Cannabidiol Lipid Nanoparticles Stabilize Gut–Brain–Bone Axis Integrity and Enhance Neuroplasticity in Stressed Rats: A Comparison with Atomoxetine and Escitalopram
Year: 2025
Type: article
Abstract: Chronic stress induces mood disturbances, disrupts gut barrier function, and promotes low-grade systemic inflammation. This study assessed the therapeutic effects of atomoxetine (ATX), escitalopram (ESC), cannabidiol (CBD), and CBD-loaded lipid nanoparticles (CBD/LNP) in male rats exposed to repeated restraint stress. Stressed rats exhibited a 2.03-fold increase in interleukin-6 and a 1.89-fold increase in TNF-α, a 1.20-fold decrease in brain-derived neurotrophic factor, a 1.36-fold decrease in osteocalcin, accompanied by alterations in gut metabolites, particularly short-chain fatty acids (SCFAs; from 155.3 to 94.83 μmol/L), polyamines (from 273.6 to 192.4 μmol/L), and bile acids (BAs; from 21.19 to 14.53 μmol/L), compared with the control group. Protein analysis revealed gut barrier disruption and microglial/macrophage activation, accompanied by reduced synaptic plasticity. ATX improved gut permeability and reduced glial activation but did not restore osteocalcin. ESC provided neuroimmune benefits with limited and BA gut restoration and modulated the gut-brain axis and improved anxiety-like behaviors, partly by altering gut microbiota and metabolites. CBD and CBD/LNP treatment restored intestinal barrier function, as indicated by intestinal permeability in the range of 1.15-1.61-fold. These treatments also normalized bile acids (1.0-1.38-fold) and osteocalcin (1.0-1.28-fold) and significantly reduced glial activation (0.63-1.12-fold) as opposed to the non-treated stressed group. All treatments were found to be effective in correcting SCFA and polyamine levels. Histological analysis confirmed that CBD/LNP, ATX, and ESC ameliorated tissue alterations. These findings highlight CBD/LNP as a promising intervention for stress-induced gut-brain-bone axis disruption, supporting its potential as a therapeutic alternative through modulation of microbiota-driven gut-brain communication in stress-associated disorders.
DOI: 10.3390/ijms26199318
Institutions: Thammasat University, Mahidol University, Naresuan University, Praboromarajchanok Institute Ministry of Public Health, Ratchathani University, Ubon Ratchathani University, Prince of Songkla University, National Science and Technology Development Agency, National Nanotechnology Center, King Mongkut's Institute of Technology Ladkrabang
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
Award: G5179065427
OpenAlex ID: W4414475584