Role Of Carnosine Research Articles

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.

The Role of Carnosine in Protection Against the Damaging Effect of Maternal Nicotine Exposure During Gestation and Lactation on the Lung of Albino Rat Offspring

The Role of Carnosine in Protection Against the Damaging Effect of Maternal Nicotine Exposure During Gestation and Lactation on the Lung of Albino Rat Offspring

Carnosine protects against the inactivation of esterase induced by glycation and a steroid

Carnosine, an endogenous histidine-containing dipeptide, protects protein from oxidation and glycation, which may contribute to a potential treatment for some conformational diseases including cataract. Glycation, the non-enzymic reaction of sugars with proteins, promotes cross-linking and further aggregation. Prolonged use of glucocorticoids is a risk factor for cataract, as is diabetes. Esterase activity in the lens is decreased in senile cataract and diabetes. Previously, we reported that glycation and a steroid inactivate esterase. Here we tested the inactivation of esterase with fructose, fructose 6-phosphate (F6P) and ribose as model glycation reactions and prednisolone-21-hemisuccinate (P-21-H) as a model steroid and investigated the ability of carnosine to protect esterase against inactivation. The activity of esterase was measured by a spectrophotometric assay using p-nitrophenyl acetate as the substrate. The modified esterase was examined electrophoretically. The esterase was progressively inactivated by F6P, fructose, ribose and P-21-H. P-21-H was more effective than the sugars. Carnosine significantly inhibited the inactivation of esterase induced by all four compounds. Carnosine decreased the extent of the cross-linking. These results provide further evidence for carnosine's role as an anti-glycation compound. It is also proposed that carnosine may be an anti-steroid agent.

Calcineurin, Mitochondrial Membrane Potential, and Cardiomyocyte Apoptosis

Mitochondria comprise ≈30% of the total intracellular volume within a mammalian cardiomyocyte.1 2 Not surprisingly, subtle alterations in mitochondrial function or membrane potential can have a dramatic influence on cardiomyocyte energy production and, ultimately, the health of an individual cell. Indeed, cellular injury or stress stimulation directly elicits alterations in mitochondrial architecture, membrane potential, and oxidative capacity, which are associated with an irreversible loss of mitochondrial matrix contents and integral membrane protein constituents such as cytochrome c oxidase.3 The release of cytochrome c and/or mitochondrial permeability transition directly mediates cellular apoptosis through calcium-sensitive proteases or through coupling proteins that coordinate the activation of caspases and DNA fragmentation enzymes.3 Given the high intracellular content of mitochondria in cardiomyocytes and the unabated requirement for high-energy phosphate carriers to maintain ionic gradients and active force generation, coordinated disturbances in mitochondrial function can dramatically affect cell survival. Recent investigation has suggested an emerging paradigm whereby stress-responsive intracellular signaling pathways directly and indirectly influence mitochondrial membrane potential, oxidative capacity, and the coupling of apoptosis initiating factors. For example, stress-responsive signaling through the c-Jun N-terminal kinases (JNKs) has been shown to initiate apoptosis in certain cell types by directly influencing proteins within the mitochondrial membranes.4 In addition, increased expression of the mitochondrial stabilizing Bcl proteins can be transcriptionally regulated through stress-responsive signaling pathways, which subsequently antagonize mitochondrial dysfunction and cytochrome c release.5 Activation of the intracellular kinase Akt also directly antagonizes mitochondrial-directed apoptosis by phosphorylating the mitochondrial destabilizing protein Bad, reducing cytochrome c release and caspase activation.6 Lastly, activation of nuclear factor-κB (NF-κB) signaling induces expression of stress-adaptive proteins such as Bcl-2, antioxidants, and calcium-regulating proteins.7 In general, signaling pathways such as the stress- and mitogen-activated protein kinases (SAPKs and MAPKs), protein kinase C (PKC), Akt, NF-κB, and the …

Carnosine protects against excitotoxic cell death independently of effects on reactive oxygen species

The role of carnosine, N-acetylcarnosine and homocarnosine as scavengers of reactive oxygen species and protectors against neuronal cell death secondary to excitotoxic concentrations of kainate and N-methyl- d-aspartate was studied using acutely dissociated cerebellar granule cell neurons and flow cytometry. We find that carnosine, N-acetylcarnosine and homocarnosine at physiological concentrations are all potent in suppressing fluorescence of 2′,7′-dichlorofluorescein, which reacts with intracellularly generated reactive oxygen species. However, only carnosine in the same concentration range was effective in preventing apoptotic neuronal cell death, studied using a combination of the DNA binding dye, propidium iodide, and a fluorescent derivative of the phosphatidylserine-binding dye, Annexin-V. Our results indicate that carnosine and related compounds are effective scavengers of reactive oxygen species generated by activation of ionotropic glutamate receptors, but that this action does not prevent excitotoxic cell death. Some other process which is sensitive to carnosine but not the related compounds is a critical factor in cell death. These observations indicate that at least in this system reactive oxygen species generation is not a major contributor to excitotoxic neuronal cell death.

Carnosine-induced inward currents in rat olfactory bulb neurons in cultured slices

Olfactory neurons are rich in carnosine, which is regarded as a possible neurotransmitter between olfactory neurons and the olfactory bulb neurons. In the present study, we used the organotypic slice culture technique to culture olfactory bulb neurons and explore carnosine's role in the olfactory system. Inward current responses to carnosine upon increases in membrane conductance were recorded under whole-cell voltage-clamp conditions. The inward currents were desensitized during continuous application of carnosine. At carnosine concentrations above 50 μM, the current responses increased with increases in carnosine concentrations. The present results suggest that carnosine serves as an excitable neuroeffector between olfactory neurons and olfactory bulb neurons.

Carnosine is a novel peptide modulator of intracellular calcium and contractility in cardiac cells.

Myocardial contractile failure is a common cause of morbidity and mortality in patients with ischemic heart disease and systemic inflammatory states such as sepsis. Accumulating evidence indicates that contractile failure is associated with dysregulation of myoplasmic calcium levels. In a search for biochemical causes for contractile dysfunction, we found that the dipeptide carnosine improves cardiac contractility and tested the possibility that carnosine plays a role in the regulation of intracellular calcium. Carnosine increased contractility in a dose-dependent manner (1-10 mM) in isolated perfused rat hearts. and it also increased free intracellular calcium levels in isolated myocytes. Carnosine increased myocyte tension via calcium release from the ryanodine receptor calcium release channel in skinned myocardial fibers and increased open-state probability and dwell time of the isolated ryanodine receptor calcium release channel in lipid bilayers. In addition. we report that carnosine sensitizes the contractile proteins so calcium. These results suggest a novel role for carnosine as a modulator of intracellular calcium and contractility in cardiac tissue.

Antioxidant activity of carnosine, homocarnosine, and anserine present in muscle and brain.

Carnosine, homocarnosine, and anserine are present in high concentrations in the muscle and brain of many animals and humans. However, their exact function is not clear. The antioxidant activity of these compounds has been examined by testing their peroxyl radical-trapping ability at physiological concentrations. Carnosine, homocarnosine, anserine, and other histidine derivatives all showed antioxidant activity. All of these compounds showing peroxyl radical-trapping activity were also electrochemically active as reducing agents in cyclic voltammetric measurements. Furthermore, carnosine inhibited the oxidative hydroxylation of deoxyguanosine induced by ascorbic acid and copper ions. Other roles of carnosine, such as chelation of metal ions, quenching of singlet oxygen, and binding of hydroperoxides, are also discussed. The data suggest a role for these histidine-related compounds as endogenous antioxidants in brain and muscle.

Physiology and pharmacology of olfactory bulb neurons in dissociated cell culture

Cells from olfactory bulbs of embryonic rats were grown in dissociated cell culture for up to 5 weeks. Both neurons and non-neuronal cells grew in these cultures, with a variety of neuronal populations appearing. A population of 20–25% of the neurons were GABAergic by the criterion of [ 3H]GABA uptake. Electrophysiologic measurements were made of the baseline activity of the cultured neurons. Cells showed a mean resting potential of60.1 ± 1.2mV and a mean input resistance of87.6 ± 9.5MΩ. All cells were sensitive to microperfusion of GABA with half-maximal effect occurring at about 20 μM. Glutamate was universally excitatory but with variations in degree. Carnosine (β-Ala- l-His), tested over the concentration range of 10 nM to 100 μM, had no effect on input resistance, resting potential, action potential shape, on-going synaptic activity or the responsiveness to either GABA or glutamate. These results are further evidence against a role for carnosine as the excitatory transmitter of the primary olfactory afferents.

A role for carnosine and anserine in histamine metabolism of the traumatized rat.

SummaryAdult cocks were wounded by incisions on the left side of the pectoral muscles and tissues taken 24 and 48 hr later for determination of anserine and carnosine. Both the anserine and carnosine concentrations were lower in the wounded tissue 24 hr after injury in comparison with uninjured controls and tissue from the uninjured area of the same animals. By 48 hr levels of anserine and carnosine were essentially back to normal. Young rats were injured by fracture of the femur and simultaneously injected ip with either saline, histamine or histidine (0.2 μmoles). The leg muscle concentrations of carnosine, anserine and free-histidine were approximately 25% lower in the injured, as compared to the uninjured animals. Histidine or histamine injection prevented the decrease, and in the case of uninjured rats induced an increase, particularly of carnosine.