Cerebrospinal Fluid Adenosine Concentration and Uncoupling of Cerebral Blood Flow and Oxidative Metabolism after Severe Head Injury in Humans

Clark, Robert S. B.; Carcillo, Joseph A.; Kochanek, Patrick M.; Obrist, Walter D.; Jackson, Edwin K.; Mi, Zichuan; Wisneiwski, Stephen R.; Bell, Michael J.; Marion, Donald W.

doi:10.1097/00006123-199712000-00010

Cited by 83 publications

(50 citation statements)

References 42 publications

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“…Similar adenosine concentrations for substrate inhibition were reported in rodent samples (Yamada et al, 1982;Fisher and Newsholme, 1984). Whereas physiologic adenosine concentrations in the range of 25-300 nM (Lonnroth et al, 1989) are not likely to affect ADK activity, substrate inhibition of ADK by higher concentrations of adenosine might be an important physiologic mechanism to potentiate endogenous adenosine responses under conditions of stress or distress, which can lead to micromolar concentrations of adenosine (Clark et al, 1997;Fredholm, 2007).…”

Section: F Regulation By Metabolitesmentioning

confidence: 54%

“…Remarkably, suppression of respiratory function is a major cause of death following a severe TBI, and high levels of adenosine in the cerebrospinal fluid were associated with acute lethal outcome in human victims of a severe TBI (Clark et al, 1997). Consequently, a combination of an excessive injury-related surge in adenosine, in combination with deficiencies in metabolic clearance of brain stem adenosine by ADK, would constitute a major risk factor for the development of lethal apnea.…”

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confidence: 99%

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Adenosine Kinase: Exploitation for Therapeutic Gain

2013

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Section: F Regulation By Metabolitesmentioning

confidence: 54%

mentioning

confidence: 99%

Adenosine Kinase: Exploitation for Therapeutic Gain

2013

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“…While A 1 and A 2A receptors have important functions under physiological conditions, A 2B and A 3 receptors may be of relevance under pathological conditions. As an example, traumatic brain injury or cerebral ischemia lead to a massive surge in adenosine, elevating ambient levels of adenosine more than tenfold to levels sufficient to activate A 2B and A 3 receptors (Clark et al, 1997;Pearson et al, 2006). Recent findings suggest that the physiological consequences of A 3 receptor activation show dose-dependent effects: While CA1 hippocampal A 3 receptors stimulated by adenosine released during brief ischemia might exert A 1 receptor-like protective effects on neurotransmission, severe ischemia (i.e.…”

Section: Adenosine a 2b And A 3 Receptorsmentioning

confidence: 99%

The adenosine kinase hypothesis of epileptogenesis

Boison

2008

Progress in Neurobiology

208

210

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Current therapies for epilepsy are largely symptomatic and do not affect the underlying mechanisms of disease progression, i.e. epileptogenesis. Given the large percentage of pharmacoresistant chronic epilepsies, novel approaches are needed to understand and modify the underlying pathogenetic mechanisms. Although different types of brain injury (e.g. status epilepticus, traumatic brain injury, stroke) can trigger epileptogenesis, astrogliosis appears to be a homotypic response and hallmark of epilepsy. Indeed, recent findings indicate that epilepsy might be a disease of astrocyte dysfunction. This review focuses on the inhibitory neuromodulator and endogenous anticonvulsant adenosine, which is largely regulated by astrocytes and its key metabolic enzyme adenosine kinase (ADK). Recent findings support the "ADK hypothesis of epileptogenesis": (i) Mouse models of epileptogenesis suggest a sequence of events leading from initial downregulation of ADK and elevation of ambient adenosine as an acute protective response, to changes in astrocytic adenosine receptor expression, to astrocyte proliferation and hypertrophy (i.e. astrogliosis), to consequential overexpression of ADK, reduced adenosine and -finally -to spontaneous focal seizure activity restricted to regions of astrogliotic overexpression of ADK. (ii) Transgenic mice overexpressing ADK display increased sensitivity to brain injury and seizures. (iii) Inhibition of ADK prevents seizures in a mouse model of pharmacoresistant epilepsy. (iv) Intrahippocampal implants of stem cells engineered to lack ADK prevent epileptogenesis. Thus, ADK emerges both as a diagnostic marker to predict, as well as a prime therapeutic target to prevent, epileptogenesis.

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“…Over and above this role for adenosine and adenosine receptors in chronic conditions, adenosine is released in large quantities during many acute insults to the mammalian, but more pertinently human, central nervous system (CNS) such as ischemia [15,16], trauma [17,18] and seizure activity [19]. Under these conditions adenosine is believed to exert an important protective influence.…”

Section: Adenosine In Cns Disease and Injurymentioning

confidence: 99%

Plasticity of purine release during cerebral ischemia: clinical implications?

Pearson

Currie

Etherington

et al. 2003

J Cellular Molecular Medi

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Adenosine is a powerful modulator of neuronal function in the mammalian central nervous system. During a variety of insults to the brain, adenosine is released in large quantities and exerts a neuroprotective influence largely via the A 1 receptor, which inhibits glutamate release and neuronal activity. Using novel enzyme-based adenosine sensors, which allow high spatial and temporal resolution recordings of adenosine release in real time, we have investigated the release of adenosine during hypoxia/ischemia in the in vitro hippocampus. Our data reveal that during the early stages of hypoxia adenosine is likely released per se and not as a precursor such as cAMP or an adenine nucleotide. In addition, repeated hypoxia results in reduced production of extracellular adenosine and this may underlie the increased vulnerability of the mammalian brain to repetitive or secondary hypoxia/ischemia.

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Cerebrospinal Fluid Adenosine Concentration and Uncoupling of Cerebral Blood Flow and Oxidative Metabolism after Severe Head Injury in Humans

Abstract: The association between increased CSF adenosine concentration and a reduction in global cross-brain extraction of oxygen supports a regulatory role for adenosine in the complex balance between CBF and oxidative and nonoxidative metabolism severe head injury in humans.

Cited by 83 publications

References 42 publications

Adenosine Kinase: Exploitation for Therapeutic Gain

Adenosine Kinase: Exploitation for Therapeutic Gain

The adenosine kinase hypothesis of epileptogenesis

Plasticity of purine release during cerebral ischemia: clinical implications?

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