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Pregled bibliografske jedinice broj: 942473

Neuroprotective effect of zolpidem against glutamate-induced toxicity is mediated via the PI3K/Akt pathway and inhibited by PK11195


Jazvinšćak Jembrek, Maja; Radovanović, Vedrana; Vlainić, Josipa; Vuković, Lidija; Hanžić, Nikolina
Neuroprotective effect of zolpidem against glutamate-induced toxicity is mediated via the PI3K/Akt pathway and inhibited by PK11195 // Toxicology, 406-407 (2018), 58-69 (međunarodna recenzija, članak, znanstveni)


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Naslov
Neuroprotective effect of zolpidem against glutamate-induced toxicity is mediated via the PI3K/Akt pathway and inhibited by PK11195

Autori
Jazvinšćak Jembrek, Maja ; Radovanović, Vedrana ; Vlainić, Josipa ; Vuković, Lidija ; Hanžić, Nikolina

Izvornik
Toxicology (0300-483X) 406-407 (2018); 58-69

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
Zolpidem ; Excitotoxicity ; Akt signalling ; p53 ; PK11195 ; NR2B subunit of NMDA receptor

Sažetak
Excitotoxicity is a pathological process in which neuronal dysfunction and death are induced by excessive glutamate stimulation, the major fast excitatory neurotransmitter in the mammalian brain. Excitotoxicity-induced neurodegeneration is a contributing factor in ischemia-induced brain damage, traumatic brain injury, and various neurodegenerative diseases. It is triggered by calcium overload due to prolonged over-activation of ionotropic N-methyl-D-aspartate (NMDA) receptors. Enhanced Ca2+ release results in neuronal vulnerability through several intertwined mechanisms, including activation of proteolytic enzymes, increased production of reactive oxygen species (ROS), mitochondrial dysfunction and modulation of intracellular signalling pathways. We investigated the neuroprotective effect of hypnotic zolpidem, a drug that exerts its central effects at the GABAA receptor complex, against glutamate-induced toxicity in P19 neurons. Zolpidem prevented death of P19 neurons exposed to glutamate, and abolished the glutamate-induced increase in ROS production, p53 and Bax expression, and caspase-3/7 activity. Zolpidem effects were mediated by marked over-activation of Akt kinase. The pro-survival effect, as well as the pAkt induction, were prevented in the presence of wortmannin, an inhibitor of phosphatidylinositol-3-kinase (PI3K) that functions upstream of Akt. The beneficial effect of zolpidem on neuronal survival was not prevented by flumazenil, a GABAA receptor antagonist. PK11195, a drug that modulates the mitochondrial translocator protein 18 kDa (TSPO) and F0F1-ATPase, prevented the beneficial effect of zolpidem, indicating that the mechanism of zolpidem action involves preservation of mitochondrial function and integrity. Zolpidem effects were further mediated by prevention of glutamate-induced increase in the expression of the NR2B subunit of NMDA receptor. The obtained results suggest the promising therapeutic potential of zolpidem against excitotoxic insults and highlight the importance of mitochondria and the Akt pathway as valuable targets for therapeutic interventions in glutamate-mediated neuropathological conditions.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti



POVEZANOST RADA


Projekti:
HKS-2016-2
098-0000000-2448 - Stres, GABA-A receptori i mehanizmi djelovanja neuropsihofarmaka (Švob Štrac, Dubravka, MZOS ) ( POIROT)

Ustanove:
Institut "Ruđer Bošković", Zagreb,
Hrvatsko katoličko sveučilište, Zagreb

Poveznice na cjeloviti tekst rada:

www.sciencedirect.com www.ncbi.nlm.nih.gov

Citiraj ovu publikaciju:

Jazvinšćak Jembrek, Maja; Radovanović, Vedrana; Vlainić, Josipa; Vuković, Lidija; Hanžić, Nikolina
Neuroprotective effect of zolpidem against glutamate-induced toxicity is mediated via the PI3K/Akt pathway and inhibited by PK11195 // Toxicology, 406-407 (2018), 58-69 (međunarodna recenzija, članak, znanstveni)
Jazvinšćak Jembrek, M., Radovanović, V., Vlainić, J., Vuković, L. & Hanžić, N. (2018) Neuroprotective effect of zolpidem against glutamate-induced toxicity is mediated via the PI3K/Akt pathway and inhibited by PK11195. Toxicology, 406-407, 58-69.
@article{article, author = {Jazvin\v{s}\'{c}ak Jembrek, Maja and Radovanovi\'{c}, Vedrana and Vlaini\'{c}, Josipa and Vukovi\'{c}, Lidija and Han\v{z}i\'{c}, Nikolina}, year = {2018}, pages = {58-69}, keywords = {Zolpidem, Excitotoxicity, Akt signalling, p53, PK11195, NR2B subunit of NMDA receptor}, journal = {Toxicology}, volume = {406-407}, issn = {0300-483X}, title = {Neuroprotective effect of zolpidem against glutamate-induced toxicity is mediated via the PI3K/Akt pathway and inhibited by PK11195}, keyword = {Zolpidem, Excitotoxicity, Akt signalling, p53, PK11195, NR2B subunit of NMDA receptor} }
@article{article, author = {Jazvin\v{s}\'{c}ak Jembrek, Maja and Radovanovi\'{c}, Vedrana and Vlaini\'{c}, Josipa and Vukovi\'{c}, Lidija and Han\v{z}i\'{c}, Nikolina}, year = {2018}, pages = {58-69}, keywords = {Zolpidem, Excitotoxicity, Akt signalling, p53, PK11195, NR2B subunit of NMDA receptor}, journal = {Toxicology}, volume = {406-407}, issn = {0300-483X}, title = {Neuroprotective effect of zolpidem against glutamate-induced toxicity is mediated via the PI3K/Akt pathway and inhibited by PK11195}, keyword = {Zolpidem, Excitotoxicity, Akt signalling, p53, PK11195, NR2B subunit of NMDA receptor} }

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE





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