Phlorofucofuroeckol Improves Glutamate-Induced Neurotoxicity through Modulation of Oxidative Stress-Mediated Mitochondrial Dysfunction in PC12 Cells

Abstract

Stroke is a complex neurodegenerative disorder with a clinically high prevalence and mortality. Despite many efforts to protect against ischemic stroke, its incidence and related permanent disabilities continue to increase. In this study, we found that pretreatment with phlorofucofuroeckol (PFF), isolated from brown algae species, significantly increased cell viability in glutamate-stimulated PC12 cells. Additionally, glutamate-stimulated cells showed irregular morphology, but PFF pretreatment resulted in improved cell morphology, which resembled that in cells cultured under normal conditions. We further showed that PFF pretreatment effectively inhibited glutamate-induced apoptotic cell death in a caspase-dependent manner. Reactive oxygen species (ROS) induced by oxidative stress are closely associated with ischemia-induced neurological diseases. Exposure of PC12 cells to glutamate induced abundant production of intracellular ROS and mitochondrial dysfunction, which was attenuated by PFF in a dose-dependent manner. In vivo studies revealed that PFF-mediated prevention was achieved predominantly through inhibition of apoptosis and mitochondrial ROS generation. Taken together, these results suggest the possibility of PFF as a neuroprotective agent in ischemic stroke.

The Detrimental Action of Adenosine on Glutamate-Induced Cytotoxicity in PC12 Cells Can Be Shifted towards a Neuroprotective Role through A1AR Positive Allosteric Modulation

“…As the activation of caspases 3 and 7 is a typical hallmark of glutamate-induced cytotoxicity, the reduction of their activation by TRR469 further confirmed the cytoprotective action of the A 1 AR positive allosteric modulator. A large number of works in the literature reports that the neurotoxic effect of glutamate in PC12 cells involves the generation of ROS and mitochondrial dysfunction [43][44][45]. Accordingly, in our experimental conditions, glutamate significantly increased ROS production, an effect that was completely abrogated by the presence of TRR469.…”

Traumatic Brain Injury Impairs Myogenic Constriction of Cerebral Arteries: Role of Mitochondria-Derived H2O2 and TRPV4-Dependent Activation of BKca Channels

“…Our studies provide direct evidence that following TBI, the production of ROS is increased in the vascular smooth muscle cells, extending previous findings. 24,47 The mechanisms by which TBI promotes mitochondrial oxidative stress in smooth muscle cells may involve changes in the hemodynamic environment/mechanosensitive mtROS production, 48,49 factors released from the damaged brain parenchyma (including glutamate neurotoxicity), [50][51][52] and/or humoral factors. 53,54 These possibilities should be tested in future studies.…”

Neuroprotective Effects of Dammarane-Type Saponins from Panax notoginseng on Glutamate-Induced Cell Damage in PC12 Cells

“…Evidence shows that oxidative stress plays an important role in the pathogenesis of NDs such as Alzheimerʼs, Parkinsonʼs, and Huntingtonʼs diseases [25]. Reportedly, overproduction of intracellular ROS is induced by glutamate, possibly resulting in neuronal damage [14]. In the complex cellular physiological processes, this overproduction can lead to a series of molecular changes.…”

“…Intracellular Ca 2+ overload activates some downstream proteins and Ca 2+ -dependent enzymes, such as CaMKII [12]. In addition, an excessive extracellular glutamate level induces mitochondrial dysfunction and abnormal expression of oxidative stress-related proteins [13,14]. These complex pathways also regulate neuronal death and survival.…”