Severity-dependent changes in hippocampal necroptosis markers and neuronal loss in a PTSD-like mouse model: potential involvement of nitric oxide signaling

AI Summary

Although hippocampal dysfunction plays a central role in PTSD pathophysiology, the molecular mechanisms underlying these alterations-especially those involving nitric oxide (NO) signaling and necroptosis-related pathways-remain incompletely understood.

CONCLUSION: These findings suggest an association between NO signaling modulation and necroptosis-related molecular changes in the hippocampus under PTSD-like stress conditions.

Basic summary

Psychopharmacology (Berl). 2026 Jul 22. doi: 10.1007/s00213-026-07134-4. Online ahead of print.

ABSTRACT

BACKGROUND: Post-traumatic stress disorder (PTSD) is a psychiatric condition triggered by traumatic events and associated with long-lasting neurobiological alterations, particularly in the hippocampus. Although hippocampal dysfunction plays a central role in PTSD pathophysiology, the molecular mechanisms underlying these alterations-especially those involving nitric oxide (NO) signaling and necroptosis-related pathways-remain incompletely understood.

METHODS: Adult male Naval Medical Research Institute (NMRI) mice (n = 70) were randomly assigned to seven groups: control, moderate PTSD (MP), MP + L-arginine (MP-Arg), MP + L-NAME (MP-Nam), severe PTSD (SP), SP + L-arginine (SP-Arg), and SP + L-NAME (SP-Nam). PTSD-like stress was induced using a two-day electric foot shock protocol. Behavioral changes were evaluated using the Open Field Test (OFT), Forced Swim Test (FST), and Tail Suspension Test (TST). L-arginine (200 mg/kg) or L-NAME (50 mg/kg) was administered intraperitoneally 60-min before testing to modulate NO signaling. Hippocampal tissue was analyzed for phosphorylated RIP1, RIP3, and MLKL, and neuronal density in the CA1 region was assessed using Nissl staining.

RESULTS: Stress exposure was associated with anxiety- and depression-like behaviors, more pronounced in SP than MP mice. Stress was also associated with reduced CA1 neuronal density and increased phosphorylation of RIP1, RIP3, and MLKL. L-arginine treatment was associated with reduced behavioral impairments and partial preservation of CA1 neuronal integrity, whereas L-NAME treatment was associated with more pronounced behavioral and molecular alterations.

CONCLUSION: These findings suggest an association between NO signaling modulation and necroptosis-related molecular changes in the hippocampus under PTSD-like stress conditions. Further studies are required to clarify causal relationships.

PMID:42484917 | DOI:10.1007/s00213-026-07134-4

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