The primary physiological function of mitochondria is to generate adenosine triphosphate through oxidative phosphorylation via the electron transport chain. Overproduction of reactive oxygen species (ROS) as byproducts generated from mitochondria have been implicated in acute brain injuries such as stroke from cerebral ischemia. It was well-documented that mitochondria-dependent apoptotic pathway involves pro- and anti-apoptotic protein binding, release of cytochrome c, leading ultimately to neuronal death. On the other hand, mitochondria also play a role to counteract the detrimental effects elicited by excessive oxidative stress. Recent studies have revealed that oxidative stress and the redox state of ischemic neurons are also implicated in the signaling pathway that involves peroxisome proliferative activated receptor-γ (PPARγ) co-activator 1α (PGC1-α). PGC1-α is a master regulator of ROS scavenging enzymes including manganese superoxide dismutase 2 and the uncoupling protein 2, both are mitochondrial proteins, and may contribute to neuronal survival. PGC1-α is also involved in mitochondrial biogenesis that is vital for cell survival. Experimental evidence supports the roles of mitochondrial dysfunction and oxidative stress as determinants of neuronal death as well as endogenous protective mechanisms after stroke. This review aims to summarize the current knowledge focusing on the molecular mechanisms underlying cerebral ischemia involving ROS, mitochondrial dysfunction, apoptosis, mitochondrial proteins capable of ROS scavenging, and mitochondrial biogenesis.
Shaw, Fu-Zen. Is spontaneous high-voltage rhythmic spike discharge in Long Evans rats an absence-like seizure activity? J Neurophysiol 91: 63-77, 2004. First published June 25, 2003 10.1152/jn.00487.2003. A distinct high-voltage rhythmic spike (HVRS) discharge characterized by a barrage of negative spikes oscillating at 5-12 Hz was observed in chronically implanted Long Evans rats. Spontaneous HVRS discharges were exhibited in 90% of 40 Long Evans rats and occurred during sudden arrest of ongoing behavior (immobility) with occasional facial/whisker twitching. However, the function of HVRS discharges in Long Evans rats remains inconclusive to date and has been associated with alpha tremor/mu rhythm, attentive mu wave, and absence seizure. To elucidate the function of HVRS discharges in Long Evans rats, several experiments were performed. In a 6-h recording session (12:00 -18:00), HVRS activities primarily occurred in several specific vigilance states, being particularly abundant in a short-lasting period before vigilance changes. Several characteristics, such as durations, oscillatory frequencies, and interspike intervals (ISIs) of HVRS discharges, were altered during wake-sleep states. Oscillatory frequencies were negatively correlated with durations of HVRS segments. In addition, ISIs of a HVRS episode exhibited a crescendo-decrescendo pattern. These variable ISIs could explain why a negative correlation was found between oscillatory frequencies and durations of HVRS episodes. Moreover, HVRS discharges were demonstrated to have widespread and near-synchronous distribution to bilateral cortical areas. In addition, innocuous electrical stimuli were unable to stop ongoing HVRS discharges. By contrast, noxious stimuli elicited behavioral arousal and immediately terminated most HVRS discharges. Cortical-evoked potentials in response to mild electrical stimulation under HVRS discharges were different from those under waking state but resemble those under slow-wave sleep with a smaller magnitude. Moreover, the temporal and spectral characteristics of spontaneous HVRS activities were analogous to those of seizure activities induced by penicillin and pentylenetetrazol. The incidence of spontaneous HVRS discharges was significantly decreased by ethosuximide administration. Based on these results, HVRS discharge might not be associated with a voluntary mu-rhythm behavior, instead it behaves as an absence-like seizure activity. These results were also collaborated using other genetic absence-seizure rats, such as WAG/Rij and GAERS rats. Possible mechanisms for the generation and termination of paroxysmal HVRS discharges are also discussed.
Neurofeedback training (NFT) of the alpha rhythm has been used for several decades but is still controversial in regards to its trainability and effects on working memory. Alpha rhythm of the frontoparietal region are associated with either the intelligence or memory of healthy subjects and are also related to pathological states. In this study, alpha NFT effects on memory performances were explored. Fifty healthy participants were recruited and randomly assigned into a group receiving a 8-12-Hz amplitude (Alpha) or a group receiving a random 4-Hz amplitude from the range of 7 to 20 Hz (Ctrl). Three NFT sessions per week were conducted for 4 weeks. Working memory was assessed by both a backward digit span task and an operation span task, and episodic memory was assessed using a word pair task. Four questionnaires were used to assess anxiety, depression, insomnia, and cognitive function. The Ctrl group had no change in alpha amplitude and duration. In contrast, the Alpha group showed a progressive significant increase in the alpha amplitude and total alpha duration of the frontoparietal region. Accuracies of both working and episodic memories were significantly improved in a large proportion of participants of the Alpha group, particularly for those with remarkable alpha-amplitude increases. Scores of four questionnaires fell in a normal range before and after NFT. The current study provided supporting evidence for alpha trainability within a small session number compared with that of therapy. The findings suggested the enhancement of working and episodic memory through alpha NFT. Hum Brain Mapp 37:2662-2675, 2016. © 2016 Wiley Periodicals, Inc.
Peroxisome proliferator-activated receptors gamma coactivator-1alpha (PGC-1alpha) may regulate the mitochondrial antioxidant defense system under many neuropathological settings. However, the exact role of PGC-1alpha in ischemic brain damage is still under debate. Based on an experimental model of transient global ischemia (TGI), this study evaluated the hypothesis that the activation of PGC-1alpha signaling pathway protects hippocampal CA1 neurons against delayed neuronal death after TGI. In Sprague-Dawley rats, significantly increased content of oxidized proteins in the hippocampal CA1 tissue was observed as early as 30 min after TGI, followed by augmentation of PGC-1alpha expression at 1 hr. Expression of uncoupling protein 2 (UCP2) and superoxide dismutases 2 (SOD2) in the hippocampal CA1 neurons was upregulated 4-48 hr after TGI. In addition, knock-down of PGC-1alpha expression by pretreatment with a specific antisense oligodeoxynucleotide in the hippocampal CA1 subfield downregulated the expression of UCP2 and SOD2 with resultant exacerbation of oxidative stress and augmentation of delayed neuronal cell death in the hippocampus after TGI. Overall, our results indicate that PGC-1alpha is induced by cerebral ischemia leading to upregulation of UCP2 and SOD2, thereby providing a neuroprotective effect against ischemic brain injury in the hippocampus by ameliorating oxidative stress.
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