Protective Effects of Licofelone on Scopolamine-Induced Spatial Learning and Memory Impairment by Enhancing Parkin-Dependent Mitophagy and Promotion of Neural Regeneration and in Adult Mice

Abstract

Inhibition of COX and LOX could contribute to memory formation and prevention of neurodegeneration, by alleviation of neuroinflammation and improvement of mitochondrial homeostasis. We aimed to assess the effect of licofelone, a dual COX and 5-LOX inhibitor on memory formation, neural apoptosis, neural regeneration, and mitophagy in acute and chronic dosages, given that licofelone could regulate nitric oxide levels. Y-maze and Passive Avoidance tests were used to evaluate memory function in NMRI mice using the EthoVision setting, following scopolamine administration (1 mg/kg, i.p.) as an acute amnestic drug. Hippocampi were used to evaluate the levels of apoptosis via TUNEL assay, neural regeneration via immunohistochemistry method detecting doublecortin and nestin, and mitophagy via western blot of mitophagy proteins Parkin and ATG5. While acute high-dose licofelone (20 mg/kg) could reverse amnestic effects of scopolamine in passive avoidance test (p=0.0001), Chronic licofelone (10 mg/kg for 10 consecutive days) could improve performance in Y-maze (p=0.0007). Molecular analysis revealed that the chronic form of the drug could enhance neural regeneration in CA1 and SGZ regions, reset mitophagy levels as much as the healthy state, and reduce apoptosis rate. Licofelone appears to show a desirable anti-amnestic profile in a low dose chronically; it is hence recommended for future clinical studies on the prevention of neuroinflammation and memory deficit.