Doxycycline alleviates acute traumatic brain injury by suppressing neuroinflammation and apoptosis in a mouse model

Marjani, Saeid; Zırh, Selim; Sever-Bahcekapili, Melike; Cakir-Aktas, Canan; Müftüoğlu, Sevda; Mut, Melike

doi:10.1016/j.jneuroim.2021.577672

Cited by 10 publications

(4 citation statements)

References 51 publications

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“…There are two groups into which the pathophysiological outcomes of TBI can be distinguished: primary brain injury and secondary brain injury [35].…”

Section: Pathophysiology Of Tbimentioning

confidence: 99%

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Neuroprotective and Anti-inflammatory Effects of Pioglitazone on Traumatic Brain Injury

Zamanian

Taheri

Opulencia

et al. 2022

Mediators of Inflammation

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Traumatic brain injury (TBI) is still a major cause of concern for public health, and out of all the trauma-related injuries, it makes the highest contribution to death and disability worldwide. Patients of TBI continue to suffer from brain injury through an intricate flow of primary and secondary injury events. However, when treatment is provided in a timely manner, there is a significant window of opportunity to avoid a few of the serious effects. Pioglitazone (PG), which has a neuroprotective impact and can decrease inflammation after TBI, activates peroxisome proliferator-activated receptor-gamma (PPARγ). The objective of the study is to examine the existing literature to assess the neuroprotective and anti-inflammatory impact of PG in TBI. It also discusses the part played by microglia and cytokines in TBI. According to the findings of this study, PG has the ability to enhance neurobehavior, decrease brain edema and neuronal injury following TBI. To achieve the protective impact of PG the following was required: (1) stimulating PPARγ; (2) decreasing oxidative stress; (3) decreasing nuclear factor kappa B (NF-κB), interleukin 6 (IL-6), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and C-C motif chemokine ligand 20 (CCL20) expression; (4) limiting the increase in the number of activated microglia; and (5) reducing mitochondrial dysfunction. The findings indicate that when PIG is used clinically, it may serve as a neuroprotective anti-inflammatory approach in TBI.

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“…There are two groups into which the pathophysiological outcomes of TBI can be distinguished: primary brain injury and secondary brain injury [35].…”

Section: Pathophysiology Of Tbimentioning

confidence: 99%

“…Some of the common mechanisms involve rapid acceleration/deceleration, direct impact, penetrating injury, and blast waves. Those chronic inflammatory procedures that extend for a few months or years following primary brain injury may lead to neurodegeneration, cell death, and neurological disabilities [35].…”

Section: Primary Brain Injurymentioning

confidence: 99%

Neuroprotective and Anti-inflammatory Effects of Pioglitazone on Traumatic Brain Injury

Zamanian

Taheri

Opulencia

et al. 2022

Mediators of Inflammation

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“…( 3 , 4 ). The mechanism of brain damage after TBI has been proved to involve both direct mechanical damage and indirect damage ( 5 , 6 ). Direct mechanical damage results from initial impact and is considered irreversible.…”

Section: Introductionmentioning

confidence: 99%

Nonoxid-HMGB1 Attenuates Cognitive Impairment After Traumatic Brain Injury in Rats

et al. 2022

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Traumatic brain injury (TBI) is a major global burden of health. As an accepted inflammatory mediator, high mobility group box 1 (HMGB1) is found to be effective in facilitating neurogenesis and axonal regeneration. SH3RF2 (also known as POSHER), an E3 ligase SH3 domain-containing ring finger 2, belongs to the SH3RF family of proteins. Here, we aimed to investigate the role of redox states of HMGB1 on neurite outgrowth and regeneration both in vitro and in vivo. In this study, distinct recombinant HMGB1 redox isoforms were used. Sequencing for RNA-seq and data analysis were performed to find the potential downstream target of nonoxid-HMGB1 (3S-HMGB1). Protein changes and distribution of SH3RF2 were evaluated by western blot assays and immunofluorescence. Lentivirus and adeno-associated virus were used to regulate the expression of genes. Nonoxid-HMGB1-enriched exosomes were constructed and used to treat TBI rats. Neurological function was evaluated by OF test and NOR test. Results demonstrated that nonoxid-HMGB1 and fr-HMGB1, but not ds-HMGB1, promoted neurite outgrowth and axon elongation. RNA-seq and western blot assay indicated a significant increase of SH3RF2 in neurons after treated with nonoxid-HMGB1 or fr-HMGB1. Notably, the beneficial effects of nonoxid-HMGB1 were attenuated by downregulation of SH3RF2. Furthermore, nonoxid-HMGB1 ameliorated cognitive impairment in rats post-TBI via SH3RF2. Altogether, our experimental results suggest that one of the promoting neurite outgrowth and regeneration mechanisms of nonoxid-HMGB1 is mediated through the upregulated expression of SH3RF2. Nonoxid-HMGB1 is an attractive therapeutic candidate for the treatment of TBI.

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“…These studies, however, lack the In vivo data. Doxy's anti-inflammatory potential is being harnessed for treatment of chronic conditions including-Brucellosis spondylitis, traumatic brain injury, abdominal aortic aneurysms, where in it has been shown to decrease levels of systemic inflammation markers, IL-6, and inhibit chemokines like MCP-1 and MMPs (Yang et al 2021, Marjani et al 2021, Yu et al 2017, Conforti et al 2020. Doxy acts in part by inhibiting protein kinase B (AKT) signaling pathway and mitogenactivated protein kinases (MAPKs) signaling proteins, including extracellular signalregulated kinase (ERK), c-Jun amino-terminal kinases (JNK) in vitro in VSMCs (Yu et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Targeted delivery of doxycycline with nanoparticles mitigates cytokine storm and reduces immune cell infiltration in LPS mediated lung inflammation.

Arora

Vyavahare

2022

Preprint

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Background and Purpose: Cytokine storm invoked during acute and chronic lung injury promotes alveolar damage and remodeling. The current study shows that degraded elastin-targeted nanoparticles releasing doxycycline (Doxy NPs) are potent in mitigating cytokines storm, migration of immune cells in the lungs, and inhibiting inflammasome pathways in the LPS mouse model. Experimental Approach: Cytokine storm and lung injury were induced using LPS and elastase in C57BL/6 mice (rodent model for emphysema). The mice were then treated with I.V. Doxy NPs, blank NPs, or Doxy a day before LPS administration. Cytokine levels, immune cell population, and MMP activity were analyzed in BALF 4 hours after LPS administration. Additionally, gene expression of IL-6, IL-1beta, MCP-1, NLRP3, Caspase 1, and MMPs were investigated in alveolar cells on day three after LPS administration. Key Results: Doxycycline NPs but not Doxycycline significantly decreased IL-6, TNF-α, and IL-23 and were significantly more effective in decreasing the percentage of immune cells in the BALF. This is the first in-vivo study to demonstrate that Doxycycline can effectively inhibit lung inflammasome pathways. Conclusion and Implications: IV administration of elastin antibody conjugated Doxycycline-loaded albumin Nps can effectively modulate the local immune environment in the lungs, which is not achieved by IV Doxycycline even at a 100-fold higher dose. This novel method of drug delivery can effectively lead to the repurposing of traditional Doxycycline as a potential adjunct treatment for managing the cytokine storm in the lungs in COPD and viral infections.

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Doxycycline alleviates acute traumatic brain injury by suppressing neuroinflammation and apoptosis in a mouse model

Cited by 10 publications

References 51 publications

Neuroprotective and Anti-inflammatory Effects of Pioglitazone on Traumatic Brain Injury

Neuroprotective and Anti-inflammatory Effects of Pioglitazone on Traumatic Brain Injury

Nonoxid-HMGB1 Attenuates Cognitive Impairment After Traumatic Brain Injury in Rats

Targeted delivery of doxycycline with nanoparticles mitigates cytokine storm and reduces immune cell infiltration in LPS mediated lung inflammation.

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