Physiologic and Metabolic Regulation of Adenosine: Mechanisms

Dulla, Chris G.; Masino, Susan A.

doi:10.1007/978-1-4614-3903-5_5

Cited by 10 publications

(11 citation statements)

References 108 publications

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“…Extracellular adenosine concentration drastically increases in response to increased extracellular ATP (Dunwiddie et al, 1997 ). In many physiological states, adenosine serves as a counter-modulator of synaptic firing by hyperpolarizing neurons (Dulla and Masino, 2013 ) inhibiting neurotransmitter release (Boison, 2007 , 2008 ) and thus decreasing cerebral activity (Dulla and Masino, 2013 ). Adenosine also functions as a regulator of sleep and wakefulness in a way that the extracellular concentration of adenosine increases during the waking hours (Huston et al, 1996 ; Porkka-Heiskanen et al, 1997 ).…”

Section: Alternative Mechanisms For Chemotherapy-induced Behavioral Tmentioning

confidence: 99%

Mechanisms of chemotherapy-induced behavioral toxicities

et al. 2015

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While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms) of chemotherapy include (i) cognitive deficiencies such as problems with attention, memory and executive functioning; (ii) fatigue and motivational deficit; and (iii) neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence, neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs) activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.

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Section: Alternative Mechanisms For Chemotherapy-induced Behavioral Tmentioning

confidence: 99%

Mechanisms of chemotherapy-induced behavioral toxicities

et al. 2015

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“…128,196 In mammals, there are two types of nucleoside transporters: bidirectional, equilibrative transporters that are driven by chemical gradients, and unidirectional, concentration transporters that are driven by sodium electrochemical gradients. 197 Adenosine uptake in the brain is mostly facilitated by the equilibrative nucleoside transporters, and when these transporters are blocked pharmacologically, adenosine accumulates in the extracellular space 128,197,198 Of the four equilibrative transporters identified (ENT1, ENT2, ENT3, and ENT4), ENT1 and ENT2 are the ones mostly present in the brain, expressed by both neurons and astrocytes. 197 Studies suggest that because of its dependence on glutamate receptor activation, the ENT1 plays a more prominent role in determining the concentration of extracellular adenosine in the brain.…”

Section: Alterations In Striatal Adenosine Tone In Hdmentioning

confidence: 99%

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

Blum

Chern

Domenici

et al. 2018

Journal of Caffeine and Adenosine Research

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Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the IT15 gene that encodes for the huntingtin protein. Mutated hungtingtin, although widely expressed in the brain, predominantly affects striato-pallidal neurons, particularly enriched with adenosine A 2A receptors (A 2A R), suggesting a possible involvement of adenosine and A 2A R is the pathogenesis of HD. In fact, polymorphic variation in the ADORA2A gene influences the age at onset in HD, and A 2A R dynamics is altered by mutated huntingtin. Basal levels of adenosine and adenosine receptors are involved in many processes critical for neuronal function and homeostasis, including modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions, and the regulation of protein degradation mechanisms. In the present review, we critically analyze the current literature involving the effect of altered adenosine tone and adenosine receptors in HD and discuss why therapeutics that modulate the adenosine system may represent a novel approach for the treatment of HD.Keywords: Huntington's disease, adenosine, adenosine receptors, equilibrative nucleoside transporter, animal models Pathogenic Mechanisms of Huntington's DiseaseOverview H untington's disease (HD) is an inherited neurodegenerative disorder that is caused by a single, autosomal dominant gene mutation. HD generally affects young adults and is characterized by involuntary, abnormal movements and postures (chorea, dyskinesia, dystonia), psychiatric disturbances, and cognitive alterations.1,2 It is estimated that 1 in 10,000 people have HD and this disorder is fatal within 15-20 years after the onset of symptoms. Multiple brain regions, including several cortical and subcortical regions (cerebral cortex, layers III, V, and VI; pallidum, sub-thalamic nucleus, cerebellum), show signs of neurodegeneration, but the most pronounced neuronal loss is present in the caudate nucleus and the putamen of the striatum.3 Within the striatum, the striato-pallidal, medium spiny neurons (MSN) that express enkephalin, dopamine D 2 receptors (D 2 R) and adenosine A 2A receptors (A 2A R), 4,5 appear to be the most vulnerable.6,7

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Section: Adenosine In Neurodegeneration (Table 1)mentioning

confidence: 99%

“…Extracellular adenosine is elevated during neuronal firing as it is co-released with some neurotransmitters [68]. The ability of adenosine to down-regulate brain activity during intense energy demands is thought to be an auto-protective mechanism [68], while diurnal fluctuations in adenosine appear relevant to sleep and wakefulness [5, 6, 56]. Injurious processes are also associated with increased extracellular adenosine in the brain [68], but in these conditions the adenosine concentration is thought to be greater [67, 68, 69] resulting in A2A AR engagement [69].…”

Section: Adenosine In Neurodegeneration (Table 1)mentioning

confidence: 99%

Modulation of neuroimmunity by adenosine and its receptors: Metabolism to mental illness

Chiu

Freund

2014

Metabolism

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Adenosine is a pleiotropic bioactive with potent neuromodulatory properties. Due to its ability to easily cross the blood-brain barrier, it can act as a signaling molecule between the periphery and the brain. It functions through four (A1, A2A, A2B, and A3) cell surface G protein-coupled adenosine receptors (AR) that are expressed in some combination on nearly all cells types within the CNS. By regulating the activity of adenylyl cyclase and changing the intracellular concentration of cAMP, adenosine can alter neuronal function and neurotransmission. A variety of illnesses related to metabolic dysregulation, such as type 1 diabetes and Alzheimer’s disease, are associated with an elevated serum concentration of adenosine and a pathogenesis rooted in inflammation. This review describes the accepted physiologic function of adenosine in neurological disease and explores its new potential as a peripheral to central danger signal that can activate the neuroimmune system and contribute to symptoms of sickness and psychopathologies.

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Physiologic and Metabolic Regulation of Adenosine: Mechanisms

Cited by 10 publications

References 108 publications

Mechanisms of chemotherapy-induced behavioral toxicities

Mechanisms of chemotherapy-induced behavioral toxicities

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

Modulation of neuroimmunity by adenosine and its receptors: Metabolism to mental illness

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