med. Sci.

View full text Add to dashboard Cite

Currently, no specific and standard treatment for traumatic brain injury (TBI) has been developed. Therefore, studies on new therapeutic drugs for TBI treatment are urgently needed. Trifluoperazine (TFP) is a therapeutic agent for the treatment of psychiatric disorders that reduces edema of the central nervous system. However, the specific working mechanism of TFP is not fully understood in TBI. In this study, the immunofluorescence co-localization analysis revealed that the area and intensity covered by Aquaporin4 (AQP4) on the surface of brain cells (astrocyte endfeet) increased significantly after TBI. In contrast, TFP treatment reversed these phenomena. This finding showed that TFP inhibited AQP4 accumulation on the surface of brain cells (astrocyte endfeet). The tunel fluorescence intensity and fluorescence area were lower in the TBI+TFP group compared to the TBI group. Additionally, the brain edema, brain defect area, and modified neurological severity score (mNSS) were lower in the TBI+TFP. The RNA-seq was performed on the cortical tissues of rats in the Sham, TBI, and TBI+TFP groups. A total of 3774 genes differently expressed between the TBI and the Sham group were identified. Of these, 2940 genes were up-regulated and 834 genes were down-regulated. A total of 1845 differently expressed genes between the TBI+TFP and TBI group were also identified, in which 621 genes were up-regulated and 1224 genes were down-regulated. Analysis of the common differential genes in the three groups showed that TFP could reverse the expression of apoptosis and inflammation genes. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that the differentially expressed genes (DEGs) were highly enriched in the signaling pathways regulating inflammation. In conclusion, TFP alleviates brain edema after TBI by preventing the accumulation of AQP4 on the surface of brain cells. Generally, TFP alleviates apoptosis and inflammatory response induced by TBI, and promotes the recovery of nerve function in rats after TBI. Thus, TFP is a potential therapeutic agent for TBI treatment.

show abstract

“…The precise regulatory mechanism remains to be further elucidated. Perhaps, the e cacy of HS in brain edema resulting from TBI was closely associated with the downregulation of aquaporin-4 (AQP4), the restoration of brain blood barrier (BBB) integrity and the suppression of in ammatory factors including Interleukin (IL-1β), tumor necrosis factor (TNF-α), NF-κB [30].…”

Section: Discussionmentioning

confidence: 99%

Effect of Continuous Hypertonic Saline Infusion on Clinical Outcomes in Patients with Traumatic Brain Injury: A Retrospective Causal Analysis

Peng¹,

Yang

Zhang³

et al. 2021

Preprint

View full text Add to dashboard Cite

Purpose: Intracranial pressure (ICP) control has long been recognized as an important requirement for traumatic brain injury (TBI) patients. Nevertheless, the long-term effect of hypertonic saline (HTS) remains unknown. The aim of this study was to elucidate the effect on clinical outcomes in TBI patients admitted to intensive care unit (ICU) settings.Methods: We retrospectively identified moderate to severe TBI patients from two public databases named Medical Information Mart for the Intensive Care (MIMIC)-IV and eICU Collaborative Research Database (eICU-CRD). A marginal structural Cox model (MSCM) was used, with time-dependent variates designed to reflect exposure over time during the ICU stay. A trajectory modeling, based on intracranial pressure evolution pattern, allowed identification of subgroups. Results: Overall, in our cohort of 1955 eligible patients, 130 (6.65%) received HTS. MSCM indicated that the HTS was significantly associated with better Glasgow coma score [(GCS): hazard ratio (HR) 1.19, 95% confidence interval (95% CI) 1.01-1.40, p = 0.041], higher infection complications [eg. urinary tract infection (HR 1.88, 95% CI 1.26-2.81, p = 0.002)], and increased ICU LOS (HR 2.02, 95% CI 1.71-2.40, p < 0.001). A protective effect from GCS by the HTS was found in the subgroup with medium and low ICP. Conclusion: Our study revealed no significant difference in the all-cause mortality rates between patients receiving HTS or not. Increased occurrence rates of infection and electrolyte imbalance were inevitable outcomes caused by continuous HTS infusion. Although the study suggested the slight beneficial effects including better neurological outcome, the results warrant further validation.

show abstract

Hypertonic saline improves brain edema resulting from traumatic brain injury by suppressing the NF‑κB/IL‑1β signaling pathway and AQP4

Cited by 7 publications

References 56 publications

An osmolarity dependent mechanism partially ameliorates retinal cysts and rescues cone function in a mouse model of X-linked Retinoschisis

An osmolarity dependent mechanism partially ameliorates retinal cysts and rescues cone function in a mouse model of X-linked Retinoschisis

Trifluoperazine reduces apoptosis and inflammatory responses in traumatic brain injury by preventing the accumulation of Aquaporin4 on the surface of brain cells

Effect of Continuous Hypertonic Saline Infusion on Clinical Outcomes in Patients with Traumatic Brain Injury: A Retrospective Causal Analysis

Contact Info

Product

Resources

About