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

backgroundPost-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.

methodsAdult 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.

resultsStress 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.

conclusionThese 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.