Browsing by Subject "Adenosine"

Now showing 1 - 3 of 3
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    Amplification of inhibitory mechanisms in cerebral ischemia: an alternative approach to neuronal protection
    (Murcia : F. Hernández, 1997) Shuaib, A.; Kanthan, R.
    The central nervous systern consumes 20% of the cardiac output for normal function. The neurons are very sensitive to the effects of ischemia. Cessation of cerebral blood flow results in severe damage to neurons and other brain structures. This is secondary to a combination of energy loss, excessive excitation promoting intracellular calcium (ca2+) buildup, relative lack of inhibitory responses, generation of oxygen free radicals (especially during the reperfusion period) and severa1 other destructive cascades. Medications that antagonize the effects of glutamate at post-synaptic receptors are either ineffective or have serious sideeffects. ca2+ entry blockers have shown disappointing results in clinical trials in patients with acute cerebral infarction. Data with protective effects of oxygen free radical scavengers in the post-ischemic period have shown conflicting results. There is recent interest with the use of agents that increase cerebral inhibitory responses after an ischemic insult. Such agents are effective when used before, during or up to 4 hours after the ischemic insult. Many such rnedications have few side-effects and are in clinical use for other indications. This review will surnmarize inhibitory rnechanisms that may be important in cerebral ischernia, and provide experimental evidence for their potential efficacy.
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    Neuronal A2A receptor exacerbates synapse loss and memory deficits in APP/PS1 mice.
    (2024-08-01) Launay, Agathe; Carvalho, Kévin; Burgard, Anaëlle; Meriaux, Céline; Caillierez, Raphaëlle; Eddarkaoui, Sabiha; Kilinc, Devrim; Siedlecki-Wullich, Dolores; Besegher, Mélanie; Bégard, Séverine; Thiroux, Bryan; Jung, Matthieu; Nebie, Ouada; Wisztorski, Maxence; Déglon, Nicole; Montmasson, Claire; Bemelmans, Alexis-Pierre; Hamdane, Malika; Lebouvier, Thibaud; Vieau, Didier; Fournier, Isabelle; Buee, Luc; Lévi, Sabine; Lopes, Luisa V; Boutillier, Anne-Laurence; Faivre, Emilie; Blum, David; Gómez Murcia, Victoria; Farmacología
    Early pathological upregulation of adenosine A2A receptors (A2ARs), one of the caffeine targets, by neurons is thought to be involved in the development of synaptic and memory deficits in Alzheimer's disease (AD) but mechanisms remain ill-defined. To tackle this question, we promoted a neuronal upregulation of A2AR in the hippocampus of APP/PS1 mice developing AD-like amyloidogenesis. Our findings revealed that the early upregulation of A2AR in the presence of an ongoing amyloid pathology exacerbates memory impairments of APP/PS1 mice. These behavioural changes were not linked to major change in the development of amyloid pathology but rather associated with increased phosphorylated tau at neuritic plaques. Moreover, proteomic and transcriptomic analyses coupled with quantitative immunofluorescence studies indicated that neuronal upregulation of the receptor promoted both neuronal and non-neuronal autonomous alterations, i.e. enhanced neuroinflammatory response but also loss of excitatory synapses and impaired neuronal mitochondrial function, presumably accounting for the detrimental effect on memory. Overall, our results provide compelling evidence that neuronal A2AR dysfunction, as seen in the brain of patients, contributes to amyloid-related pathogenesis and underscores the potential of A2AR as a relevant therapeutic target for mitigating cognitive impairments in this neurodegenerative disorder.
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    Targeting the methionine cycle for melanoma therapy with 3-O-(3,4,5-trimethoxybenzoyl)-(-)-epicatechin
    (WILEY, 2008-11-15) Rodríguez López, José Neptuno; Sánchez del Campo Ferrer, Luis; Bioquímica y Biología Molecular A
    The higher expression of methionine cycle genes in melanoma cells than in normal melanocytes may be related with increased protein synthesis and transmethylation reactions and the subsequent need for high levels of methionine. 3-O-(3,4,5-trimethoxybenzoyl)-(-)epicatechin (TMECG), a trimethoxy derivative of epicatechin-3-gallate (ECG), effectively suppressed proliferation of melanoma cells in cultures by inducing apoptosis. TMECG modulates the expression of genes involved in methionine metabolism, cellular methylation and glutathione synthesis in.,melanoma cells. TMECG treatment of melanoma cells resulted in the downregulation of antiapoptotic Bcl-2, the upregulation of proapoptotic Bax and the activation of caspase-3; however, it did not induce the expression of the apoptosis protease-activating factor-1 (Apaf-1). Having elucidated the effects of TMECG on the melanoma methionine cycle, we designed therapeuthical strategies to increase its effectiveness. Combinations of TMECG with S-adenosylmethionine or compounds that modulate the intracellular concentration of adenosine strongly increase the anti proliferative effects of TMECG. The ability of TMECG to target multiple aspects related with melanoma survival, with a high degree of potency, points to its clinical value in melanoma therapy.