• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • Accompanied with apoptosis other ways of neuronal


    Accompanied with apoptosis, other ways of neuronal death also occur in ischemic fda approved vegf inhibitor due to the impairment of mitochondrial homeostasis [16]. Oxidative DNA damage activates poly (ADP-ribose) polymerase 1 (PARP-1) to induce regulated necrosis, referred to as parthanatos, in the brain [17]. Over-activated PARP-1 increases the accumulation of poly (ADP-ribose) (PAR) accompanied with the excessive consumption of NAD+ and subsequent depletion of ATP level [18]. Nuclear translocation of apoptosis inducing factor (AIF) is required for DNA damage in parthanatos. AIF is located in mitochondria; however, PAR induces AIF translocation from mitochondria to the nucleus, leading to DNA fragmentation through chromatin degradation [19], [20]. Really, inhibition of AIF release is shown to prevent glutamate-induced neuronal death [21]. Given the role of HK-II in mitochondrial integrity, it is logical to reason that protection of mitochondrial HK-II could prevent AIF release by preserving the permeability barrier of IMM. Astragaloside IV (AIV) is a natural saponin abandent in Astragalus membranaceus and exhibits a wide range of biological activities [22]. The neuroprotective effects of AIV have been well documented, but these studies are mainly limited in neurodegenerative disorders [23]. Some studies also report that AIV ameliorates oxidative stress-induced mitochondrial dysfunction in cardiac cells and attenuates cerebral ischemia/reperfusion injury through suppressing oxidative stress and inflammation [24], [25]. In addition, AIV activates Akt to protect mitochondrial function in cardiomyocytes and inhibit lipolysis in adipose tissue [26], [27]. Because HK-II binding to mitochondria is mediated by Akt activation, it is tempting to know if AIV could promote HK-II binding to mitochondria and protect neurons from excitotoxicity during ischemic insult. In the present study, we demonstrated that apoptosis and parthanatos simultaneously occurred in glutamate-mediated neuronal damage and the impaired mitochondrial integrity is the common cause for the different ways of cell death. AIV activated Akt to increase the association of HK-II with mitochondria and the reduced release of pro-apoptotic proteins and AIF contributed to preventing neuronal death.
    Materials and methods
    Discussion Various types of cell death pathways are manifested in ischemic neuronal damage, and we noticed the increment of PAR formation and TUNEL-positive cells in cortical neurons exposed to OGD challenge, indicating the co-existence of parthanatos and apoptosis during nutrient depletion. Brain ischemia leads to glutamate release [1] and excessive accumulation of glutamate plays a critical role in mitochondrial dysfunction due to excitotoxicity [31]. Oxidative stress, inflammation and endoplasmic reticulum stress are involved in glutamate excitotoxicity, contributing to mitochondrial dysfunction [32]. ROS production in ischemic heart and brain is mainly derived from mitochondria and oxidative DNA damage activates PARP-1, indicative of the implication of mitochondrial dysfunction in DNA damage. PARP-1 inhibitor, 3-AB protected mitochondrial function with reduced PAR formation and apoptosis in neurons subjected to OGD, demonstrating the important role of mitochondrial integrity in the protection of neuron survival, despite the different pathways for apoptosis and parthanatos. AIV maintained the permeability barrier of the inner mitochondrial membrane, partially explained its action to protect neuron survival from cell death. Consistent with this, AIV is documented to activate anti-oxidant signaling and improve mitochondrial function in the vessel [33], [34]. Although AIV reduced glutamate accumulation in cultured neurons, it was tempting to know if it directly combats excitotoxicity to protect mitochondrial function, because glutamate-mediated excitotoxicity could damage cellular components and compromise cell viability. Different from the heart, which uses fatty acids as the major oxidative fuel, glucose is the obligatory energy substrate of the brain. HK is essential for glucose metabolism, because it converts glucose to glucose 6-phosphate, the first step in glycolysis. AIV improved glycolysis in the brain by protecting HK activity and this action should contribute to neuroprotection´╝îespecially in brain ischemia. Mitochondrial HK-II participates in mitochondrial integrity and facilitates energy efficiency. However, glutamate challenge induced HK-II detachment from mitochondria in neurons. The binding of HK-II to mitochondria is mediated by Akt activation, because HK-II has an Akt consensus sequence at Thr473 residue, which can be directly phosphorylated by Akt to facilitate the binding to mitochondria [35]. Consistent with docking result which indicated that AIV exhibited strong binding affinity for Akt, AIV effectively activated Akt by phosphorylation in neurons, even Akt activity was impaired by glutamate stimulation. Akt traverses the cell interior with regulated localization, and we found that AIV promoted Akt interaction with HK-II, well explaining its action to protect mitochondria HK-II against excitotoxicity. Pharmacological inhibition and Akt knockdown diminished the protective effect of AIV, providing solid evidence to support the conclusion. AIV activates Akt to inhibit lipolysis in adipose tissue and protects neurite outgrowth [27], [36], and our work provides new insight into its action.