Repurposing citicoline for single prolonged stress-induced behavioral and hippocampal molecular abnormalities in male mice: novel mechanistic attenuation of endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, and apoptosis.

Citation:
Fahmy, N. G. (2026).  Repurposing citicoline for single prolonged stress-induced behavioral and hippocampal molecular abnormalities in male mice: novel mechanistic attenuation of endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, and apoptosis.. Neuropharmacology. 111082. copy at www.tinyurl.com/2ybkc4bg

Date Published:

2026 Jun 19

ISSN:

1873-7064

Abstract:

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder with limited effective pharmacological options. Endoplasmic reticulum (ER) stress and mitochondrial dysfunction have emerged as pivotal pathological mechanisms in PTSD pathophysiology, yet therapies targeting these pathways remain largely unexplored. Citicoline, recognized for its neuroprotective properties and capacity to modulate mitochondrial homeostasis, presents a promising candidate for intervention. This study investigated citicoline's therapeutic efficacy against behavioral and hippocampal molecular abnormalities induced by single prolonged stress (SPS) in male mice. Thirty-six mice were subdivided into control, citicoline (Citi) (100 mg/kg, p.o for 7 days), SPS (2-hour restraint, 20-minute forced swim, ether exposure), and SPS+Citi (SPS followed by citicoline for 7 days) groups. Citicoline administration effectively reversed stress-induced behavioral impairments in social novelty preference, marble burying, and cue-induced freezing. At the molecular level, citicoline restored ER homeostasis by attenuating the toxic unfolded protein response characterized by reductions in phosphorylated protein kinase RNA-like ER kinase, activating transcription factor (ATF) 4, and ATF6 while upregulating the protective X-box binding protein 1. Such improvements were accompanied by reactivation of impaired mitophagy through enhanced PTEN-induced kinase 1 and parkin expression, facilitating clearance of damaged mitochondria and reactive oxygen species. Furthermore, citicoline effectively countered oxidative stress, evidenced by suppressing malondialdehyde-mediated lipid peroxidation while restoring glutathione antioxidant reserves. Citicoline also normalized mitochondrial biogenesis by upregulating peroxisome proliferator-activated receptor gamma coactivator 1-alpha and prevented neuronal apoptosis by suppressing caspase-3. Collectively, these findings establish citicoline as a promising multi-targeted therapeutic candidate for behavioral and hippocampal molecular abnormalities after SPS in male mice.

Alternate Journal:

Neuropharmacology