Neurotrophic effects of a cyanine dye via the PI3K-Akt pathway: attenuation of motor discoordination and neurodegeneration in an ataxic animal model

Autor: Shigeyuki Arai, Shigeharu Fukuda, Kenji Akita, Tsunetaka Ohta, Hitomi Ohta
Rok vydání: 2010
Předmět:
Male
Intracellular Space
lcsh:Medicine
PC12 Cells
p38 Mitogen-Activated Protein Kinases
chemistry.chemical_compound
Phosphatidylinositol 3-Kinases
Purkinje Cells
Behavioral Neuroscience
Neurotrophic factors
Cricetinae
Molecular Cell Biology
Neurobiology of Disease and Regeneration
Signaling in Cellular Processes
Cyanine
lcsh:Science
Coloring Agents
Apoptotic Signaling
Cellular Stress Responses
Multidisciplinary
Cell Death
Neuronal Morphology
Neurodegeneration
Biological activity
Neurodegenerative Diseases
Antiapoptotic Signaling
Neurochemistry
Carbocyanines
Cell biology
Neuroprotective Agents
Female
Neurochemicals
Neurotrophin
Signal Transduction
Research Article
Cerebellar Ataxia
Neurotoxins
Biology
Signaling Pathways
Cell Growth
Animal model
medicine
Neurites
Animals
PI3K/AKT/mTOR pathway
Cell Proliferation
Motor Systems
lcsh:R
JNK Mitogen-Activated Protein Kinases
medicine.disease
Rats
Disease Models
Animal
Oxidative Stress
chemistry
Cellular Neuroscience
Mutation
biology.protein
lcsh:Q
Atrophy
Molecular Neuroscience
Proto-Oncogene Proteins c-akt
Psychomotor Performance
Neuroscience
Zdroj: PLoS ONE
PLoS ONE, Vol 6, Iss 2, p e17137 (2011)
ISSN: 1932-6203
Popis: BACKGROUND: Neurotrophic factors may be future therapeutic agents for neurodegenerative disease. In the screening of biologically active molecules for neurotrophic potency, we found that a photosensitizing cyanine dye, NK-4, had remarkable neurotrophic activities and was a potent radical scavenger. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we evaluated the effect of NK-4 on the protection of neurons against oxidative damage and investigated the associated intracellular signaling pathways. Subsequently, we evaluated the effect of NK-4 in an animal model of neurodegeneration. In vitro, NK-4 showed dose-dependent protection of PC12 cells from toxicity induced by oxidative stress caused by hydrogen peroxide (H(2)O(2)) or 6-hydroxydopamine (6-OHDA). Comparison of extracellular signal-regulated kinase signaling pathways between treatment with NK-4 and nerve growth factor (NGF) using K252a, an inhibitor of the NGF receptor TrkA, revealed that NK-4 activity occurs independently of NGF receptors. LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, blocked the protective effect of NK-4, and NK-4 caused activation of Akt/protein kinase B, a downstream effector of PI3K. These results suggest that the neuroprotective effects of NK-4 are mediated by the PI3K-Akt signaling pathway. NK-4 treatment also attenuated stress-induced activation of SAPK/JNK, which suggests that NK-4 activates a survival signaling pathway and inhibits stress-activated apoptotic pathways independently of the TrkA receptor in neuronal cells. In vivo, administration of NK-4 improved motor coordination in genetic ataxic hamsters, as assessed by rota-rod testing. Histological analysis showed that cerebellar atrophy was significantly attenuated by NK-4 treatment. Notably, the Purkinje cell count in the treated group was threefold higher than that in the vehicle group. CONCLUSIONS/SIGNIFICANCE: These results suggest that NK-4 is a potential agent for therapy for neurodegenerative disorders based on the activation of survival signaling pathways.
Databáze: OpenAIRE
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