Elamipretide (SS-31) improves mitochondrial dysfunction, synaptic and memory impairment induced by lipopolysaccharide in mice

Background: It is widely accepted that mitochondria have a direct impact on neuronal function and survival. Oxidative stress caused by mitochondrial abnormalities play an important role in the pathophysiology of lipopolysaccharide (LPS)-induced memory impairment. Elamipretide (SS-31) is a novel mitochondrion-targeted antioxidant. However, the impact of elamipretide on the cognitive sequelae of inflammatory and oxidative stress is unknown.

Methods: We utilized MWM and contextual fear conditioning test to assess hippocampus-related learning and memory performance. Molecular Biology techniques and ELISA were used to examine mitochondrial function, oxidative stress, and the inflammatory response. TUNEL and Golgi-staining was used to detect neural cell Apoptosis and the density of dendritic spines in the mouse hippocampus.

Results: Mice treated with LPS exhibited mitochondrial dysfunction, oxidative stress, an inflammatory response, neural cell Apoptosis, and loss of dendritic spines in the hippocampus, leading to impaired hippocampus-related learning and memory performance in the MWM and contextual fear conditioning test. Treatment with elamipretide significantly ameliorated LPS-induced learning and memory impairment during behavioral tests. Notably, elamipretide not only provided protective effects against mitochondrial dysfunction and oxidative stress but also facilitated the regulation of brain-derived neurotrophic factor (BDNF) signaling, including the reversal of important synaptic-signaling proteins and increased synaptic structural complexity.

Conclusion: These findings indicate that LPS-induced memory impairment can be attenuated by the mitochondrion-targeted antioxidant elamipretide. Consequently, elamipretide may have a therapeutic potential in preventing damage from the oxidative stress and neuroinflammation that contribute to perioperative neurocognitive disorders (PND), which makes mitochondria a potential target for treatment strategies for PND.

Antioxidant; Elamipretide; Memory impairment; Mitochondrial dysfunction; Neuroinflammation; Oxidative stress; SS-31; Synaptic plasticity.