engleski

The neuroprotective effect of hypnotic zolpidem against glutamate-induced apoptotic death is mediated via the PI3K/Akt signalling pathway

Introduction: Excitotoxicity is a form of neuronal death induced by increased glutamate signaling. It is involved in ischemia-induced brain damage, traumatic brain injury and various neurodegenerative diseases. Prolonged activation of ionotropic glutamate receptors results in substantial calcium overload that ends in oxidative stress-related apoptotic death. We studied neuroprotective potential of zolpidem, a drug that posses structural similarity to antioxidant melatonin and exerts its central effects acting at GABAA receptor complex. Materials and methods: Effects of zolpidem were studied in the culture of P19 neurons. Neuronal death was induced by exposure to 300 microM glutamate for 3 hours. 24 h later we monitored changes in neuronal viability, generation of reactive oxygen species (ROS) and caspase-3/7 activity. Protein expression of transcription factor p53 and phosphorylated Akt was determined by western blot method, whereas gene expression analysis of Bax, Bcl-2 and p53 was assessed by the semiquantitative RT-PCR method. Results: Zolpidem prevented glutamate-induced neuronal death. It attenuated enhancement of ROS generation, increase in p53 and Bax expression and caspase-3/7 activity, and induced prominent over-activation of Akt kinase. The pro-survival effect and pAkt induction were prevented in the presence of wortmannin, an inhibitor of phosphatidylinositol-3-kinase (PI3K). Interestingly, flumazenil, a GABAA receptor antagonist, did not affect zolpidem-mediated neuroprotection, whereas PK11195, a drug that modulates mitochondrial translocator protein 18 kDa (TSPO) and F0F1-ATPase, prevented effect of zolpidem. Conclusion: The obtained results suggest promising therapeutic potential of zolpidem against excitotoxic insults and highlight importance of mitochondria and Akt signalling as valuable therapeutic targets against glutamate-mediated neurodegeneration.

Zolpidem ; Excitotoxicity ; PI3K/Akt signalling, P19 neurons

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