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Background <p>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.</p> Methods <p>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&#xa0;mg/kg) or L-NAME (50&#xa0;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.</p> Results <p>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.</p> Conclusion <p>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.</p> Graphical abstract <p>Modulation of the Nitric Oxide Pathway and Its Association with Necroptotic Markers and Depression-like Behaviors in a PTSD-like Mouse Model: Neuroprotective Potential of L-Arginine vs. Exacerbating Effects of L-NAME.</p> <p></p>

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

  • 期刊论文

  • 发表日期：

    2026年7月22日

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  • Alireza Barati,
  • Ramin Khaghani,
  • Amir Ahmad Salarian,
  • Mehdi Aghsami,
  • Zahra Hami,
  • Ehsan Nassireslami

摘要

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.

Graphical abstract

Modulation of the Nitric Oxide Pathway and Its Association with Necroptotic Markers and Depression-like Behaviors in a PTSD-like Mouse Model: Neuroprotective Potential of L-Arginine vs. Exacerbating Effects of L-NAME.