Investigating the potential impact of a low-fat high fiber diet in limiting TBI-induced neurodegenerative and inflammatory changes.

Project Summary: The sequelae of traumatic brain injury (TBI) pathology comprises primary injury
where impacting force(es) induce physical damage, including the breakdown of the blood-brain barrier (BBB).
Thus the primary injury launches secondary injury comprising chronic inflammation that includes
migration of leukocytes, gliosis, and the release of numerous inflammatory mediators. Thus, secondary injury
exacerbates the damage incurred during the primary injury and is considered more devastating. Though
various drugs are tested to curtail secondary injury, these trials have failed, and the prospect of identifying a
TBI drug looks bleak. Hence, the treatment options for TBI survivors are restricted to palliative care. Recently,
there have been several publications emphasizing the neuroprotective and anti-inflammatory effects of various
diets. Additionally, since cardiovascular diseases (CVDs) are one of the most important comorbid changes in
TBI survivors, studies emphasizing the role of CVD in TBI pathology are non-existent. Our proposed research
aims to compare the beneficial effects of a low-fat, high-fiber diet (LFHFD) in reducing TBI-associated BBB
breakdown, neuroinflammation, and immune response over the standard western diet (WD) that is high-fat
and cholesterol, and low in fiber in a mouse model with chronic CVD and TBI. We are employing American
Heart Association (AHA) recommended mouse model (LDL receptor-deficient mouse model (LDLr-KO)) for
this study. We hypothesize that the uptake of WD further exacerbates the combined effects of CVD and TBI
and will cause chronic BBB dysfunction, predisposing individuals to chronic inflammatory changes. To test
this hypothesis, we will maintain LDLr-KO mice either on WD or LFHFD from the second month to the sixth
month. In the first week of the seventh month, half of the LDLr-KO mice maintained on a WD or LFHFD diet
will undergo TBI (Controlled Cortical Impact, CCI) or Sham injury (Craniotomy without CCI). All animals on
their respective diets will be maintained for three to six months. Animals will be euthanized at the end of the
9th and 12th month, and brain samples will be extracted and processed for routine paraffin-embedded tissue
processing and bright field immunohistochemistry for investing BBB function (aim 1). We will also study the
impact of diets on the expression of various neuroinflammatory markers and overall immune responses (aim
2). A second set of animals will be prepared, and their brain samples will be used for protein and gene
expression studies of various neuroinflammation markers by employing Western blot and real-time
polymerase chain reaction. We will also collect pre-injury and post-injury blood samples from these mice and
run a Luminex assay to monitor serum levels of various immune mediators in blood samples. We expect WD to
exacerbate BBB dysfunction and inflammatory sequelae compared to LFHFD. Upon completing this study, we
will have preliminary data emphasizing the beneficial effects of LFHFD over WD in reducing BBB permeability,
neuroinflammation, and immune responses in long-term TBI survivors.

Grant Number: 1R15NS137260-01
NIH Institute/Center: NIH
Principal Investigator: Nimish Acharya