# Caloric restriction promotes sustained neurological recovery after TBI

> **NIH VA I01** · BALTIMORE VA MEDICAL CENTER · 2021 · —

## Abstract

Traumatic brain injury (TBI) results in extensive cellular structural damage followed by widespread dysfunctions in
molecular cascades; including maladaptive activation and/or dysregulation of endogenous injury-response
mechanisms. These lead to progressive tissue loss and chronic neurological deficits - secondary injury. The
maladaptive strong and persistent activation of microglia to a dysfunctional neurotoxic activation phenotype after
brain trauma, contributes to progressive neurodegeneration and cognitive decline. A better understanding of the
processes that control secondary injury vs. repair pathways is crucial for the design of effective therapeutic
interventions that promote sustained recovery of neurological function-rehabilitation.
Our long-term goal is to devise effective disease-modifying treatments that are relevant to patients in the
Veterans Affairs system by examining non-pharmacologic therapeutic interventions focused as much on the
promotion of repair/neuroplasticity pathways, as on attenuation of secondary injury neuropathology, and that are
active in the chronic phase after TBI. Veterans are a distinct group of brain trauma patients because military TBI
features specific conditions that impact the developing neuropathology. A critical unsolved question is what
therapeuticinterventionsareeffective in the chronic phase after TBI to attenuate thepro-inflammatory and neurotoxic
microglial activation state; and thus, promote repair and restoration of neurological function - rehabilitation.
Intermittent fasting (caloric restriction) has been shown to attenuate key inflammatory pathways, stimulate
production of new neurons from stem cells (neurogenesis); as well as enhance synaptic plasticity, cognitive
function, and increase the ability of the brain to recover after trauma. Oral ketone esters have been shown to
attenuate TBI neuropathology leading to changes in brain metabolism that promote repair after brain trauma.
Dietary treatment with oral nicotinamide riboside may improve cognitive function and synaptic plasticity in
neurodegenerative diseases, as well as attenuate excitotoxicity-induced axonal degeneration.
We hypothesize that non-pharmacologic interventions including intermittent fasting; as well as oral ketone esters
and nicotinamide riboside attenuate brain and peripheral inflammation in the chronic phase after TBI. Thus,
promoting sustained neurological rehabilitation associated with neurorestorative microglia phenotypes.
We will test these novel hypotheses by addressing the following specific aims:
Aim 1: Caloric restriction attenuates the maladaptive activation of pro-inflammatory microglia, and results in
sustained neurological function rehabilitation in the chronic phase after TBI.
Aim 2: Oral ketone esters inhibit progressive neuroinflammation and foster neurological function rehabilitation in
the chronic phase after TBI.
Aim 3: Oral nicotinamide riboside reduces persistent microglia activation and promotes neurolog...

## Key facts

- **NIH application ID:** 10186844
- **Project number:** 1I01RX003379-01A2
- **Recipient organization:** BALTIMORE VA MEDICAL CENTER
- **Principal Investigator:** BOGDAN ADRIAN STOICA
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10186844

## Citation

> US National Institutes of Health, RePORTER application 10186844, Caloric restriction promotes sustained neurological recovery after TBI (1I01RX003379-01A2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10186844. Licensed CC0.

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