Loss of AMPK potentiates inflammation by activating the infammasome in a preclinical mouse model of TBI

Document Type

Article

Publication Date

3-2-2026

Publication Title

NeuroImmune Pharm Ther

Keywords

NLRP3 inflammasome; adenosine monophosphate-activated protein kinase (AMPK); functional impairment; inflammation; lipopolysaccharides

Abstract

OBJECTIVES: Traumatic brain injury (TBI) is a major cause of mortality and long-term neurological disabilities. Adenosine monophosphate-activated protein kinase (AMPK), a key cellular energy sensor, plays a critical role in maintaining energy homeostasis. Loss of AMPK phosphorylation following TBI impairs the restoration of cellular energy homeostasis and promotes inflammation. In this study, we investigated whether post-TBI loss of AMPK worsens functional impairments, amplifies inflammation, and exacerbates tissue damage in a mouse model of TBI.

METHODS: Adult male C57BL/6 wild-type (WT) and (AMPKα1-KO) mice were subjected to TBI or sham surgery. Behavioral assessments were performed at 24 h post-TBI, followed by mice were anesthetized, and their brains were rapidly collected for histological and biochemical analyses. To further support our findings, mixed glial cells isolated from WT and AMPKα1-KO pups were treated with lipopolysaccharides and interferon-gamma (LI) (0.1 μg/ml LPS and 20 ng/ml IFNg) for 6 h to induce an inflammatory response.

RESULTS: Our results show that TBI reduces AMPK phosphorylation in WT mice and that AMPK loss correlates with worsened behavioral deficits, enhanced NLRP3 inflammasome activation, and elevated levels of pro-inflammatory mediators, including IL-1β. Similarly, AMPKα1-KO glial cells exhibited greater activation of NLRP3 inflammasome and higher expression of pro-inflammatory markers, such as IL-1β, IL-6, TNF-α, iNOS, and Cox 2, compared with WT cells.

CONCLUSIONS: Collectively, our results demonstrate that AMPKα1 is a critical endogenous regulator of glial-driven neuroinflammation and secondary tissue damage following TBI. Restoring AMPKα1 activity after TBI may therefore represent a promising therapeutic strategy to attenuate neuroinflammation and limit TBI-associated neurological damage.

PubMed ID

41918568

Volume

5

Issue

1

First Page

93

Last Page

104

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