Fenofibrate administration reduces alcohol and Saccharin Intake in rats: possible effects at peripheral and central levels

We have previously shown that the administration of fenofibrate to high-drinker UChB rats markedly reduces voluntary ethanol intake. Fenofibrate is a peroxisome proliferator-activated receptor alpha (PPAR a) agonist, which induces the proliferation of peroxisomes in the liver, leading to increases in catalase levels that result in acetaldehyde accumulation at aversive levels in the blood when animals consume ethanol. In these new studies, we aimed to investigate if the effect of fenofibrate on ethanol intake is produced exclusively in the liver (increasing catalase and systemic levels of acetaldehyde) or there might be additional effects at central level. High drinker rats (UChB) were allowed to voluntary drink 10% ethanol for 2 months. Afterward, a daily dose of fenofibrate (25, 50 or 100 mg/kg/day) or vehicle (as control) was administered orally for 14 days. Voluntary ethanol intake was recorded daily. After that time, animals were deprived of ethanol access for 24 h and administered with an oral dose of ethanol (1 g/kg) for acetaldehyde determination in blood. Fenofibrate reduced ethanol voluntary intake by 60%, in chronically drinking rats, at the three doses tested. Acetaldehyde in the blood rose up to between 80 mu M and 100 mu M. Considering the reduction of ethanol consumption, blood acetaldehyde levels and body weight evolution, the better results were obtained at a dose of 50 mg fenofibrate/kg/day. This dose of fenofibrate also reduced the voluntary intake of 0.2% saccharin by 35% and increased catalase levels 2.5-fold in the liver but showed no effects on catalase levels in the brain. To further study if fenofibrate administration changes the motivational properties of ethanol, a conditioned-place preference experiment was carried out. Animals treated with fenofibrate (50 mg/kg/day) did not develop ethanol-conditioned place preference (CPP). In an additional experiment, chronically ethanol-drinking rats underwent two cycles of ethanol deprivation/reaccess, and fenofibrate (50 mg/kg/day) was given only in deprivation periods; under this paradigm, fenofibrate was also able to generate a prolonged (30 days) decreasing of ethanol consumption, suggesting some effect beyond the acetaldehydegenerated aversion. In summary, reduction of ethanol intake by fenofibrate appears to be a consequence of a combination of catalase induction in the liver and central pharmacological effects.Fondo Nacional de Desarrollo Cientifico y Tecnologico (FONDECYT), 1150850 / 11130241 / Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT), ACT141

Lip-like genes in Phanerochaete sordida and Ceriporiopsis subvermispora, white rot fungi with no detectable lignin peroxidase activity.

Lignin peroxidase-like genes were PCR amplified from Phanerochaete sordida and Ceriporiopsis subvermispora, fungi lacking lignin peroxidase (LiP) activity. Amplification products were highly similar to previously described LiP genes. Using reverse transcription-coupled PCR a LiP-like cDNA clone was amplified from P. sordida RNA. In contrast, no evidence was obtained for transcription of C. subvermispora LiP genes

Cloning and molecular analysis of a cDNA and the Cs-mnpl gene encoding a manganese peroxidase isoenzyme from the lignin-degrading basidiomycete Ceriporiopsis subvermispora

A cDNA (MnP13-1) and the Cs-mnp1 gene encoding for an isoenzyme of manganese peroxidase (MnP) from C. subvermispora were isolated separately and sequenced. The cDNA, identified in a library constructed in the vector Lambda ZIPLOX, contains 1285 nucleotides, excluding the poly(A) tail, and has a 63% G+C content. The deduced protein sequence shows a high degree of identity with MnPs from other fungi. The mature protein contains 364 amino acids, which are preceded by a 24-amino-acid leader sequence. Consistent with the peroxidase mechanism of MnP, the proximal histidine, the distal histidine and the distal arginine are conserved, although the aromatic binding site (L/V/I-P-X-P) is less hydrophilic than those of other peroxidases. A gene coding for the same protein (Cs-mnpl) was isolated from a genomic library constructed in Lambda GEM-11 vector using the cDNA MnP13-1 as a probe. A subcloned SacI fragment of 2.5 kb contained the complete sequence of the Cs-mnpl gene, including 162 bp and

Fenofibrate Decreases Ethanol-Induced Neuroinflammation and Oxidative Stress and Reduces Alcohol Relapse in Rats by a PPAR-α-Dependent Mechanism

High ethanol consumption triggers neuroinflammation, implicated in sustaining chronic alcohol use. This inflammation boosts glutamate, prompting dopamine release in reward centers, driving prolonged drinking and relapse. Fibrate drugs, activating peroxisome proliferator-activated receptor alpha (PPAR-α), counteract neuroinflammation in other contexts, prompting investigation into their impact on ethanol-induced inflammation. Here, we studied, in UChB drinker rats, whether the administration of fenofibrate in the withdrawal stage after chronic ethanol consumption reduces voluntary intake when alcohol is offered again to the animals (relapse-type drinking). Furthermore, we determined if fenofibrate was able to decrease ethanol-induced neuroinflammation and oxidative stress in the brain. Animals treated with fenofibrate decreased alcohol consumption by 80% during post-abstinence relapse. Furthermore, fenofibrate decreased the expression of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukins IL-1β and IL-6, and of an oxidative stress-induced gene (heme oxygenase-1), in the hippocampus, nucleus accumbens, and prefrontal cortex. Animals treated with fenofibrate showed an increase M2-type microglia (with anti-inflammatory proprieties) and a decrease in phagocytic microglia in the hippocampus. A PPAR-α antagonist (GW6471) abrogated the effects of fenofibrate, indicating that they are dependent on PPAR-α activation. These findings highlight the potential of fenofibrate, an FDA-approved dyslipidemia medication, as a supplementary approach to alleviating relapse severity in individuals with alcohol use disorder (AUD) during withdrawal

Gene therapy reduces ethanol intake in an animal model of alcohol dependence

Background: Some gene polymorphisms strongly protect against the development of alcoholism. A large proportion of East Asians carry a protective inactivating mutation in aldehyde dehydrogenase (ALDH2*2). These subjects display high levels of blood acetaldehyde when consuming alcohol, a condition that exerts a 66 to 99% protection against alcohol abuse and alcoholism. Present knowledge allows the incorporation of therapeutic genes that can modify the expression of disease predisposing genes, an effect that can last from months to years. In line with the above, we have tested if inhibiting the expression of the aldehyde dehydrogenase gene (ALDH2) by an anti-Aldh2 antisense gene can curtail the drive of alcohol-dependent animals to consume alcohol. Methods: Wistar-derived rats bred as high alcohol drinkers (UChB; Universidad de Chile Bibulous) were rendered alcohol dependent by a 2-month period of voluntary ethanol (10%) intake, subjected to a 3-day withdrawal period and further allowed