Inhibition of fatty acid binding protein 5 prevents stress-induced anxiogenic and depressive-like symptoms through modulation of hippocampal neurogenesis, cannabinoid and neurotrophic signaling in the limbic circuitry.
Uzuneser. Taygun C TC; Jones. Matthew J MJ; Sarikahya. Mohammed H MH; Gummerson. Dana D; Whitehead. Shawn N SN; Hardy. Daniel B DB; Rushlow. Walter J WJ; Laviolette. Steven R SR
Key Findings
- Inhibiting FABP5 prevented stress‑induced anxiety‑ and depressive‑like behaviors in rodents.
- FABP5 inhibition restored hippocampal neurogenesis that is normally reduced by chronic stress.
- The treatment altered transcription of IGF‑1, CB2, and GPR55 receptors and affected Erk1/2, Akt, and p70S6K signaling in limbic brain regions.
Practical Outcomes
- For biohackers, the main takeaway is that targeting FABP5 could become a future strategy to mitigate stress‑related mood issues and support brain cell growth. However, no human data or ready‑to‑use protocols exist yet, so it’s not an actionable supplement or dosage recommendation today.
Summary
A study in rats found that blocking a protein called FABP5 can stop stress from causing anxiety, depression, and a drop in new brain cells. This effect seems linked to changes in IGF‑1 and other signaling pathways in the brain. While the research is early‑stage and done in animals, it suggests a new way to protect mood and brain health under stress.
Abstract
The endocannabinoid (eCB) system modulates many biological processes, including adult neurogenesis, emotional behaviour and stress-related signaling pathways. Intrinsic levels of eCB ligands, such as anandamide, are regulated in part, by fatty acid binding protein 5 (FABP5), a chaperone protein that transports anandamide for hydrolysis. Here, using preclinical rodent models, we examined the effects of pharmacological FABP5 inhibition on anxiety- and depressive-like behaviours and associated molecular signaling pathways, following exposure to chronic stress. In addition, we investigated the impacts of chronic stress on hippocampal neurogenesis and how FABP5 inhibition may modulate stress-induced deficits in hippocampal neurogenic mechanisms. Remarkably, we report that anxiety- and depressive-like behaviours are strongly prevented by systemic FABP5 inhibition and associated with altered transcription of IGF-1, CB<sub>2</sub> and GPR<sub>55</sub> receptors as well as by altered phosphorylation of Erk1/2, Akt and p70S6 kinase pathways in the limbic circuitry. Finally, FABP5 inhibition potently blocked stress-induced reductions in hippocampal neurogenesis, identifying FABP5 inhibition as a promising pharmacotherapeutic candidate for stress-induced mood and anxiety symptoms.
Study Information
pubmed
2025
2025-11-22T00:00:00.000Z
10.1016/j.nbd.2025.107201
92