Carnitine depletion in rat pups from mothers given mildronate: a model of carnitine deficiency in late fetal and neonatal life.
Mildronate (3-(2,2,2,-trimethylhydrazinium)propionate), is a butyrobetaine analogue that is known to inhibit gamma-butyrobetaine hydroxylase, the enzyme catalyzing the last step of carnitine biosynthesis. When administered to adult rats it determines a systemic carnitine deficiency and may therefore serve as an animal model for human carnitine depletion. The aim of this study was to evaluate the effect of mildronate administration to pregnant and lactating rats on tissue carnitine concentrations in 4- and 13-day-old rat pups. At 14 days of gestation female rats began to receive mildronate in the diet (200 mg/kg/d) and this continued for entire lactation period. Mildronate treatment determined a large reduction of carnitine levels in the milk of lactating dams. Because organ carnitine concentrations in neonatal rats are directly related to dietary supply, pups from mildronate group had significantly depleted levels of total carnitine in serum, heart, liver, muscle, brain and pancreas relative to controls, at 4 and 13 days of age. Correspondingly, an increase in triglyceride levels was observed in liver, heart and muscle of mildronate pups. This is in agreement with a reduction of basal rate of oxidation of [U-(14)C]-palmitate to (14)CO(2) and (14)C-acid-soluble products observed in liver homogenates from carnitine-deficient pups. All functional and biochemical modifications were compatible with a carnitine deficiency status. In conclusion our results describe a model of carnitine depletion in pups, suitable for the investigation of carnitine deficiency in fetal-neonatal nutrition, without any concomitant mildronate-mediated metabolic alterations.
Department of Endocrinology and Metabolism Sigma-Tau Pharmaceuticals Industries, Via Pontina Km 30,400 Pomezia, Rome, Italy.
Alessandro
A
Peschechera
Maurizio
M
Scalibastri
Francesco
F
Russo
Mauro Giorgio
MG
Giarrizzo
Paolo
P
Carminati
Fabio
F
Giannessi
Arduino
A
Arduini
Rita
R
Ricciolini
D000818:Animals; D000831:Animals, Newborn; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002331:Carnitine / Q000172:deficiency* / Q000378:metabolism; D005260:Female; D006321:Heart / Q000502:physiology; D007774:Lactation; D008099:Liver / Q000378:metabolism; D008763:Methylhydrazines / Q000494:pharmacology*; D008892:Milk / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D010168:Palmitates / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D014280:Triglycerides / Q000378:metabolism
D002317:Cardiovascular Agents; D008763:Methylhydrazines; D010168:Palmitates; D014280:Triglycerides; C050147:3-(2,2,2-trimethylhydrazine)propionate; D002331:Carnitine