Carnitine and lipoate ameliorates lipofuscin accumulation and monoamine oxidase activity in aged rat heart

In this study we have focused on the levels of lipofuscin, monoamine oxidase and cholesterol phospholipid ratio in the heart muscle of young, middle aged and aged rats. In parallel, we have also investigated the levels of carnitine and lipoic acid during aging. We observed an increase in lipofuscin accumulation and monoamine oxidase activity in both middle aged and aged rats. Levels of both carnitine and lipoic acid decreased along with a decrease in cholesterol phospholipid ratio. These changes were normalized upon cosupplementation of carnitine and lipoic acid. Our results thus reveal that carnitine along with lipoic acid can be used as an effective supplement against free radical induced damage to the cardiac tissue.     

左旋卡尼汀对大鼠睾丸缺血再灌注损伤的防护作用

目的 探讨左旋卡尼汀对大鼠睾丸缺血再灌注后生精功能的影响.方法 30只成年健康雄性SD大鼠随机分为对照组、扭转组和治疗组,每组10只,建立右侧睾丸扭转复位动物模型(720°,2 h).扭转组和治疗组于复位前30 min分别腹腔注射生理盐水和左旋卡尼汀(500 mg/kg).复位后4 +h,每组各处死5只取扭转侧睾丸,分别检测组织丙二醛(MDA)含量和超氧化物歧化酶(SOD)、过氧化氖酶(CAT)、谷胱甘肽过氧化物酶(GPx)活性以及热休克蛋白70(HSP70)的含量.复位后24 h,取每组剩余大鼠的扭转侧睾丸,检测生精细胞凋亡指数(AI)和组织病理学参数.结果 治疗组平均生精细胞AJ和MDA水平明显低于扭转组[AJ(6.87 4±2.47)比(17.13 4±3.56),MDA(160±15)比(199 ±15)nmoL/g],抗氧化酶活性和HSP70含量显著高于扭转组[SOD(1638±153)比(1078 4±158)U/g,CAT(317±28)比(188 ±33)U/g,GPx(667 ±94)比(311±65)U/g,HSP70(0.87±0.13)比(0.25 ±0.04)],组织病理学损害较扭转组轻,差异均有统计学意义(均P<0.05).结论 左旋卡尼汀对睾丸缺血再灌注后的生精能力具有保护作用,其机制可能是通过诱导热休克蛋白表达而实现.     

Identification of 16 new disease-causing mutations in the CPT2 gene resulting in carnitine palmitoyltransferase II deficiency

The exonic regions of the carnitine palmitoyltransferase 2 (CPT2) gene were characterized from 101 patients with defined clinical and biochemical evidence for the adult onset form of CPT II deficiency and in 2 patients detected as newborns with abnormal acylcarnitine profiles. Twenty-seven disease-causing mutations within the CPT2 gene were identified in this cohort, 16 of which were novel. A total of 60 disease-causing mutations have been identified to date in CPT2 and 41 of these are predicted to produce amino acid substitution/deletions. The implications of these mutations are described in light of recent advances in our understanding of the molecular structure of members of the carnitine acyltransferase family.     

Molecular analysis of a presymptomatic case of carnitine palmitoyl transferase І (CPT I) deficiency detected by tandem mass spectrometry newborn screening in Japan

Carnitine palmitoyl transferase ? (CPT ?) deficiency is a rare disorder of long-chain fatty acid oxidation. It is one of the metabolic diseases detectable by tandem mass spectrometry. We report herein a presymptomatic CPT ? deficiency detected in a Japanese female newborn by tandem mass spectrometry newborn screening. A mutation analysis of the CPT1A gene revealed two novel mutations, p.R446X and p.G719D.     

ANNOUNCEMENTS

L-carnitine (25 mM) reduced oxygen uptake immediately by 40% in ejaculated bovine spermatozoa, but not in ejaculated human spermatozoa or in spermatozoa from bovine and rat epididymis. [³H]-L-carnitine was bound five times as much to ejaculated bovine spermatozoa as to bovine spermatozoa from the cauda epididymis and to human ejaculated spermatozoa. This indicates the presence of a factor in the accessory male sex organs which, through changes in the membrane and/or intracellulary, increases the [³H]-L-carnitine binding sites and makes the spermatozoa susceptible to carnitine inhibition.     

Very long-chain fatty acids in Rett syndrome

Rett syndrome (RS), found exclusively in girls, is characterised by a global deceleration of psychomotor development, loss of acquired speech, loss of manual skills and subsequent deceleration of head growth. The cause of this syndrome is so far unknown. To date there are no biological markers for RS; clinical diagnostic criteria were proposed by the Rett Syndrome Diagnostic Criteria Work Group 1988. The first objective of this study was to assay the levels of very long-chain fatty acids (VLCFA), i.e. C22:0, C24:0, C26:0, by gas chromatography in sera of 30 girls with RS. The VLCFA levels in the studied group were lower than the reference range for healthy children and control group. VLCFA levels were again measured after 2 months of l-carnitine administration in the same groups. VLCFA levels had increased. It is possible that the low VLCFA levels have some relation to the lowered carnitine levels. It may be that low carnitine levels impede transportation to mitochondria, thus the oxidation of long-chain fatty acids is inhibited, and compensated to a certain extent by intensified β-oxidation of VLCFA in the peroxisomal system. Raising carnitine levels could improve substrate delivery for mitochondrial β-oxidation of long-chain fatty acids, thus reducing the use of VLCFA as substrates for β-oxidation. We consider VLCFA to be secondary to the pathogenesis of RS, but the possible abnormalities in their levels may provide an insight into the development of this disease. Conclusion Very long-chain fatty acid and carnitine levels are decreased in Rett syndrome l-Carnitine administration increased very long-chain fatty acid levels in serum. Received: 8 April 1998 / Accepted in revised form: 2 September 1998     

The use of levo-carnitine in children with renal disease: a review and a call for future studies

Carnitine is an amino acid derivative that has a key role in the regulation of fatty acid metabolism and ATP formation. Carnitine deficiency has been described in various conditions, including chronic kidney disease (CKD) and end stage renal disease (ESRD). The deficiency of this micronutrient is postulated to lead to adverse effects across multiple organ systems. There is a paucity of information on carnitine deficiency and its effects in the pediatric CKD and ESRD populations. Currently, there is no evidence supporting the routine use of carnitine supplementation in children with ESRD. In this article, we review the pathophysiology, pharmacokinetics and the potential effects of levo-carnitine supplementation with a focus on the pediatric CKD and ESRD populations. Finally, potential future directions of research are discussed.     

左-卡尼汀对心内直视手术患者心肌酶CK、CK-MB的影响

目的:探讨左-卡尼汀对体外循环(CPB)下行先天性心脏病(CHD)心内矫治术患者CK、CK-MB的影响。方法:选择CPB下行心内直视手术的CHD患者40例,随机分为实验组及对照组,每组各20例。实验组在术中于ST.Thomas号冷晶体停跳液中加入左-卡尼汀(6g/L)行冠状动脉顺行灌注;对照组则使用ST.Thomas号冷晶体停跳液。两组其他处理相同。分别于术前、主动脉阻断10min、主动脉开放后0h、1h、2h、6h及24h采取静脉血,测定血清肌酸激酶(CK)及其同功酶(CK-MB)水平。结果:两组CK、CK-MB水平于主动脉开放后显著升高,但实验组CK水平在主动脉开放后2h及6h显著低于对照组(P<0.05),实验组CK-MB水平于主动脉开放后1h、2h及6h显著低于对照组(P<0.05)。结论:在心内直视手术中,左-卡尼汀作为心脏停跳液的成分,对心肌具有较好的保护作用。     

Carnitine prevents NMDA receptor-mediated activation of MAP-kinase and phosphorylation of microtubule-associated protein 2 in cerebellar neurons in culture

Activation of N-methyl-D-aspartate (NMDA) receptors leads to increased phosphorylation of the microtubule-associated protein MAP-2 by a mechanism that involves activation of nitric oxide synthase and nitric oxide-induced activation of mitogen-activated protein kinase (MAP-kinase). We have assessed the effects of carnitine on this signal transduction pathway in primary cultures of rat cerebellar neurons. We show that carnitine inhibits NMDA-induced phosphorylation of MAP-2 and that this is due to decreased activation of MAP-kinase. This effect is not due to inhibition by carnitine of NMDA-induced activation of nitric oxide synthase or to quenching of the nitric oxide formed, which are not affected by carnitine. Carnitine also inhibits the increase in phosphorylation of MAP-2 induced by the nitric oxide-generating agent S-nitroso-N-acetylpenicillamine, but not nitric oxide-induced activation of soluble guanylate cyclase. These results indicate that carnitine interferes with NMDA-induced, nitric oxide mediated activation of MAP-kinase at a step subsequent to nitric oxide formation.     

Prevention of Ammonia and Glutamate Neurotoxicity by Carnitine: Molecular Mechanisms

Carnitine has beneficial effects in different pathologies and prevents acute ammonia toxicity (ammonia-induced death of animals). Acute ammonia toxicity is mediated by excessive activation of the NMDA-type of glutamate receptors, which mediates glutamate neurotoxicity. We showed that carnitine prevents glutamate neurotoxicity in primary cultures of cerebellar neurons. This supports the idea that the protective effect of carnitine against ammonia toxicity is due to the protective effect against glutamate neurotoxicity. We are studying the mechanism by which carnitine protects against glutamate neurotoxicity. Carnitine increases the binding affinity of glutamate for metabotropic glutamate receptors. The protective effect of carnitine is lost if metabotropic glutamate receptors are blocked with specific antagonists. Moreover, activation of metabotropic glutamate receptors by specific agonists also prevents glutamate neurotoxicity. This indicates that the protective effect of carnitine against glutamate neurotoxicity is mediated by activation of metabotropic glutamate receptors. The molecule of carnitine has a trimethylamine group. Different compounds containing a trimethylamine group (carbachol, betaine, etc.) also prevent ammonia-induced animal death and glutamate-induced neuronal death. Moreover, metabotropic glutamate receptor antagonists also prevent the protective effect of most of these compounds. We summarize here some studies aimed to identify the mechanism and the molecular target that are responsible for the protective effect of carnitine against ammonia and glutamate neurotoxicity. Finally it is also shown that carnitine inhibits the hydrolysis of inositol phospholipids induced by activation of different types of metabotropic receptors, but this effect seems not responsible for its protective effects.