Concussion/Mild Traumatic Brain Injury (TBI) Induces Brain Insulin Resistance: A Positron Emission Tomography (PET) Scanning Study.

Sathiya Sekar,Raja Solomon Viswas,Hajar Miranzadeh Mahabadi,Humphrey Fonge,Changiz Taghibiglou,Elahe Alizadeh

doi:10.3390/ijms22169005

Sathiya Sekar, Raja Solomon Viswas + Show 4 more

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https://doi.org/10.3390/ijms22169005

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Abstract

Brain injury/concussion is a growing epidemic throughout the world. Although evidence supports association between traumatic brain injury (TBI) and disturbance in brain glucose metabolism, the underlying molecular mechanisms are not well established. Previously, we reported the release of cellular prion protein (PrPc) from the brain to circulation following TBI. The PrPc level was also found to be decreased in insulin-resistant rat brains. In the present study, we investigated the molecular link between PrPc and brain insulin resistance in a single and repeated mild TBI-induced mouse model. Mild TBI was induced in mice by dropping a weight (~95 g at 1 m high) on the right side of the head. The procedure was performed once and thrice (once daily) for single (SI) and repeated induction (RI), respectively. Micro PET/CT imaging revealed that RI mice showed significant reduction in cortical, hippocampal and cerebellum glucose uptake compared to SI and control. Mice that received RI also showed significant motor and cognitive deficits. In co-immunoprecipitation, the interaction between PrPc, flotillin and Cbl-associated protein (CAP) observed in the control mice brains was disrupted by RI. Lipid raft isolation showed decreased levels of PrPc, flotillin and CAP in the RI mice brains. Based on observation, it is clear that PrPc has an interaction with CAP and the dislodgment of PrPc from cell membranes may lead to brain insulin resistance in a mild TBI mouse model. The present study generated a new insight into the pathogenesis of brain injury, which may result in the development of novel therapy.

Highlights

Traumatic brain injury (TBI) is a growing epidemic throughout the world with global incidences of 69 million individuals every year [1,2]
We investigated the molecular link between PrPc and brain insulin resistance (CAP/Cbl/TC10 pathway) in a single and repeated mild traumatic brain injury (TBI)-induced mouse model
To study glucose uptake in TBI mice brains, mice received 18F-FDG via a tail vein following single or repeated induction followed by dynamic micro Positron emission tomography (PET)/CT imaging of the head for 30 min

Summary

Introduction

Traumatic brain injury (TBI) is a growing epidemic throughout the world with global incidences of 69 million individuals every year [1,2]. The occurrences of TBI have not been well documented as patients are not hospitalized due to mild injury. Studies showed the dysregulation of insulin-dependent glucose utilization in the brain links to cognitive deficits and neurodegeneration in TBI [18,19]. Positron emission tomography (PET) imaging using 18F-FDG tracer was the most widely used technique to non-invasively measure any changes in glucose uptake in TBI patients and animal models [22,23,24,25]. Considerable evidence in animal models of mild TBI and human subjects succumbing to sport concussions or veterans exposed to blast-induced mild TBI suggests dysregulation in brain glucose metabolism, the underlying molecular mechanisms are not well established [26,27,28]

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