d-arg-dmt-lys-phe-nh2 and Cognitive-Dysfunction

Aging has been attributed to oxidative stress and inflammatory response, in which NF-κB and Nrf2-ARE signaling pathways play significant roles. Senescence accelerated mouse prone 8 (SAMP8) is generally used an animal model for aging studies. Here, we investigated the NF-κB and Nrf2-ARE signaling pathways in SAMP8 brains at different ages and their responses to SS31 peptide treatment. Thirty six SAMP8 mice were separated into aging groups and SS31-treatment groups. The hippocampus from each mouse was dissected for RNA and protein extraction. Cytokines and ROS levels were measured using ELISA and standardised method. Gene expressions of NF-κB, Nrf2 and HO-1 were measured by RT-qPCR. Total protein amount of NF-κB and HO-1, as well as the concentrations of nuclear and cytoplasmic Nrf2 were measured using Western blots. Our data showed that aging could activate both NF-κB and Nrf2-ARE signaling pathways, which could be suppressed and activated by SS31 treatment respectively. Regression analysis revealed that NF-κB gene expression was the most important parameter predicting aging process and SS31 treatment effects in SAMP8. Our findings suggested that SS31 treatment may modulate the inflammatory and oxidative stress status of the aged brains and exert protective effects during brain aging.

Topics: Aging; Animals; Antioxidants; Cognitive Dysfunction; Disease Models, Animal; Male; Mice; NF-kappa B; Oligopeptides; Oxidative Stress; Reactive Oxygen Species; Signal Transduction

Mitochondrial dysfunction has been linked to the earliest pathogenesis of isoflurane-induced cognitive impairments in developing or aging mammalian brain. However, its molecular mechanism is poorly understood and a pharmacologic treatment to rapidly reverse mitochondrial dysfunction is lacking. Fifteen-month-old male C57BL/6 mice were exposed to isoflurane for two hours following intraperitoneal administration of mitochondrion-targeted peptide SS-31 or vehicle with 30min interval. The hippocampus was immediately removed for biochemical assays and mitochondria isolation after inhalation. Behavioral tests were evaluated by the open field test and fear conditioning test 24h after the experiment. We showed that cognitive deficits induced by exposure of the aging mice to isoflurane were accompanied by mitochondrial dysfunction in hippocampus due to loss of the enzymatic activity of complex I. This loss resulted in the increase of reactive oxygen species production, decrease of ATP production and mitochondrial membrane potential, and opening of mitochondrial permeability transition pore. Further, we provided evidence that the BDNF signaling pathway was involved in this process to regulate synaptic plasticity-related proteins, for instance, downregulation of synapsin 1, PSD-95 and p-CREB, and upregulation of NR2A, NR2B, CaMKIIα and CaMKIIβ. Of note, the isoflurane-induced cognitive deficits were rescued by SS-31 through reversal of mitochondrial dysfunction, which facilitated the regulation of BDNF signaling including the expression reversal of aforementioned important synaptic-signaling proteins in aging mice. Our data demonstrate that reversing mitochondrial dysfunction by SS-31 enhances BDNF signaling pathway and synaptic plasticity, and provides protective effects on cognitive function, thereby support the notion that SS-31 may have therapeutic benefits for elderly humans undertaking anesthesia.

Topics: Aging; Anesthetics, Inhalation; Animals; Brain-Derived Neurotrophic Factor; Cognitive Dysfunction; Disease Models, Animal; Electron Transport Chain Complex Proteins; Exploratory Behavior; Hippocampus; Isoflurane; Locomotion; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Neuroprotective Agents; Oligopeptides; Reactive Oxygen Species; Signal Transduction