Carnosine-like immunoreactivity in the central nervous system of rats during postnatal development

Marchis, Silvia De; Modena, Chiara; Peretto, Paolo; Giffard, Cyrille; Fasolo, Aldo

doi:10.1002/1096-9861(20001023)426:3<378::aid-cne3>3.0.co;2-1

Cited by 23 publications

(16 citation statements)

References 41 publications

(77 reference statements)

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“…L-Carnosine is present at particularly high concentrations in mammalian skeletal muscles and the brain, and it has been implicated in neuroprotection (2), the olfactory system (1), and hypothalamic neuronal networks (3). Our recent observations suggest that central and peripheral administration of L-carnosine at low doses attenuates 2-deoxyglucose-induced hyperglycemia (4) and suppresses peripheral sympathetic nerve activity (5,6).…”

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confidence: 93%

Structural Basis for Substrate Recognition and Hydrolysis by Mouse Carnosinase CN2

Unno

Yamashita

Ujita

et al. 2008

Journal of Biological Chemistry

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L-Carnosine is a bioactive dipeptide (␤-alanyl-L-histidine) present in mammalian tissues, including the central nervous system, and has potential neuroprotective and neurotransmitter functions. In mammals, two types of L-carnosine-hydrolyzing enzymes (CN1 and CN2) have been cloned thus far, and they have been classified as metallopeptidases of the M20 family. The enzymatic activity of CN2 requires Mn 2؉ , and CN2 is inhibited by a nonhydrolyzable substrate analog, bestatin. Here, we present the crystal structures of mouse CN2 complexed with bestatin together with Zn 2؉ at a resolution of 1.7 Å and that with Mn 2؉ at 2.3 Å . CN2 is a homodimer in a noncrystallographic asymmetric unit, and the Mn 2؉ and Zn 2؉ complexes closely resemble each other in the overall structure. Each subunit is composed of two domains: domain A, which is complexed with bestatin and two metal ions, and domain B, which provides the major interface for dimer formation. The bestatin molecule bound to domain A interacts with several residues of domain B of the other subunit, and these interactions are likely to be essential for enzyme activity. Since the bestatin molecule is not accessible to the bulk water, substrate binding would require conformational flexibility between domains A and B. The active site structure and substrate-binding model provide a structural basis for the enzymatic activity and substrate specificity of CN2 and related enzymes.L-Carnosine (␤-alanyl-L-histidine) and structurally related dipeptides, such as homocarnosine (␥-aminobutyryl-L-histidine) and anserine (␤-alanyl-L-1-methylhistidine) are distributed in a wide variety of vertebrate tissues (1). L-Carnosine is present at particularly high concentrations in mammalian skeletal muscles and the brain, and it has been implicated in neuroprotection (2), the olfactory system (1), and hypothalamic neuronal networks (3). Our recent observations suggest that central and peripheral administration of L-carnosine at low doses attenuates 2-deoxyglucose-induced hyperglycemia (4) and suppresses peripheral sympathetic nerve activity (5, 6). These effects of L-carnosine are suppressed by central administration of thioperamide, a histamine H3 blocker. This suggests that L-carnosine regulates the autonomic nervous system via the hypothalamic histaminergic neurons (4 -6). In addition, the dipeptide exhibits antioxidant and free radical scavenger properties via complexation of transition metals, such as zinc and copper, suggesting that it is also involved in neuroprotection from oxidative stress (2, 8, 9). L-Carnosine is synthesized from ␤-alanine and L-histidine by carnosine synthetase and is degraded by intra-and extracellular dipeptidases known as carnosinases. Their enzymatic activities are regulated under various physiological conditions (10). Carnosinase was first isolated (11) from the porcine kidney in 1949 and was subsequently found to be widely distributed in tissues of rodents and higher mammals (12-15). Recently, two types of carnosinases were identified in humans and mice: h...

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mentioning

confidence: 93%

Structural Basis for Substrate Recognition and Hydrolysis by Mouse Carnosinase CN2

Unno

Yamashita

Ujita

et al. 2008

Journal of Biological Chemistry

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“…Although the physiological roles of carnosine in the olfactory bulb are still unclear, olfactory bulb neurons are less sensitive to damage after ischemia compared to hippocampal neurons, despite the accumulation of Zn. Furthermore, carnosine levels have been shown to vary during development [3], and the content of carnosine in muscle is decreased in aged animals [82]. Therefore, carnosine may play protective roles in Zn-induced neuro-degeneration after ischemia in the olfactory bulb.…”

Section: Resultsmentioning

confidence: 99%

“…In the primary olfactory neurons, carnosine synthase activity is decreased upon denervation and is recovered upon regeneration [20,21]. The sensory neurons may be primarily responsible for the presence of carnosine in the olfactory bulb [3]. Carnosine and its related compounds are not degraded by regular dipeptidases, but are metabolized by specific hydrolytic enzymes, named carnosinases.…”

Section: Expression and Distribution Of Carnosinementioning

confidence: 99%

“…Carnosine and its related compounds, homocarnosine and anserine ( Figure 1A), are found in birds, fish, and mammals, including humans [1][2][3][4]. Carnosine is synthesized by muscle cells, glial cells, and oligodendrocytes [5], and the biggest concentration is observed in skeletal muscle tissue, the stomach, the kidney, cardiac muscle, and the brain [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…During the search for protective substances against Zn-induced neurotoxicity, we found that carnosine exhibits marked inhibitory effects on Zninduced neurotoxicity and proposed its use as a possible therapeutic agent for VD. The level of carnosine varies during development and is low in the aged animals [3]. Therefore, it is highly possible that carnosine protects against external toxins and acts as an endogenous protective substance against neuronal injury and aging.…”

Section: Introductionmentioning

confidence: 99%

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Carnosine: A Possible Drug for Vascular Dementia

Kawahara¹

2014

J Vasc Med Surg

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Carnosine (β-alanyl histidine) is a small dipeptide with numerous beneficial effects, including the maintenance of the acid-base balance, antioxidant, chelating, anti-crosslinking, and anti-glycation activities in the living organism. High levels of carnosine are found in the skeletal muscles and in the brain. We have found that carnosine inhibits Zn2+-induced neuronal death, which plays acrucial role in the pathogenesis of vascular dementia. Our previous research demonstrated that carnosine participates in the Endoplasmic Reticulum (ER)-stress pathway in Zninduced neurotoxicity and we have applied for a patent related to drugs for Vascular Dementia (VD). Here, we review the roles of carnosine in VD and otherneuro degenerative diseases and discuss perspectives about the future therapeutic use ofthis dipeptide.

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