Ligustilide alleviates the mitophagy and anxiety-like behavior produced by nighttime lighting

Artificial light at night (ALAN) is an emerging environmental pollutant that disrupts circadian rhythms and increases the risk of neuropsychiatric disorders. Mitochondrial dysfunction and aberrant mitophagy are implicated in ALAN-induced anxiety-like behaviors, yet the underlying mechanisms remain elusive. Plant-derived compounds represent a promising avenue for neuroprotection.

This study aimed to explore the therapeutic potential of Ligustilide (LIG)-a natural dihydrophthalide compound extracted from Ligusticum chuanxiong hort (Rhizoma Chuanxiong) and Angelica sinensis (Oliv)-in alleviating ALAN-induced anxiety-like behavior, focusing on the novel mechanistic link between mitophagy modulation and PI3K-AKT pathway regulation to protect mitochondrial and synaptic integrity.

Male mice were exposed to ALAN to induce anxiety-like behaviors, assessed using the elevated plus maze, novelty-suppressed feeding, marble burying, and open field tests. LIG (10 and 30 mg/kg, i.p.) was administered daily for 14 days. Mitochondrial morphology, synaptic integrity, mitophagy activity, and PI3K-AKT pathway activation in the cerebral cortex were examined by electron microscopy, immunofluorescence, and Western blotting.

ALAN exposure triggered significant anxiety-like behaviors, synaptic damage, and mitophagy hyperactivation, along with PI3K-AKT pathway overactivation. LIG treatment represents the first demonstration of a plant-derived compound simultaneously mitigating ALAN-induced mitophagy dysregulation and PI3K-AKT overactivation, thereby preserving neuronal ultrastructure and behavioral function.

This study demonstrates that Ligustilide exerts neuroprotective effects against ALAN-induced neuronal injury, likely through modulation of mitophagy and PI3K-AKT signaling. Our findings provide novel insights into the mechanistic basis of ALAN neurotoxicity and suggest a promising therapeutic strategy grounded in traditional medicinal compounds.