Usnic acid enantiomers restore cognitive deficits and neurochemical alterations induced by Aβ1-42 in mice

Alzheimer's disease (AD) is the most prevalent form of dementia with a complex pathophysiology not fully elucidated but with limited pharmacological treatment. The Usnic acid (UA) is a lichen secondary metabolite found in two enantiomeric forms: (R)-(+)-UA or (S) ( ) UA, with antioxidant and anti-inflammatory potential. Thus, given the role of neuroinflammation and oxidative injury in the AD, this study aimed to investigate experimentally the cognitive enhancing and anti-neuroinflammatory effects of UA enantiomers. First, the interactions of UA on acetylcholinesterase (AChE) was assessed by molecular docking and its inhibitory capability on AChE was assessed in vitro. In vivo trials investigated the effects of UA enantiomers in mice exposed to A beta(1-42) peptide (400 pmol/mice) intracerebroventricularly (i.c.v.). For this, mice were treated orally during 24 days with (R)-(+)-UA or (S)-(-)-UA at 25, 50, or 100 mg/kg, vehicle, or donepezil (2 mg/kg). Animals were submitted to the novel object recognized, Morris water maze, and inhibitory-avoidance task to assess the cognitive deficits. Additionally, UA antioxidant capacity and neuroinflammatory biomarkers were measured at the cortex and hippocampus from mice. Our results indicated that UA enantiomers evoked complex-receptor interaction with AChE like galantamine in silico. Also, UA enantiomers improved the learning and memory of the animals and in parallel decreased the myeloperoxidase activity and the lipid hydroperoxides (LOOH) on the cortex and hippocampus and reduced the IL-1 beta levels on the hippocampus. In summary, UA restored the cognitive deficits, as well as the signs of LOOH and neuroinflammation induced by A beta 1-42 administration in mice.

Automated summary

This study investigated the effects of UA enantiomers on cognitive deficits and neuroinflammation in mice with AD. The results showed that UA improved learning and memory, reduced oxidative stress markers, decreased neuroinflammation, and restored cognitive deficits induced by A beta 1-42 administration in mice.