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Tailored Therapeutic Doses of Dexmedetomidine in Evolving Neuroinflammation after Traumatic Brain Injury

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Abstract

Background

Understanding the secondary damage mechanisms of traumatic brain injury (TBI) is essential for developing new therapeutic approaches. Neuroinflammation has a pivotal role in secondary brain injury after TBI. Activation of NLRP3 inflammasome complexes results in the secretion of proinflammatory mediators and, in addition, later in the response, microglial activation and migration of the peripheral immune cells into the injured brain are observed. Therefore, these components involved in the inflammatory process are becoming a new treatment target in TBI. Dexmedetomidine (Dex) is an effective drug, widely used over the past few years in neurocritical care units and during surgical operations for sedation and analgesia, and has anti-inflammatory effects, which are shown in in vivo studies. The aim of this original research is to discuss the anti-inflammatory effects of different Dex doses over time in TBI.

Methods

Brain injury was performed by using a weight-drop model. Half an hour after the trauma, intraperitoneal saline was injected into the control groups and 40 and 200 μg/kg of Dex were given to the drug groups. Neurological evaluations were performed with the modified Neurological Severity Score before being killed. Then, the mice were killed on the first or the third day after TBI and histopathologic (hematoxylin–eosin) and immunofluorescent (Iba1, NLRP3, interleukin-1β, and CD3) findings of the brain tissues were examined. Nonparametric data were analyzed by using the Kruskal–Wallis test for multiple comparisons, and the Mann–Whitney U-test was done for comparing two groups. The results are presented as mean ± standard error of mean.

Results

The results showed that low doses of Dex suppress NLRP3 and interleukin-1β in both terms. Additionally, high doses of Dex cause a remarkable decrease in the migration and motility of microglial cells and T cells in the late phase following TBI. Interestingly, the immune cells were influenced by only high-dose Dex in the late phase of TBI and it also improves neurologic outcome in the same period.

Conclusions

In the mice head trauma model, different doses of Dex attenuate neuroinflammation by suppressing distinct components of the neuroinflammatory process in a different timecourse that contributes to neurologic recovery. These results suggest that Dex may be an appropriate choice for sedation and analgesia in patients with TBI.

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Availability of Data and Materials

The data supporting the conclusions of this article are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank Mesut Fırat for his technical support.

Funding

This study was supported by Hacettepe University Scientific Research Projects Coordination Unit (Project Number: THD-2017-16630), Ankara, Turkey.

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Author notes

  1. Dicle Karakaya and Canan Cakir-Aktas these authors contributed equally to this work.

Authors and Affiliations

  1. Faculty of Medicine, Department of Neurosurgery, Hacettepe University, Ankara, Turkey

    Dicle Karakaya & Melike Mut

  2. Institute of Neurological Sciences and Psychiatry, Hacettepe University, Ankara, Turkey

    Canan Cakir-Aktas

  3. Faculty of Medicine, Department of Anesthesiology and Reanimation, Hacettepe University, Ankara, Turkey

    Sennur Uzun

  4. Faculty of Medicine, Department of Pathology, Hacettepe University, Ankara, Turkey

    Figen Soylemezoglu

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  1. Dicle Karakaya
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Contributions

Conception and design: MMA, DK, CCA, FS, and SU. Project administration: MMA, DK and CCA. Acquisition of data: DK and CCA. Analysis and interpretation of data: DK and CCA. Drafting the article: DK and CCA. Critically revising the article: MMA, DK, CCA and FS. Statistical analysis: CCA. Study supervision: MMA. DK and CCA contributed equally. All authors approved the final manuscript.

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Correspondence to Melike Mut.

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Ethical Approval/Animal Rights

All experimental procedures involving animals were approved by the Animal Experimentations Local Ethics Board of Hacettepe University (No. 2017/67-01), Ankara, Turkey. All applicable institutional and/or national guidelines for the care and use of animals were followed.

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Karakaya, D., Cakir-Aktas, C., Uzun, S. et al. Tailored Therapeutic Doses of Dexmedetomidine in Evolving Neuroinflammation after Traumatic Brain Injury. Neurocrit Care 36, 802–814 (2022). https://doi.org/10.1007/s12028-021-01381-3

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