Parp mutations protect against mitochondrial dysfunction and neurodegeneration in a PARKIN model of Parkinson's disease.

The co-enzyme nicotinamide adenine dinucleotide (NAD(+)) is an essential co-factor for cellular energy generation in mitochondria as well as for DNA repair mechanisms in the cell nucleus involving NAD(+)-consuming poly (ADP-ribose) polymerases (PARPs). Mitochondrial function is compromised in animal models of Parkinson's disease (PD) associated with PARKIN mutations. Here, we uncovered alterations in NAD(+) salvage metabolism in Drosophila parkin mutants. We show that a dietary supplementation with the NAD(+) precursor nicotinamide rescues mitochondrial function and is neuroprotective. Further, by mutating Parp in parkin mutants, we show that this increases levels of NAD(+) and its salvage metabolites. This also rescues mitochondrial function and suppresses dopaminergic neurodegeneration. We conclude that strategies to enhance NAD(+) levels by administration of dietary precursors or the inhibition of NAD(+)-dependent enzymes, such as PARP, that compete with mitochondria for NAD(+) could be used to delay neuronal death associated with mitochondrial dysfunction.

Metabolic parameters in rats receiving different levels of oral glycerol supplementation.

The use of glycerol in the diets for animals is of interest because it is a residue of biodiesel production and rich in energy. Thus, this study aimed to evaluate metabolic and physiological parameters of rats receiving supplemental pure glycerol by gavage. We used 30 Wistar rats (initial weight 202.7 ± 29.98 g) receiving 0 (control/saline), 200, 400, 800 and 1600 mg glycerol/kg of body weight (bidistilled glycerine, 99.85% glycerol) beside food and water ad libitum for 28 days. We used a completely randomised design with five treatments and six replicates. At the end of the experiment, the animals were killed, and the results showed that there was no change (p > 0.05) in the intake and excretion of water, the average daily weight gain, dry matter, ash and crude protein in the carcass or plasma triacylglycerols. There was a beneficial effect (p < 0.05) up to a dose of 800 mg/kg glycerol on feed intake, percentage of carcass fat, plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), high-density lipoprotein (HDLc) and low-/very low-density lipoprotein (LDLc + VLDLc). The levels of total cholesterol and glucose were increased with up to a dose of 800 mg/kg glycerol (but remained within the normal range); they were reduced with the dose of 1600 mg/kg. The total leucocyte count tended to be reduced, although it was within the reference values for rats. There were no renal or pancreatic lesions. In conclusion, glycerol presented as a safe supplement at the studied doses, even having some beneficial effects in a dose-dependent manner in rats.

Increased body temperature, cortisol secretion, and hypothalamic expression of c-fos, corticotrophin releasing hormone and interleukin-1 beta mRNAs, following central administration of interleukin-1 beta in the sheep.

There is evidence to indicate that cytokines of the interleukin series act within the brain to influence physiological responses to pathological states or stressful events. This investigation examined the effects of intracerebroventricular (lateral ventricle) injection of human recombinant interleukin-1 beta (IL-1 beta) on body temperature, hormone (catecholamine, cortisol, prolactin, growth hormone) release and hypothalamic expression of c-fos, corticotrophin-releasing hormone (CRH), vasopressin (AVP) and IL-1 beta mRNAs in the sheep. A preliminary study showed that central administration of 10 micrograms IL-1 beta significantly (P < 0.05) increased body temperature (by 1.2 degrees C) over a 140 min period but did not affect catecholamine secretion. A second experiment using graded doses (100 ng, 1 microgram, 10 micrograms) of IL-1 beta indicated that only the highest dose significantly (P < 0.01) increased cortisol concentrations and that none of the treatments altered the secretion of prolactin or growth hormone. In a third study, changes in gene expression in the hypothalamus were examined using in situ hybridization histochemistry following treatment with 10 micrograms IL-1 beta. The results showed that IL-1 beta increased c-fos mRNA in the paraventricular (PVN, P < 0.05) and supraoptic (SON, P < 0.05) nuclei, CRH mRNA in the PVN (P < 0.01) and IL-1 beta mRNA in the PVN (P < 0.05). There was, however, no change in AVP mRNA in either the PVN or the SON.