RESUMO

Lead (Pb) and ethanol (EtOH) are neurotoxicants that affect the dopaminergic (DAergic) system. We first sought to assess the morphology of the DAergic neurons in the Caenorhabditis elegans BY200 strain. The results demonstrated dose-dependent damage in these neurons induced by developmental Pb exposure. Secondly, transgenic worms exposed to 24 µM Pb and administered with 200 mM EtOH were evaluated in the basal slowing response (BSR). Pb induced impairment in the BSR in the wild-type strain that did not improve in response to EtOH, an effect also observed in strains that lack the DOP-1, DOP-2, and DOP-3 receptors. The animals that overexpress tyrosine hydroxylase (TH), or lack the vesicular transport (VMAT) showed a Pb-induced impairment in the BSR that seemed to improve after EtOH. Interestingly, a dramatic impairment in the BSR was observed in the Pb group in strains lacking the DOP-4 receptor, resembling the response of the TH-deficient strain, an effect that in both cases showed a non-significant reversal by EtOH. These results suggest that the facilitatory effect of EtOH on the impaired BSR observed in Pb-exposed null mutant strains may be the result of a compensatory effect in the altered DAergic synapse present in these animals.

Assuntos

RESUMO

Developmentally-lead (Pb)-exposed rats showed an enhanced vulnerability to the stimulating and motivational effects of ethanol (EtOH). This is accompanied by differential activity of the brain EtOH-metabolizing enzymes catalase (CAT) and mitochondrial aldehyde dehydrogenase (ALDH2). Based on the theory that brain acetaldehyde accumulation is associated with the reinforcing properties of EtOH, this study sought to determine brain CAT and ALDH2 expression in limbic areas of control and Pb-exposed animals after voluntary EtOH intake. Thirty-five-day-old rats perinatally exposed to 220 ppm Pb were offered with water or increasing EtOH solutions (2-10% v/v) during 28 days until postnatal day (PND) 63. Once intake was stable, the animals were administered: 1) saline (SAL; test days 21-24 or 21-28, as corresponds), or 2) a CAT inhibitor: 3-amine 1, 2, 4-triazole (AT; 250 mg/kg intraperitoneally [i.p.], 5 h before the last eight EtOH intake sessions -test days 21-24 and 25-28), or 3) a CAT booster: 3-nitropropionic acid (3NPA; 20 mg/kg subcutaneously [s.c.], 45 min before the last four EtOH intake sessions -test days 25-28). Two additional groups were centrally-administered cyanamide (CY, an ALDH2 inhibitor, 0.3 mg i.c.v. immediately before the last four EtOH sessions, test days 25-28) or its corresponding vehicle (VEH). Lead exposure increased EtOH intake, an effect potentiated in both groups by 3NPA or CY pretreatments and reduced by AT, albeit selectivity in the Pb group. Catalase abundance in limbic areas parallels these observations in the Pb group, showing higher CAT expression in all areas after EtOH consumption respect to the controls, an effect prevented by AT administration. In contrast, ALDH2 expression was reduced in the Pb animals after EtOH intake, with CY potentiating this effect in all brain areas under study. Based on these results and on previous evidences, we suggest that Pb exposure promotes acetaldehyde accumulation in limbic regions, providing some insights into the mechanism of action that underlies the vulnerability to the excessive EtOH consumption reported in these animals.

Assuntos

RESUMO

Lead (Pb) is a developmental neurotoxicant. We have demonstrated that perinatally Pb-exposed rats consume more ethanol than their control counterparts, a response that seems to be mediated by catalase (CAT) and centrally-formed acetaldehyde, ethanol's first metabolite with attributed reinforcing effects in the brain. The present study sought to disrupt ethanol intake (2-10% ethanol v/v) in rats exposed to 220 ppm Pb or filtered water during gestation and lactation. Thus, to block brain CAT expression, a lentiviral vector coding for a shRNA against CAT (LV-antiCAT vector) was microinfused in the posterior ventral tegmental area (pVTA) either at the onset or towards the end of a chronic voluntary ethanol consumption test. At the end of the study, rats were euthanized and pVTA dissected to measure CAT expression by Western blot. The LV-antiCAT vector administration not only reversed, but also prevented the emergence of the elevated ethanol intake reported in the perinatally Pb-exposed animals, changes that were supported by a significant reduction in CAT expression in the pVTA. These results provide further evidence of the crucial role of this enzyme in the reinforcing properties of ethanol and in the impact of the perinatal Pb programming to challenging events later in life.

Assuntos

RESUMO

Growing body of evidence suggests that mitochondrial dysfunctions and resultant oxidative stress are likely responsible for many neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). Aldehyde dehydrogenase (ALDH) superfamily plays a crucial role in several biological processes including development and detoxification pathways in the organism. In particular, ALDH2 is crucial in the oxidative metabolism of toxic aldehydes in the brain, such as catecholaminergic metabolites (DOPAL and DOPEGAL) and the principal product of lipid peroxidation process 4-HNE. This review aims to deepen the current knowledge regarding to ALDH2 function and its relation with brain-damaging processes that increase the risk to develop neurodegenerative disorders. We focused on relevant literature of what is currently known at molecular and cellular levels in experimental models of these pathologies. The understanding of ALDH2 contributions could be a potential target in new therapeutic approaches for PD and AD due to its crucial role in mitochondrial normal function maintenance that protects against neurotoxicity.

Assuntos

RESUMO

The flavonoids effect on gentamicin (GEN)-induced oxidative stress (OS) in systemic circulation was evaluated in terms of reactive oxygen species (ROS) production, enzymatic antioxidant defenses superoxide dismutase (SOD) and catalase (CAT), and lipid peroxidation (LP) in vitro on human leukocytes and in vivo on rat whole blood. The inhibitory activity of ROS was ATS < QTS < isovitexin < vitexin < luteolin. Luteolin, the most active, showed more inhibition in ROS production than vitamin C (reference inhibitor) in mononuclear cells and a slightly lower protective behavior compared to this inhibitor in polymorphonuclear cells. In both cellular systems, luteolin tends to level SOD and CAT activities modified by GEN, reaching basal values and preventing LP. In Wistar rats, GEN plus luteolin can suppress ROS generation, collaborate with SOD and CAT and diminish LP produced by GEN at therapeutic doses. Finally, luteolin and antibiotic association was evaluated on the antimicrobial activity in S. aureus and E. coli showing a synergism between GEN and luteolin on S. aureus ATCC and an additive effect on E. coli ATCC. Therefore, simultaneous administration of luteolin and GEN could represent a potential therapeutic option capable of protecting the host against OS induced by GEN in the systemic circulation while enhancing the antibacterial activity of GEN.

Assuntos

RESUMO

This review article provides evidence of the impact of the environmental contaminant lead (Pb) on the pattern of the motivational effects of ethanol (EtOH). To find a mechanism that explains this interaction, the focus of this review article is on central EtOH metabolism and the participating enzymes, as key factors in the modulation of brain acetaldehyde (ACD) accumulation and resulting effect on EtOH intake. Catalase (CAT) seems a good candidate for the shared mechanism between Pb and EtOH due to both its antioxidant and its brain EtOH-metabolizing properties. CAT overactivation was reported to increase EtOH consumption, while CAT blockade reduced it, and both scenarios were modified by Pb exposure, probably as the result of elevated brain and blood CAT activity. Likewise, the motivational effects of EtOH were enhanced when brain ACD metabolism was prevented by ALDH2 inhibition, even in the Pb animals that evidenced reduced brain ALDH2 activity after chronic EtOH intake. Overall, these results suggest that brain EtOH metabolizing enzymes are modulated by Pb exposure with resultant central ACD accumulation and a prevalence of the reinforcing effects of the metabolite in brain against the aversive peripheral ACD accumulation. They also support the idea that early exposure to an environmental contaminant, even at low doses, predisposes at a later age to differential reactivity to challenging events, increasing, in this case, vulnerability to acquiring addictive behaviors, including excessive EtOH intake.

RESUMO

Lead (Pb) is a developmental neurotoxicant that elicits differential responses to drugs of abuse. Particularly, ethanol consumption has been demonstrated to be increased as a consequence of environmental Pb exposure, with catalase (CAT) and brain acetaldehyde (ACD, the first metabolite of ethanol) playing a role. The present study sought to interfere with ethanol metabolism by inhibiting ALDH2 (mitochondrial aldehyde dehydrogenase) activity in both liver and brain from control and Pb-exposed rats as a strategy to accumulate ACD, a substance that plays a major role in the drug's reinforcing and/or aversive effects. To evaluate the impact on a 2-h chronic voluntary ethanol intake test, developmentally Pb-exposed and control rats were administered with cyanamide (CY, an ALDH inhibitor) either systemically or intracerebroventricularly (i.c.v.) on the last 4 sessions of the experiment. Furthermore, on the last session and after locomotor activity was assessed, all animals were sacrificed to obtain brain and liver samples for ALDH2 and CAT activity determination. Systemic CY administration reduced the elevated ethanol intake already reported in the Pb-exposed animals (but not in the controls) accompanied by liver (but not brain) ALDH2 inactivation. On the other hand, a 0.3 mg i.c.v. CY administration enhanced both ethanol intake and locomotor activity accompanied by brain ALDH2 inactivation in control animals, while an increase in ethanol consumption was also observed in the Pb-exposed group, although in the absence of brain ALDH2 blockade. No changes were observed in CAT activity as a consequence of CY administration. These results support the participation of liver and brain ACD in ethanol intake and locomotor activity, responses that are modulated by developmental Pb exposure.

Assuntos