Regulation of hippocampal Fas receptor and death-inducing signaling complex after kainic acid treatment in mice

Keller, Benjamin; Garcı́a-Sevilla, Jesús A.

doi:10.1016/j.pnpbp.2015.04.009

Cited by 8 publications

(13 citation statements)

References 66 publications

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“…A decrease in p25 can also influence CDK5 activity, as implicated in Tau phosphorylation [58,59]. These results indicate that CDK5 phosphorylation activity should be diminished after I 2 -IR ligand treatment, corroborating results obtained previously for MCR5 in a kainate model of neuronal damage [60].…”

Section: Changes In App Processing and Aβ Degradation Induced By Mcr5supporting

confidence: 89%

Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice

et al. 2019

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As populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer's disease have become more common. I 2 -Imidazoline receptors (I 2 -IR) are widely distributed in the central nervous system, and dysregulation of I 2 -IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I 2 -IR ligands potentially contribute to the delay of neurodegeneration. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I 2 -IR ligands, MCR5 and MCR9, produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I 2 -IR ligands diminished the amyloid precursor protein processing pathway and increased Aβ degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I 2 -IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases.

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Section: Changes In App Processing and Aβ Degradation Induced By Mcr5supporting

confidence: 89%

Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice

et al. 2019

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“…As expected, KA (45 mg/kg) induced a severe behavioural syndrome in mice, including recurrent motor seizures that peaked at 60-90 minutes after injection and declined within 48-72 hours to almost normal behaviour (Keller and García-Sevilla, 2015b). Notably, repeated treatment (five days) with the mixed I 1 /I 2 -IR ligand LSL61122 (10 mg/kg) significantly attenuated this early KA-induced behavioural neurotoxicity (within 90 minutes) in mice, whereas repeated treatment with I 1 -IR-selective moxonidine (1 mg/kg) or I 2 -IR-selective BU224 (20 mg/kg) did not prevent KA-induced motor seizures.…”

Section: Discussionsupporting

confidence: 78%

“…Due to the small amount of hippocampal tissue, total homogenates of both hippocampi and one cortical hemisphere were prepared for Western blot analysis of target proteins as described elsewhere (Keller and García-Sevilla, 2015b). The other cortical hemisphere was used for preparation of subcellular fractions as follows.…”

Section: Mouse Brain Total Homogenate and Subcellular Fractionationmentioning

confidence: 99%

Inhibitory effects of imidazoline receptor ligands on basal and kainic acid-induced neurotoxic signalling in mice

Keller

Garcı́a-Sevilla

2016

J Psychopharmacol

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This in vivo study assessed the potential of the imidazoline receptor (IR) ligands moxonidine (selective I1-IR), BU224 (selective I2-IR) and LSL61122 (mixed I1/I2-IR) to dampen excitotoxic signalling induced by kainic acid (KA; 45 mg/kg) in the mouse brain (hippocampus and cerebral cortex). KA triggered a strong behavioural syndrome (seizures; maximal at 60-90 minutes) and sustained stimulation (at 72 hours with otherwise normal mouse behaviour) of pro-apoptotic c-Jun-N-terminal kinases (JNK) and calpain with increased cleavage of p35 into neurotoxic p25 (cyclin-dependent kinase 5 [Cdk5] activators) in mouse hippocampus. Pretreatment (five days) with LSL61122 (10 mg/kg), but not moxonidine (1 mg/kg) or BU224 (20 mg/kg), attenuated the KA-induced behavioural syndrome, and all three IR ligands inhibited JNK and calpain activation, as well as p35/p25 cleavage after KA in the hippocampus (effects also observed after acute IR drug treatments). Efaroxan (I1-IR, 10 mg/kg) and idazoxan (I2-IR, 10 mg/kg), postulated IR antagonists, did not antagonise the effects of moxonidine and LSL61122 on KA targets (these IR ligands showed agonistic properties inhibiting pro-apoptotic JNK). Brain subcellular preparations revealed reduced synaptosomal postsynaptic density-95 protein contents (a mediator of JNK activation) and indicated increased p35/Cdk5 complexes (with pro-survival functions) after treatment with moxonidine, BU224 and LSL61122. These results showed that I1- and I2-IR ligands (moxonidine and BU224), and especially the mixed I1/I2-IR ligand LSL61122, are partly neuroprotective against KA-induced excitotoxic signalling. These findings suggest a therapeutic potential of IR drugs in disorders associated with glutamate-mediated neurodegeneration.

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“…Multifunctional FADD works in vivo as a common and major signaling step in the initial activation of structurally different receptors (e.g. neurotransmitter G protein-coupled receptors and receptor channels; see [25–27]). Although FADD has a crucial role during embryogenesis/development [28], little is known about its expression or functions as the brain ages [29] and in age-related neurophatologies.…”

Section: Introductionmentioning

confidence: 99%

Decreased cortical FADD protein is associated with clinical dementia and cognitive decline in an elderly community sample

Ramos-Miguel

Garcı́a-Sevilla

Barr

et al. 2017

Mol Neurodegeneration

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BackgroundFADD (Fas-associated death domain) adaptor is a crucial protein involved in the induction of cell death but also mediates non-apoptotic actions via a phosphorylated form (p-Ser194-FADD). This study investigated the possible association of FADD forms with age-related neuropathologies, cognitive function, and the odds of dementia in an elderly community sample.MethodsFADD forms were quantified by western blot analysis in dorsolateral prefrontal cortex (DLPFC) samples from a large cohort of participants in a community-based aging study (Memory and Aging Project, MAP), experiencing no-(NCI, n = 51) or mild-(MCI, n = 42) cognitive impairment, or dementia (n = 57).ResultsCortical FADD was lower in subjects with dementia and lower FADD was associated with a greater load of amyloid-β pathology, fewer presynaptic terminal markers, poorer cognitive function and increased odds of dementia. Together with the observations of FADD redistribution into tangles and dystrophic neurites within plaques in Alzheimer’s disease brains, and its reduction in APP23 mouse cortex, the results suggest this multifunctional protein might participate in the mechanisms linking amyloid and tau pathologies during the course of the illness.ConclusionsThe present data suggests FADD as a putative biomarker for pathological processes associated with the course of clinical dementia.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-017-0168-x) contains supplementary material, which is available to authorized users.

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Regulation of hippocampal Fas receptor and death-inducing signaling complex after kainic acid treatment in mice

Cited by 8 publications

References 66 publications

Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice

Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice

Inhibitory effects of imidazoline receptor ligands on basal and kainic acid-induced neurotoxic signalling in mice

Decreased cortical FADD protein is associated with clinical dementia and cognitive decline in an elderly community sample

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