Colocalization of a carnosine-splitting enzyme,tissue carnosinase (CN2)/cytosolic non-specific dipeptidase 2 (CNDP2), with histidine decarboxylase in the tuberomammillary nucleus of the hypothalamus

Carnosine is a naturally occurring dipeptide (β-alanyl-l-histidine) present in mammalian tissues such as the brain and skeletal muscles. Carnosine is not only a radical scavenger but also a possible neurotransmitter-like molecule that regulates neuronal functions such as hypothalamic control of the autonomic nervous system. CN2 (CNDP2) is a cytosolic enzyme that can hydrolyze carnosine to yield l-histidine and β-alanine. In order to understand the functions of carnosine and CN2 in the brain, we have investigated the immunohistochemical localization of CN2 in the hypothalamus. CN2-immunoreactivity was highly concentrated in neuronal cells in the dorsal part of the tuberomammillary nucleus of the posterior hypothalamus. Since the tuberomammillary nucleus is the exclusive origin of histaminergic neurons, we further investigated whether CN2 is present in the histaminergic neurons. We found that CN2-immunoreactivity was colocalized with that of histidine decarboxylase, which is the key enzyme for histamine biosynthesis specifically expressed in the histaminergic neurons of the tuberomammillary nucleus. These results suggest that CN2 is highly expressed in the histaminergic neurons in the tuberomammillary nucleus, implying that it may supply histidine to histaminergic neurons for histamine synthesis.     

Carnosine inhibits pentylenetetrazol-induced seizures by histaminergic mechanisms in histidine decarboxylase knock-out mice

In the present study, we used both histidine decarboxylase-deficient (HDC-KO) mice and wild-type (WT) mice to elucidate the possible role of carnosine in pentylenetetrazol (PTZ)-induced seizures. In the acute PTZ challenge study, PTZ (75 mg/kg) was injected intraperitoneally (i.p.) to induce seizures. Carnosine (200, 500 or 1000 mg/kg, i.p.) significantly decreased seizure stage, and prolonged the latency for myoclonic jerks in WT mice in a dose-dependent manner. The effects of carnosine (500 mg/kg) were time-dependent and reached a peak at 1 h. However, it had no significant effect on HDC-KO mice. Carnosine (500 mg/kg) also significantly elevated the thresholds in WT mice but not HDC-KO mice following intravenous (tail vein) administration of PTZ. We also found that α-fluoromethylhistidine substantially reversed the protective effects of carnosine in WT mice. In addition, carnosine pretreatment reduced the cortical EEG activity induced by PTZ (75 mg/kg, i.p.). These results indicate that carnosine can protect against PTZ-induced seizures and its action is mainly through the carnosine–histidine–histamine metabolic pathway. This suggests that carnosine may be an endogenous anticonvulsant factor in the brain and may be used as a new antiepileptic drug in the future.     

在Phen-Cu-Vc系统中肌肽对DNA损伤的作用

采用TBA法在脱氧核糖水平上研究了肌肽对Phen -CuSO4-Vc系统引起的DNA损伤的作用 ,并对其作用机理作了初步探讨。同时设甘露醇、苯甲酸钠、二甲基亚砜作对照 ,发现肌肽对DNA损伤的保护作用明显优于甘露醇、苯甲酸钠、二甲基亚砜     

肌肽药理活性研究新进展

肌肽是一种内源性二肽,广泛存在于哺乳动物的大脑、肌肉和心脏中,具有广泛的药理活性。肌肽作为具有多种药理活性的内源性二肽,近年来逐渐引起了医药界的重视,经研究证实其是一个药理活性广泛、高效、低毒的化合物,肌肽在治疗内质网应激,金属离子内稳态失衡,阿尔茨海默症,糖尿病及其并发症,肝脏疾病,眼科疾病,肿瘤等显示出良好的药理活性,为肌肽进一步的研究开发提供参考。     

Influence of extremely low frequency magnetic fields on Ca2+ signaling and NMDA receptor functions in rat hippocampus

The nervous tissue of many vertebrates, including humans, can synthesize beta-alanyl-L-histidine (carnosine). The biological functions of carnosine are still open to question, although several theories supported by strong experimental data have been proposed. The objective of this study was to examine the effects of carnosine on neurotoxicity in differentiated rat pheochromocytoma (PC12) cells. Neurotoxicity was induced by N-methyl-D-aspartate (NMDA), which caused time- and concentration-dependent cell death as measured by MTT and LDH assays. Pretreatment with carnosine significantly prevented the neurotoxicity in a concentration-dependent manner. The protective effect of carnosine was antagonized by the H1 receptor antagonist pyrilamine, but not by the H2 receptor antagonist cimetidine. In addition, alpha-fluoromethylhistidine, a histidine decarboxylase inhibitor, slightly reversed the protective action of carnosine. These results indicate that carnosine can effectively protect against NMDA-induced necrosis in PC12 cells, and its protection may in part be due to the activation of the postsynaptic histamine H1 receptor. The study suggests that carnosine may be an endogenous protective factor and calls for its further study as a new anti-excitotoxic agent.     

Effect of carnosine supplementation on lipid profile,fasting blood glucose,HbA1C and insulin resistance: A systematic review and meta-analysis of long-term randomized controlled trials

ObjectiveGlucose disorders and dyslipidemia are closely associated with obesity and metabolic disease. The purpose of this study was to investigate the effect of Carnosine supplementation on lipid profile, fasting blood glucose, HbA1C and Insulin resistance.MethodMEDLINE/PubMed, Scopus and Web of sciences were investigated to identify relevant articles up to June 2019. The search strategy combined the Medical Subject Heading and Title and/or abstract keywords. The combined effect sizes were calculated as weight mean difference (WMD) using the random-effects model. Between study heterogeneity was evaluated by the Cochran’s Q test and I².ResultsFour RCTs studies investigated Carnosine use versus any control for at least 2 weeks were identified and analyzed. Overall results from the random-effects model on included studies, with 184 participants, indicated that carnosine intervention reduced HbA1C levels in intervention vs control groups (WMD: −0.92 %, 95 % CI: −1.20, −0.63, I²:69 %). Four studies, including a total of 183 participants, reported TG changes as an outcome measure variable, but combined results did not show significant reduction in this outcome (WMD: −14.46 mg/dl, 95 % CI: −29.11, 0.19, I²:94 %). Furthermore, combined results did not show any significant change in HOMA-IR, Cholesterol, fasting blood sugar, or HDL-C.ConclusionCarnosine supplementation results in a decrease in HbA1C, but elicits no effect on HOMA-IR, Cholesterol, fasting blood sugar, TG and HDL-C. Future studies with a larger sample sizes, varied doses of carnosine, and population-specific sub-groups are warranted to confirm, and enhance, the veracity of our findings.     

NAD+ Availability and Proteotoxicity

It has been shown that NAD⁺ availability is important for neuronal survival following ischemia (Liu et al., Neuromolecular Med 11:28–42, 2009). It is proposed here that NAD⁺ may also control proteotoxicity by influencing both formation and catabolism of altered proteins. It is suggested that low NAD⁺ availability promotes synthesis of methylglyoxal (MG) which can induce formation of glycated proteins, ROS, and dysfunctional mitochondria. That glyoxalase overexpression and carnosine are both protective against MG and ischemic injury support this proposal. Recognition and elimination of altered proteins is enhanced by NAD⁺ through effects on stress protein expression and autophagy.     

Carnosine in the brain and olfactory system of amphibia and reptilia: A comparative study using immunocytochemical and biochemical methods

The pattern of distribution of carnosine-like immunoreactivity and its relation to glial fibrillary acidic protein immunoreactivity have been studied in two lizards (Gallotia galloti and Tarentola delalandii) and in two anuran amphibians (Rana esculenta and Xenopus laevis) using immunocytochemical techniques. Biochemical data obtained by paper electrophoresis show that the dipeptides carnosine and homocarnosine are both present in the brain of all the species examined. In the central nervous system of both anurans and reptilians, carnosine immunoreactivity is localized in glial cells. An important species difference is, however, seen in the olfactory system since primary olfactory neurons and their processes extending to the olfactory bulb are carnosine positive in reptiles, whereas they are not immunostained in anurans. Thus, the cellular distribution of carnosine immunoreactivity in reptilians is very similar to that observed in birds and mammals and is distinct from that seen in amphibia.     

Olfactory bulb glycogen metabolism: noradrenergic modulation in the young rat

The olfactory bulb exhibits high glycogen phosphorylase activity, the rate-limiting enzyme in the mobilization of glycogen. The bulb also receives dense noradrenergic innervation and noradrenaline is known to stimulate glycogen breakdown. We determined the levels of glycogen in the bulb over the course of development and then determined the ability of noradrenaline to mobilize bulb glycogen. At birth, olfactory bulbs have very high levels of glycogen, with levels declining as the pups develop. Picomolar levels of noradrenaline mobilize glycogen in the bulb. Initially, β-noradrenergic receptors mediate the glycogenolysis and subsequently, the α-noradrenergic receptors in the bulb stimulate the breakdown of glycogen. Carnosine is involved in the repletion of bulb glycogen levels. The stimulation of glycogen breakdown by noradrenaline may play a role in allowing the increased activity that accompanies early olfactory stimulation.     

The distribution of carnosine and related dipeptides in rat and human tissues

Carnosine and anserine are present in high concentrations in most skeletal muscles. In addition, carnosine and homocarnosine have been detected in brain and cardiac muscle. Other tissues have been found to be devoid of these histidine-containing dipeptides. However, Flancbaum et al. [5] reported that carnosine was present in every rodent and human tissue analyzed. These authors postulated that carnosine serves as a non-mast cell reservoir for histidine which becomes available for histamine synthesis during periods of physiological stress. We have analyzed many rat and human tissues using an immunohistochemical procedure. Carnosine and related dipeptides were detected in skeletal muscle, cardiac muscle and brain, but not in kidney, liver, lung or several other organs. These negative results seem valid since the immunoassay gave positive staining in the tissues generally known to contain carnosine.accepted by W. Lorenz