Browsing by Author "Olivares, Belen"
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Item Aspirin and N‐acetylcysteine co‐administration markedly inhibit chronic ethanol intake and block relapse binge drinking: Role of neuroinflammation‐oxidative stress self‐perpetuation(2020) Israel, Yedy; Quintanilla, María Elena; Ezquer, Fernando; Morales, Paola; Santapau, Daniela; Berríos-Cárcamo, Pablo; Ezquer, Marcelo; Olivares, Belen; Herrera-Marschitz, MarioChronic alcohol intake leads to neuroinflammation and cell injury, proposed to result in alterations that perpetuate alcohol intake and cued-relapse. Studies show that brain oxidative stress is consistently associated with alcohol-induced neuroinflammation, and literature implies that oxidative stress and neuroinflammation perpetuate each other. In line with a self-perpetuating mechanism, it is hypothesized that inhibition of either oxidative stress or neuroinflammation could reduce chronic alcohol intake and relapse. The present study conducted on alcohol-preferring rats shows that chronic ethanol intake was inhibited by 50-55% by the oral administration of low doses of either the antioxidant N-acetyl cysteine (40 mg/kg/day) or the anti-inflammatory aspirin (ASA; 15 mg/kg/day), while the co-administration of both dugs led to a 70-75% (p<0.001) inhibition of chronic alcohol ntake. Following chronic alcohol intake, a prolonged alcohol deprivation and subsequent alcohol reaccess, relapse-drinking resulted in blood-alcohol levels of 95-100 mg/dl in 60 minutes which were reduced by 60% by either N-acetyl cysteine or aspirin, and by 85% by the co-administration of both drugs (blood-alcohol: 10-15 mg/dl; p<0.001). Alcohol intake either on the chronic phase or following deprivation and re-access led to a 50% reduction of cortical glutamate transporter GLT-1 levels, while aspirin administration fully returned GLT-1 to normal levels. N-acetyl cysteine administration did not alter GLT-1 levels, while N-acetyl cysteine may activate the cystine/glutamate transport xCT, presynaptically inhibiting relapse. Overall, the study suggests that a neuroinflammation/oxidative stress self-perpetuation cycle maintains chronic alcohol intake and relapse drinking. The coadministration of anti-inflammatory and antioxidant agents may have translational value in alcoholuse-disorders.Item N-Acetylcysteine and Acetylsalicylic Acid Inhibit Alcohol Consumption by Different Mechanisms: Combined Protection(2020-07) Quintanilla, María Elena; Ezquer, Fernando; Morales, Paola; Ezquer, Marcelo; Olivares, Belen; Santapau, Daniela; Herrera-Marschitz, Mario; Israel, YedyChronic ethanol intake results in brain oxidative stress and neuroinflammation, which have been postulated to perpetuate alcohol intake and to induce alcohol relapse. The present study assessed the mechanisms involved in the inhibition of: (i) oxidative stress; (ii) neuroinflammation; and (iii) ethanol intake that follow the administration of the antioxidant N-acetylcysteine (NAC) and the anti-inflammatory acetylsalicylic acid (ASA) to animals that had consumed ethanol chronically. At doses used clinically, NAC [40 mg/kg per day orally (p.o.)] and ASA (15 mg/kg per day p.o.) significantly inhibited chronic alcohol intake and relapse intake in alcohol-preferring rats. The coadministration of both drugs reduced ethanol intake by 65% to 70%. N-acetylcysteine administration: (a) induced the Nrf2-ARE system, lowering the hippocampal oxidative stress assessed as the ratio of oxidized glutathione (GSSG)/reduced glutathione (GSH); (b) reduced the neuroinflammation assessed by astrocyte and microglial activation by immunofluorescence; and (c) inhibited chronic and relapse ethanol intake. These effects were blocked by sulfasalazine, an inhibitor of the xCT transporter, which incorporates cystine (precursor of GSH) and extrudes extracellular glutamate, an agonist of the inhibitory mGlu2/3 receptor, which lowers the synaptic glutamatergic tone. The inhibitor of mGlu2/3 receptor (LY341495) blocked the NAC-induced inhibition of both relapse ethanol intake and neuroinflammation without affecting the GSSG/GSH ratio. Unlike N-acetylcysteine, ASA inhibited chronic alcohol intake and relapse via lipoxin A4, a strong anti-inflammatory metabolite of arachidonic acid generated following the ASA acetylation of cyclooxygenases. Accordingly, the lipoxin A4 receptor inhibitor, WRW4, blocked the ASA-induced reduction of ethanol intake. Overall, via different mechanisms, NAC and ASA administered in clinically relevant doses combine their effects inhibiting ethanol intake.Item Preconditioning of adipose tissue-derived mesenchymal stem cells with deferoxamine increases the production of pro-angiogenic, neuroprotective and anti-inflammatory factors: Potential application in the treatment of diabetic neuropathy(PLoS, 2017) Oses, Carolina; Olivares, Belen; Ezquer, Marcelo; Acosta, Cristian; Bosch, Paul; Donoso, Macarena; Leniz, Patricio; Ezquer, FernandoDiabetic neuropathy (DN) is one of the most frequent and troublesome complications of diabetes mellitus. Evidence from diabetic animal models and diabetic patients suggests that reduced availability of neuroprotective and pro-angiogenic factors in the nerves in combination with a chronic pro-inflammatory microenvironment and high level of oxidative stress, contribute to the pathogenesis of DN. Mesenchymal stem cells (MSCs) are of great interest as therapeutic agents for regenerative purposes, since they can secrete a broad range of cytoprotective and anti-inflammatory factors. Therefore, the use of the MSC secretome may represent a promising approach for DN treatment. Recent data indicate that the paracrine potential of MSCs could be boosted by preconditioning these cells with an environmental or pharmacological stimulus, enhancing their therapeutic efficacy. In the present study, we observed that the preconditioning of human adipose tissue-derived MSCs (AD-MSCs) with 150μM or 400μM of the iron chelator deferoxamine (DFX) for 48 hours, increased the abundance of the hypoxia inducible factor 1 alpha (HIF-1α) in a concentration dependent manner, without affecting MSC morphology and survival. Activation of HIF-1α led to the up-regulation of the mRNA levels of pro-angiogenic factors like vascular endothelial growth factor alpha and angiopoietin 1. Furthermore this preconditioning increased the expression of potent neuroprotective factors, including nerve growth factor, glial cell-derived neurotrophic factor and neurotrophin-3, and cytokines with anti-inflammatory activity like IL4 and IL5. Additionally, we observed that these molecules, which could also be used as therapeutics, were also increased in the secretome of MSCs preconditioned with DFX compared to the secretome obtained from non-preconditioned cells. Moreover, DFX preconditioning significantly increased the total antioxidant capacity of the MSC secretome and they showed neuroprotective effects when evaluated in an in vitro model of DN. Altogether, our findings suggest that DFX preconditioning of AD-MSCs improves their therapeutic potential and should be considered as a potential strategy for the generation of new alternatives for DN treatment.