# Interaction of GCSF with the Endocannabinoid System in Promoting Brain Repair

> **NIH VA I01** · JAMES A. HALEY VA MEDICAL CENTER · 2020 · —

## Abstract

Background: G-CSF has been identified as a potential therapeutic agent for TBI. Administration of G-
CSF soon after injury results in proliferation and release into the circulation of bone marrow-derived cells
(BMDC). Monocytes from blood are recruited into the brain to the site of the lesion where they
differentiate into microglia. These, in turn generate a number of neurotrophic factors and cytokines
involved in repair and regenerative processes. Numerous studies indicate that TBI impacts the
endogenous cannabinoid system (eCBs), altering expression of eCB receptors CB1 and CB2, and
changing levels of the endocannabinoids anandamide (N-arachidonoyl-ethanolamine; AEA) and 2-AG (2-
arachidonoylglycerol). Moreover, administration of cannabinoid agents have been shown to enhance
recovery from TBI mediated by anti-inflammatory cytokines and regenerative processes that parallel those
triggered by G-CSF. Specific Aims of this research program are designed to test the hypotheses a) that
G-CSF interacts with the endocannabinoid system (eCS) to promote brain repair and b) that blockade of
CB1 and/or CB2 receptors will diminish or enhance the brain’s repair response to TBI. Aim 1: To
investigate the effects of G-CSF on the expression of CB1 and CB2 and their natural ligands in mouse
brain (cortex, striatum and hippocampus) following TBI. Dependent variables: CB1 and CB2 receptor
expression (mRNA and protein), levels of the eCB ligands AEA and 2-AG, extent of apoptosis,
microgliosis, astrocytosis, neuro-inflammation, levels of neurotrophic factors (BDNF, GDNF); changes in
hippocampal neurogenesis. Aim 2a: To determine if stimulation of the brain endocannabinoid system with
a) an inhibitor of fatty acid amide (FAAH) to increase levels of AEA and 2AG, or b) administration of
selective CB1 and CB2 receptor antagonists will potentiate (or diminish) the known beneficial effects of G-
CSF on brain repair and recovery. Dependent variables are the same as in Aim 1, with the additional
parameter of recovery of performance in the radial arm water maze (RAWM). Aim 2b: To determine the
extent to which the CB1-R or the CB2-R is responsible for enhanced recovery from TBI, the CB1-R and
CB2-R knockout mice will be studied using the protocol detailed in Aim1. Dependent variables: CB1 and
CB2 receptor expression (mRNA and protein), levels of AEA, 2AG in cortex, striatum and hippocampus;
extent of microgliosis and astrocytosis in these 3 brain regions; levels of BDNF and GDNF, hippocampal
neurogenesis and recovery of performance in RAWM. Aim 3: To determine the role of the CB2 receptor
in the mobilization of BMDC in mediating the beneficial effects of G-CSF, we will administer a CB2
antagonist (or utilize CB2-R knockout mice) to animals treated with G-CSF or vehicle. Tracking of BMDC
will utilize chimeric mice that have had bone marrow transplants from transgenic “green mice”. Dependent
variables: percentage of total circulating white blood cells that co-express GFP and mar...

## Key facts

- **NIH application ID:** 9815355
- **Project number:** 5I01BX004037-02
- **Recipient organization:** JAMES A. HALEY VA MEDICAL CENTER
- **Principal Investigator:** Shijie Song
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815355

## Citation

> US National Institutes of Health, RePORTER application 9815355, Interaction of GCSF with the Endocannabinoid System in Promoting Brain Repair (5I01BX004037-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9815355. Licensed CC0.

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