Dataset Information

Irisin stimulates protective signaling pathways in rat hippocampal neurons.

ABSTRACT: Physical exercise stimulates neuroprotective pathways, has pro-cognitive actions, and alleviates memory impairment in Alzheimer's disease (AD). Irisin is an exercise-linked hormone produced by cleavage of fibronectin type III domain containing protein 5 (FNDC5) in skeletal muscle, brain and other tissues. Irisin was recently shown to mediate the brain benefits of exercise in AD mouse models. Here, we sought to obtain insight into the neuroprotective actions of irisin. We demonstrate that adenoviral-mediated expression of irisin promotes extracellular brain derived neurotrophic factor (BDNF) accumulation in hippocampal cultures. We further show that irisin stimulates transient activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), and prevents amyloid-β oligomer-induced oxidative stress in primary hippocampal neurons. Finally, analysis of RNA sequencing (RNAseq) datasets shows a trend of reduction of hippocampal FNDC5 mRNA with aging and tau pathology in humans. Results indicate that irisin activates protective pathways in hippocampal neurons and further support the notion that stimulation of irisin signaling in the brain may be beneficial in AD.

SUBMITTER: Lourenco MV

PROVIDER: S-EPMC9518673 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Irisin stimulates protective signaling pathways in rat hippocampal neurons.

Lourenco Mychael V MV de Freitas Guilherme B GB Raony Ícaro Í Ferreira Sergio T ST De Felice Fernanda G FG

Frontiers in cellular neuroscience 20220909

Physical exercise stimulates neuroprotective pathways, has pro-cognitive actions, and alleviates memory impairment in Alzheimer's disease (AD). Irisin is an exercise-linked hormone produced by cleavage of fibronectin type III domain containing protein 5 (FNDC5) in skeletal muscle, brain and other tissues. Irisin was recently shown to mediate the brain benefits of exercise in AD mouse models. Here, we sought to obtain insight into the neuroprotective actions of irisin. We demonstrate that adenovi ...[more]

PMID: 36187295

Similar Datasets

Project description:Volatile anesthetics alter presynaptic function through effects on Ca2+ influx and neurotransmitter release. These actions are proposed to play important roles in their pleiotropic neurophysiological effects including immobility, unconsciousness and amnesia. Nitric oxide and cyclic guanosine monophosphate (NO/cGMP) signaling has been implicated in presynaptic mechanisms, and disruption of NO/cGMP signaling has been shown to alter sensitivity to volatile anesthetics in vivo. We investigated volatile anesthetic actions NO/cGMP signaling in relation to presynaptic function in cultured rat hippocampal neurons using pharmacological tools and genetically encoded biosensors and sequestering probes of cGMP levels. Using the fluorescent cGMP biosensor cGull, we found that electrical stimulation-evoked NMDA-type glutamate receptor-independent presynaptic cGMP transients were inhibited 33.2% by isoflurane (0.51 mM) and 26.4% by sevoflurane (0.57 mM) (p < 0.0001) compared to control stimulation without anesthetic. Stimulation-evoked cGMP transients were blocked by the nonselective inhibitor of nitric oxide synthase N-ω-nitro-l-arginine, but not by the selective neuronal nitric oxide synthase inhibitor N5-(1-imino-3-butenyl)-l-ornithine. Isoflurane and sevoflurane inhibition of stimulation-evoked increases in presynaptic Ca2+ concentration, measured with synaptophysin-GCaMP6f, and of synaptic vesicle exocytosis, measured with synaptophysin-pHlourin, was attenuated in neurons expressing the cGMP scavenger protein sponge (inhibition of exocytosis reduced by 54% for isoflurane and by 53% for sevoflurane). The anesthetic-induced reduction in presynaptic excitability was partially occluded by inhibition of HCN channels, a cGMP-modulated excitatory ion channel that can facilitate glutamate release. We propose that volatile anesthetics depress presynaptic cGMP signaling and downstream effectors like HCN channels that are essential to presynaptic function and excitability. These findings identify novel mechanisms by which volatile anesthetics depress synaptic transmission via second messenger signaling involving the NO/cGMP pathway in hippocampal neurons.

Project description:BackgroundPropofol is a commonly used general anesthetic that may cause neuronal damage, especially in infants and young children. Mitochondria play an essential role in cellular metabolism and signal transduction. Propofol may cause neurotoxicity by inhibiting mitochondrial function, but the mechanism by this which occurs remains unclear.MethodsFirst, the primary rat hippocampal neurons were cultured for 7 days in vitro. The neurons were incubated with propofol at different times or different concentrations, and then the adenosine triphosphate (ATP), reactive oxygen species (ROS), mitochondrial membrane potential, and apoptosis-related proteins were analyzed. Based on the results of the 1st phase, the neurons were then incubated with propofol (100 µM) or corresponding reagents, including 5-aminoimidazole-4-carboxamide ribonucleotide, tenovin-1, and pifithrin-α. Subsequently, the ATP, ROS, mitochondrial membrane potential, phospho-adenosine 5'-monophosphate-activated protein kinase (p-AMPK), protein 53 (p53), and related apoptosis proteins were analyzed.ResultsHigher propofol concentrations or longer incubation times were associated with more pronounced decreases in ATP, B-cell lymphoma 2 (Bcl-2), and mitochondrial membrane potential, and more pronounced increases in ROS, BCL2-associated X (Bax), Cytochrome C (CytC), and cleaved caspase-9. Additionally, after incubation with propofol (100 µM), neuronal Bcl-2, p-AMPK, ATP, and mitochondrial membrane potential were downregulated, and ROS, p53, CytC, Bax, cleaved caspase-3, and cleaved caspase-9 were upregulated. AMPK activators or p53 inhibitors reversed the above-mentioned changes.ConclusionsPropofol (100 µM)-induced mitochondrial damage in fetal rat hippocampal neurons may be mediated by the AMPK/p53 signaling pathway. Propofol (100 µM) was shown to inhibit the activity of AMPK in neurons, upregulate the expression of p53, and then activate the mitochondrial-dependent apoptosis pathway, which may lead to neuronal apoptosis.

Dataset Information

Irisin stimulates protective signaling pathways in rat hippocampal neurons.

Publications

Irisin stimulates protective signaling pathways in rat hippocampal neurons.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets