Metabolic regulation of Neutrophil Extracellular Traps (NETs) in TBI - Abstract: Traumatic brain injury (TBI) is a significant global public health issue, leading to high mortality rates, disabilities, and substantial socioeconomic burdens. TBI results in the loss of AMPKα activity, disruption in regional metabolism, persistent changes in metabolic rates and energy utilization, and elevated glycolysis which enhance the pentose phosphate pathway and promote inflammation. The association between metabolic changes in the brain tissue and the subsequent neutrophil activation and inflammation remains unclear. In this study, male/female C57BL/6 and AMPK-KO mice were subjected to CCI-induced TBI or sham surgery. After assessing behavioral impairments, the mice were sacrificed for the histological and biochemical assay. Our preliminary results show that post-TBI administration of AMPKα1 attenuates the formation of NETs, downregulates inflammation, and promotes neuroprotection. These promising findings suggest that further investigation into the mechanism of neuroprotection by specific AMPK activators such as A-769662, could lead to new therapies for human TBI, potentially extending the therapeutic window for rescuing neurons. The overall goal of the current proposal is to identify the optimal doses and timing for the benefit of A-769662 and to elucidate how AMK activation protects the brain by reducing NETs formation and inflammation following TBI. we hypothesize that the loss of AMPK activates circulating neutrophils to form NETs and incites inflammation, contributing to aggravated outcomes. Modulating AMPK by targeting neutrophil-primed NET formation could have therapeutic potential for protecting against neuronal injury and functional deficits in a preclinical mouse model of TBI. The proposed preclinical studies aim to be the first to determine the efficacy of A-769662 in protecting the brain following TBI. Our hypothesis will be tested through the following aims: Aim 1: Determine the role of AMPK modulation on the functional outcomes and neuropathology after TBI. Aim 2: Determine the effects of AMPK modulation on NETs formation and inflammation using genetically modified mouse models. Aim 3: To identify the alternate novel source(s) of cellular fuel driving the hyper-inflammatory role of AMPK-KO neutrophils. These studies will advance the field by providing critical insight into the therapeutic potential of AMPK modulation in TBI.
