A comparison of LKB1/AMPK/mTOR metabolic axis response to global ischaemia in brain, heart, liver and kidney in a rat model of cardiac arrest.

BACKGROUND: Cellular energy failure in high metabolic rate organs is one of the underlying causes for many disorders such as neurodegenerative diseases, cardiomyopathies, liver and renal failures. In the past decade, numerous studies have discovered the cellular axis of LKB1/AMPK/mTOR as an essential modulator of cell homeostasis in response to energy stress. Through regulating adaptive mechanisms, this axis adjusts the energy availability to its demand by a systematized control on metabolism. Energy stress, however, could be sensed at different levels in various tissues, leading to applying different strategies in response to hypoxic insults. METHODS: Here the immediate strategies of high metabolic rate organs to time-dependent short episodes of ischaemia were studied by using a rat model (n = 6/group) of cardiac arrest (CA) (15 and 30 s, 1, 2, 4 and 8 min CA). Using western blot analysis, we examined the responses of LKB1/AMPK/mTOR pathway in brain, heart, liver and kidney from 15 s up to 8 min of global ischaemia. The ratio of ADP/ATP was assessed in all ischemic and control groups, using ApoSENSOR bioluminescent assay kit. RESULTS: Brain, followed by kidney showed the early dephosphorylation response in AMPK (Thr172) and LKB1 (Ser431); in the absence of ATP decline (ADP/ATP elevation). Dephosphorylation of AMPK was followed by rephosphorylation and hyperphosphorylation, which was associated with a significant ATP decline. While heart's activity of AMPK and LKB1 remained at the same level during short episodes of ischaemia, liver's LKB1 was dephosphorylated after 2 min. AMPK response to ischaemia in liver was mainly based on an early alternative and a late constant hyperphosphorylation. No significant changes was observed in mTOR activity in all groups. CONCLUSION: Together our results suggest that early AMPK dephosphorylation followed by late hyperphosphorylation is the strategy of brain and kidney in response to ischaemia. While the liver seemed to get benefit of its AMPK system in early ischameia, possibly to stabilize ATP, the level of LKB1/AMPK activity in heart remained unchanged in short ischaemic episodes up to 8 min. Further researches must be conducted to elucidate the molecular mechanism underlying LKB1/AMPK response to oxygen supply.

Early glycogen synthase kinase-3ß and protein phosphatase 2A independent tau dephosphorylation during global brain ischaemia and reperfusion following cardiac arrest and the role of the adenosine monophosphate kinase pathway.

Abnormal tau phosphorylation (p-tau) has been shown after hypoxic damage to the brain associated with traumatic brain injury and stroke. As the level of p-tau is controlled by Glycogen Synthase Kinase (GSK)-3ß, Protein Phosphatase 2A (PP2A) and Adenosine Monophosphate Kinase (AMPK), different activity levels of these enzymes could be involved in tau phosphorylation following ischaemia. This study assessed the effects of global brain ischaemia/reperfusion on the immediate status of p-tau in a rat model of cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR). We reported an early dephosphorylation of tau at its AMPK sensitive residues, Ser(396) and Ser(262) after 2 min of ischaemia, which did not recover during the first two hours of reperfusion, while the tau phosphorylation at GSK-3ß sensitive but AMPK insensitive residues, Ser(202) /Thr(205) (AT8), as well as the total amount of tau remained unchanged. Our data showed no alteration in the activities of GSK-3ß and PP2A during similar episodes of ischaemia of up to 8 min and reperfusion of up to 2 h, and 4 weeks recovery. Dephosphorylation of AMPK followed the same pattern as tau dephosphorylation during ischaemia/reperfusion. Catalase, another AMPK downstream substrate also showed a similar pattern of decline to p-AMPK, in ischaemic/reperfusion groups. This suggests the involvement of AMPK in changing the p-tau levels, indicating that tau dephosphorylation following ischaemia is not dependent on GSK-3ß or PP2A activity, but is associated with AMPK dephosphorylation. We propose that a reduction in AMPK activity is a possible early mechanism responsible for tau dephosphorylation.

Neuronal response in Alzheimer's and Parkinson's disease: the effect of toxic proteins on intracellular pathways.

Accumulation of protein aggregates is the leading cause of cellular dysfunction in neurodegenerative disorders. Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease, Prion disease and motor disorders such as amyotrophic lateral sclerosis, present with a similar pattern of progressive neuronal death, nervous system deterioration and cognitive impairment. The common characteristic is an unusual misfolding of proteins which is believed to cause protein deposition and trigger degenerative signals in the neurons. A similar clinical presentation seen in many neurodegenerative disorders suggests the possibility of shared neuronal responses in different disorders. Despite the difference in core elements of deposits in each neurodegenerative disorder, the cascade of neuronal reactions such as activation of glycogen synthase kinase-3 beta, mitogen-activated protein kinases, cell cycle re-entry and oxidative stress leading to a progressive neurodegeneration are surprisingly similar. This review focuses on protein toxicity in two neurodegenerative diseases, AD and PD. We reviewed the activated mechanisms of neurotoxicity in response to misfolded beta-amyloid and α-synuclein, two major toxic proteins in AD and PD, leading to neuronal apoptosis. The interaction between the proteins in producing an overlapping pathological pattern will be also discussed.

Basic and advanced cardiac life support--what's new?

BACKGROUND: Australian Resuscitation Council guidelines on basic and advanced life support are amended periodically. These changes are informed by recent evidence on best practice in resuscitation medicine. In December 2010, the latest guidelines were released for implementation in 2011. OBJECTIVE: This article outlines the key messages from the latest Australian Resuscitation Council guidelines on basic and advanced life support. DISCUSSION: The latest Australian Resuscitation Council guidelines on basic and advanced life support emphasise the importance of early recognition of deterioration before cardiac arrest. Once resuscitation commences, there is a focus on early defibrillation and early chest compressions with a simplification of drug treatment. Postresuscitation phase changes emphasise early intervention to re-establish coronary artery patency and therapeutic hypothermia.

Emergency management of acute cardiac arrhythmias.

BACKGROUND: Anything other than normal sinus rhythm can be classified as an arrhythmia. However not all arrhythmias need acute intervention. OBJECTIVE: This article reviews which arrhythmias need intervention in an acute setting, and the various options available for intervention. DISCUSSION: The impact of an arrhythmia upon perfusion determines what intervention should be considered. Conscious level, cardiac ischaemia secondary to poor perfusion of the coronary arteries and blood pressure need to be assessed. Patients with bradycardias with adequate perfusion are treated initially with oxygen and observation. Sinus bradycardia not responding to increased oxygenation is treated with atropine. For other bradycardias the two alternatives are to drive the inherent rate with a sympathomimetic drug or to pace the patient with an external or internal pacer. Usually supraventricular tachycardias are not life threatening. Unconscious patients with wide complex tachycardia should be treated in a standard cardiac arrest approach. Conscious patients in ventricular fibrillation however, can be treated either chemically or with synchronised cardioversion. If a patient is in cardiac arrest the approach is to establish effective resuscitation and early defibrillation as per Australian Resuscitation Council guidelines.

The impact of tau hyperphosphorylation at Ser262 on memory and learning after global brain ischaemia in a rat model of reversible cardiac arrest.

An increase in phosphorylated tau (p-tau) is associated with Alzheimer's disease (AD), and brain hypoxia. Investigation of the association of residue-specific tau hyperphosphorylation and changes in cognition, leads to greater understanding of its potential role in the pathology of memory impairment. The aims of this study are to investigate the involvement of the main metabolic kinases, Liver Kinase B1 (LKB1) and Adenosine Monophosphate Kinase Protein Kinase (AMPK), in tau phosphorylation-derived memory impairment, and to study the potential contribution of the other tau kinases and phosphatases including Glycogen Synthase Kinase (GSK-3ß), Protein kinase A (PKA) and Protein Phosphatase 2A (PP2A). Spatial memory and learning were tested in a rat global brain ischemic model of reversible cardiac arrest (CA). The phosphorylation levels of LKB1, AMPK, GSK-3ß, PP2A, PKA and tau-specific phosphorylation were assessed in rats, subjected to ischaemia/reperfusion and in clinically diagnosed AD and normal human brains. LKB1 and AMPK phosphorylation increased 4 weeks after CA as did AMPK related p-tau (Ser262). The animals showed unchanged levels of GSK-3ß specific p-tau (Ser202/Thr205), phospho-PP2A (Tyr307), total GSK-3ß, PP2A, phospho-cAMP response element-binding protein (CREB) which is an indicator of PKA activity, and no memory deficits. AD brains had hyperphosphorylated tau in all the residues of Ser262, Ser202 and Thr205, with increased phosphorylation of both AMPK (Thr172) and GSK-3ß (Ser9), and reduced PP2A levels. Our data suggests a crucial role for a combined activation of tau kinases and phosphatases in adversely affecting memory and that hyperphosphorylation of tau in more than one specific site may be required to create memory deficits.

Team Echo: observations and lessons learned in the recovery phase of the 2004 Asian tsunami.

The 26 December 2004 Tsunami resulted in a death toll of >270,000 persons, making it the most lethal tsunami in recorded history. This article presents performance data observations and the lessons learned by a civilian team dispatched by the Australian government to "provide clinical and surgical functions and to make public health assessments". The team, prepared and equipped for deployment four days after the event, arrived at its destination 13 days after the Tsunami. Aspiration pneumonia, tetanus, and extensive soft tissue wounds of the lower extremities were the prominent injuries encountered. Surgical techniques had to be adapted to work in the austere environment. The lessons learned included: (1) the importance of team member selection; (2) strategies for self-sufficiency; (3) personnel readiness and health considerations; (4) face-to-face handover; (5) coordination and liaison; (6) the characteristics of injuries; (7) the importance of protocols for patient discharge and hospital staffing; and (8) requirements for interpreter services. Whereas disaster medical relief teams will be required in the future, the composition and equipment needs will differ according to the nature of the disaster. National teams should be on standby for international response.

Team Echo: Observations and Lessons Learned in the Recovery Phase of the 2004 Asian Tsunami.

The 26 December 2004 Tsunami resulted in a death toll of >270,000 persons, making it the most lethal tsunami in recorded history. This article presents performance data observations and the lessons learned by a civilian team dispatched by the Australian government to "provide clinical and surgical functions and to make public health assessments". The team, prepared and equipped for deployment four days after the event, arrived at its destination 13 days after the Tsunami. Aspiration pneumonia, tetanus, and extensive soft tissue wounds of the lower extremities were the prominent injuries encountered. Surgical techniques had to be adapted to work in the austere environment. The lessons learned included: (1) the importance of team member selection; (2) strategies for self-sufficiency; (3) personnel readiness and health considerations; (4) race-to-face handover; (5) coordination and liaison; (6) the characteristics of injuries; (7) the importance of protocols for patient discharge and hospital staffing; and (8) requirements for interpreter services. Whereas disaster medical relief teams will be required in the future, the composition and equipment needs will differ according to the nature of the disaster. National teams should be on standby for international response.