Purinergic signalling in brain ischemia

Pedata, Felicita; Dettori, Ilaria; Coppi, Elisabetta; Melani, Alessia; Fusco, Irene; Corradetti, Renato; Pugliese, Anna Maria

doi:10.1016/j.neuropharm.2015.11.007

Cited by 144 publications

(134 citation statements)

References 448 publications

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“…Adenosine, however, is not a practical adjunct to brain slice incubation solutions given its profound actions on the CNS through its four receptors, some of which provided the neuroprotection described above [26,27]. In the context of brain slice electrophysiology these actions include: adenosine-mediated internalisation of the inhibitory adenosine A 1 and A 3 receptors, but not the excitatory A 2A receptor, inhibition of neurotransmitter release, in particular of glutamate, and endocytosis of glutamate AMPA receptors [28][29][30][31][32].…”

Section: Basis For Atp Depletionmentioning

confidence: 99%

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Frenguelli

2017

Neurochem Res

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Brain slices have been the workhorse for many neuroscience labs since the pioneering work of Henry McIlwain in the 1950s. Their utility is undisputed and their acceptance as appropriate models for the central nervous system is widespread, if not universal. However, the skeleton in the closet is that ATP levels in brain slices are lower than those found in vivo, which may have important implications for cellular physiology and plasticity. Far from this being a disadvantage, the ATP-impoverished slice can serve as a useful and experimentally-tractable surrogate for the injured brain, which experiences similar depletion of cellular ATP. We have shown that the restoration of cellular ATP in brain slices to in vivo values is possible with a simple combination of d-ribose and adenine (RibAde), two substrates for ATP synthesis. Restoration of ATP in slices to physiological levels has implications for synaptic transmission and plasticity, whilst in the injured brain in vivo RibAde shows encouraging positive results. Given that ribose, adenine, and a third compound, allopurinol, are all separately in use in man, their combined application after acute brain injury, in accelerating ATP synthesis and increasing the reservoir of the neuroprotective metabolite, adenosine, may help reduce the morbidity associated with stroke and traumatic brain injury.

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Section: Basis For Atp Depletionmentioning

confidence: 99%

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Frenguelli

2017

Neurochem Res

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“…The role for adenosine in the CNS is ambiguous. Adenosine is very important for the circadian rhythm and for neuroprotective effects when bound to the adenosine A 1 receptor (28). Concomitantly, the impaired neurotransmitter release by adenosine A 1 receptor signaling blocks memory formation (29).…”

Section: Discussionmentioning

confidence: 99%

Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

Dennissen

Anglada-Huguet

Sydow

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Accumulation of Tau is a characteristic hallmark of several neurodegenerative diseases but the mode of toxic action of Tau is poorly understood. Here, we show that the Tau protein is toxic due to its aggregation propensity, whereas phosphorylation and/or missorting is not sufficient to cause neuronal dysfunction. Aggregate-prone Tau accumulates, when expressed in vitro at near-endogenous levels, in axons as spindle-shaped grains. These axonal grains contain Tau that is folded in a pathological (MC-1) conformation. Proaggregant Tau induces a reduction of neuronal ATP, concomitant with loss of dendritic spines. Counterintuitively, axonal grains of Tau are not targeted for degradation and do not induce a molecular stress response. Proaggregant Tau causes neuronal and astrocytic hypoactivity and presynaptic dysfunction instead. Here, we show that the adenosine A 1 receptor antagonist rolofylline (KW-3902) is alleviating the presynaptic dysfunction and restores neuronal activity as well as dendritic spine levels in vitro. Oral administration of rolofylline for 2-wk to 14-mo-old proaggregant Tau transgenic mice restores the spatial memory deficits and normalizes the basic synaptic transmission. These findings make rolofylline an interesting candidate to combat the hypometabolism and neuronal dysfunction associated with Tau-induced neurodegenerative diseases.tauopathies | rolofylline | hypoactivity | axons | treatment

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“…Although microglial cells are involved in vital tasks for the survival of neurons [16] , the functions of microglia have also been implicated in a range of neurodegenerative disorders [17,18] . Microglia could be activated into the classic activated state (M1) or the alternative activated state (M2), the former being cytotoxic, the latter being neurotrophic [19] .…”

mentioning

confidence: 99%

Rosmarinic Acid Attenuates the Activation of Murine Microglial N9 Cells through the Downregulation of Inflammatory Cytokines and Cleaved Caspase-3

Coelho

Viau²,

Staub³

et al. 2017

Neuroimmunomodulation

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Objective: The present study evaluated the ability of rosmarinic acid (RA) to inhibit microglia activation induced by lipopolysaccharide (LPS) in the N9 murine microglial cell line, and investigated the putative mechanisms involved in this process. Methods: In all tests, N9 murine microglial cells were pretreated with RA (0.1, 1.0, and 10 μM) for 20 h and exposed to LPS (1 μM/mL) for 4 h. Cell viability was measured by Trypan blue exclusion assay. Flow cytometry was used to detect reactive oxygen species (ROS), quantify cleaved caspase-3, and analyze the mitochondrial electrochemical potential. iNOS, Arg-1, TNF-α, IL-1β, and IL-6 proteins were analyzed by Western blotting, and their antigens were detected using the chemiluminescence technique. The effect of RA on DNA was evaluated by the Comet assay. Results: RA attenuated the expression of the M1 marker iNOS and the levels of proinflammatory factors, including TNF-α, IL-1β, and IL-6; it increased the expression of the M2 marker Arg-1, and inhibited, at least in part, ROS generation and loss of mitochondrial outer membrane permeabilization through the inhibition of cleaved caspase-3 activation. RA also inhibited DNA damage, reassuring cell protection. Conclusions: The results suggested a protective effect of RA through downregulation of inflammatory cytokines and cleaved caspase-3.

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Purinergic signalling in brain ischemia

Cited by 144 publications

References 448 publications

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

Rosmarinic Acid Attenuates the Activation of Murine Microglial N9 Cells through the Downregulation of Inflammatory Cytokines and Cleaved Caspase-3

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Purinergic signalling in brain ischemia

Cited by 144 publications

References 448 publications

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

The Purine Salvage Pathway and the Restoration of Cerebral ATP: Implications for Brain Slice Physiology and Brain Injury

Adenosine A 1 receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280

Rosmarinic Acid Attenuates the Activation of Murine Microglial N9 Cells through the Downregulation of Inflammatory Cytokines and Cleaved Caspase-3

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Adenosine A ₁ receptor antagonist rolofylline alleviates axonopathy caused by human Tau ΔK280