The Effect of Candesartan Alone and Its Combination With Estrogen on Post-traumatic Brain Injury Outcomes in Female Rats

Hajmohammadi, Mojdeh; Khaksari, Mohammad; Soltani, Zahra; Shahrokhi, Nader; Najafipour, Hamid; Abbasi, Reza

doi:10.3389/fnins.2019.01043

Cited by 13 publications

(9 citation statements)

References 65 publications

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“…Previous studies have reported that candesartan, one of the angiotensin receptor blockers, could reduce lesion volume and improve motor and memory function after traumatic brain injury in mice ( Villapol et al, 2012 ; Hajmohammadi et al, 2019 ; Attilio et al, 2021 ), however, the molecular mechanism is still poorly understood. To gain insight into the potential molecular basis of this drug, we conducted an integrative analysis of single-cell (GEO accession: GSE101901) and bulk RNA-seq data ( Attilio et al, 2021 ) (GEO accession: GSE163415) to analyze the cell-type-specific changes in gene expression patterns.…”

Section: Resultsmentioning

confidence: 99%

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With Traumatic Brain Injury

Jin

Ren

et al. 2022

Front. Genet.

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Traumatic brain injury (TBI) is currently a substantial public health problem and one of the leading causes of morbidity and mortality worldwide. However, the cellular and transcriptional changes in TBI at single-cell level have not been well characterized. In this study, we reanalyzed a single-cell RNA sequencing (scRNA-seq) dataset of mouse hippocampus to identify the key cellular and transcriptional changes associated with TBI. Specifically, we found that oligodendrocytes were the most abundant cell type in mouse hippocampus, and detected an expanded astrocyte population, which was significantly activated in TBI. The enhanced activity of inflammatory response-related pathways in the astrocytes of TBI samples suggested that the astrocytes, along with microglia, which were the major brain-resident immune cells, were responsible for inflammation in the acute phase of TBI. Hormone secretion, transport, and exocytosis were found upregulated in the excitatory neurons of TBI, which gave us a hint that excitatory neurons might excessively transport and excrete glutamate in response to TBI. Moreover, the ependymal subpopulation C0 was TBI-specific and characterized by downregulated cilium movement, indicating that the attenuated activity of cilium movement following TBI might decrease cerebrospinal fluid flow. Furthermore, we observed that downregulated genes in response to candesartan treatment were preferentially expressed in excitatory neurons and were related to pathways like neuronal systems and neuroactive ligand-receptor interaction, indicating that candesartan might promote recovery of neurons after traumatic brain injury via mediating neuroactive ligand-receptor interactions and reducing excitotoxicity. In conclusion, our study identified key cell types in TBI, which improved our understanding of the cellular and transcriptional changes after TBI and offered an insight into the molecular mechanisms that could serve as therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With Traumatic Brain Injury

Jin

Ren

et al. 2022

Front. Genet.

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“…After removal of duplicates, a total of 5629 articles remained to be screened based on title and abstract. Full-text assessment of 116 studies yielded 20 studies which met the inclusion criteria [50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69] . Excluded studies are detailed in Figure 1 and Table S3.…”

Section: Resultsmentioning

confidence: 99%

Renin Angiotensin System as a Potential Treatment Target for Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Báron

Skrobot

Palmer

et al. 2022

Journal of Neurotrauma

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Traumatic brain injury (TBI) is a major health concern and leading cause of death and disability in young adults in the UK and worldwide, however, there is a paucity of disease modifying therapies for the treatment of TBI. This review investigates the potential of the reninangiotensin system (RAS) as a treatment pathway for traumatic brain injury (TBI) in adults.Relevant electronic databases were searched on 18 December 2019, updated 16 May 2021. All English language articles with adult human or animal populations investigating RAS drugs as an intervention for TBI or reporting genetic evidence relevant to the RAS and TBI were screened.Eighteen preclinical RCTs (n=2269) and 2 clinical cohort studies (n=771) were included. Metaanalyses of 6 preclinical randomised-controlled trials (n=99) indicated candesartan improved neurological function short-term (<7 days: standardised mean difference (SMD) 0.61, 95% confidence interval (CI) 0.19 -1.03, I2=0%) and long-term (≥7 days: SMD 1.06, 95% CI 0.38; 1.73, I2=0%) post-TBI. Findings were similar for most secondary outcomes. There was a suggestion of benefit from other RAS-targeting drugs, although evidence was limited due to few small studies. There was insufficient evidence to enable strong assessment of these drugs on mortality post-TBI. We conclude that angiotensin-receptor blockers, especially candesartan, show positive outcomes post-TBI in preclinical studies with moderate quality of evidence (GRADE). More research into the effect of regulatory-RAS targeting drugs is needed. Clinical trials of candesartan following TBI are recommended, due to strong and consistent evidence of neuroprotection shown by these preclinical studies.

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“…After the induction of diffuse TBI, the rats were immediately connected to the animal respiratory pump (TSA respiratory compact, Bad Homburg, Germany). After spontaneous breathing, the rats were detached from the ventilator and returned to their cage [26].…”

Section: Induction Of Diffuse Traumatic Brain Injury (Tbi)mentioning

confidence: 99%

Using the NGF/IL-6 ratio as a reliable criterion to show the beneficial effects of progesterone after experimental diffuse brain injury

Shirazpour

Khaksari

Shahrokhi

et al. 2020

Heliyon

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Acute progesterone injection has been shown to reduce brain edema following traumatic brain injury (TBI) due to its neuroprotective effect. We investigated the effects of sustained release of progesterone through implantation of subcutaneous capsules on rat's brain edema and alteration of cerebrospinal fluid (CSF), and serum ratio of NGF/ IL-6 after TBI. This experiment was performed on ovariectomized (OVX) rats and the brain injury was induced by Marmarou's method. A high and a low dose of progesterone (HP and LP) was injected intraperitoneally two h after the brain injury. In addition, in the capsule progesterone-treated group (CP), the intervention was implemented 6 h after the brain injury. Brain edema, NGF and IL-6 biomarkers in serum and cerebrospinal fluid (CSF) were measured 48 h after the TBI in injection groups and one week after the TBI in the CP group. No significant difference was found in the two groups or in the admonition methods. After TBI, the NGF level increased and IL-6 level decreased by injection of both doses, as well as by taking the capsule. Ratio of NGF/IL-6 in CSF increased significantly by all forms of progesterone administration. The increase in the level of NGF and IL-6 after TBI was higher in CSF than in serum. These results indicated that effects of progesterone in capsule form were better than the injection form. Progesterone probably works by increasing NGF and reducing IL-6. Future studies should investigate the ratio of these biomarkers as a variable to determine the neuroprotective effects of another drug.

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The Effect of Candesartan Alone and Its Combination With Estrogen on Post-traumatic Brain Injury Outcomes in Female Rats

Cited by 13 publications

References 65 publications

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With Traumatic Brain Injury

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With Traumatic Brain Injury

Renin Angiotensin System as a Potential Treatment Target for Traumatic Brain Injury: A Systematic Review and Meta-Analysis

Using the NGF/IL-6 ratio as a reliable criterion to show the beneficial effects of progesterone after experimental diffuse brain injury

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