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- W2980468830 abstract "Endothelin B (ETB) receptor agonist, IRL-1620, is being investigated as a potential therapeutic agent in the treatment of Alzheimer's disease (AD), however, its mechanism of action of IRL-1620 is not yet established. We determined the effect of IRL-1620 on mitochondrial dysfunction, neurogenesis and synaptogenesis in a transgenic mouse model of AD. APP/PS1 transgenic mice and C57BL/6 control mice were divided into two groups (Vehicle and IRL-1620). IRL-1620 (5 μg/kg) was intravenously injected, three times at 2 hour intervals on days 1, 3 and 6 of every month until study end points (3, 6 and 12 months age). Control mice received equal volume of saline. Morris water maze test was conducted in mice to assess learning and memory abilities. Separate sets of mice were sacrificed at the end of 3, 6 and 12 months and brain harvested to determine the expression of markers for mitochondrial dysfunction, neuro- and synapto-genesis. APP/PS1 transgenic mice showed significant (p<0.001) impairment in spatial memory. IRL-1620 treatment significantly reduced (40% and 46%) learning and memory deficit in 6 and 12 months aged transgenic mice. An increased expression of neuronal differentiation marker, NeuroD1 (432%; p<0.0001) and DoubleCortin (233%; p<0.0001) along with neural marker for mature neurons, NeuN (224%; p<0.0001) was observed in IRL-1620 group compared to vehicle at 12 months of APP/PS1 transgenic mice. IRL-1620 increased the expression of presynaptic markers (synapsin1 and synaptophysin) as well as post-synaptic marker (Postsynaptic Density-95) compared to vehicle. Expression of synapsin1 (169%), synaptophysin (111%) and postsynaptic Density-95 (267%) increased in IRL-1620 treated animals compared to vehicle at 12 months. A similar increase occurred at 6 months. An upregulation (p<0.0001) of mitochondrial fusion-related proteins, Mfn1, Mfn2, Opa1, and downregulation of fission proteins, Drp1 and Fis1, in IRL-1620 group compared to vehicle at 6 and 12 months was observed. There were no changes in the expression of any markers at 3 months. Stimulation of ETB receptors with IRL-1620 improves both acquisition (learning) and retention (memory) on water maze task in APP/PS1 transgenic mice. IRL-1620 enhances the expression of neurogenic and synaptogenic markers by maintaining mitochondrial dynamic balance leading to functional recovery." @default.
- W2980468830 created "2019-10-25" @default.
- W2980468830 creator A5039522776 @default.
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- W2980468830 date "2019-07-01" @default.
- W2980468830 modified "2023-09-28" @default.
- W2980468830 title "P4-504: ENDOTHELIN-B RECEPTOR AGONIST, IRL-1620, ENHANCES NEUROGENESIS AND SYNAPTOGENESIS BY IMPROVING MITOCHONDRIAL FUNCTION IN AN APP/PS1 TRANSGENIC MOUSE MODEL OF ALZHEIMER'S DISEASE" @default.
- W2980468830 doi "https://doi.org/10.1016/j.jalz.2019.08.050" @default.
- W2980468830 hasPublicationYear "2019" @default.
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