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The mNSS score (a), and the brain water content of perihematoma (b) was performed at 72 h in sham-operated rats, vehicle-treated ICH group and rats induced ICH treated with carnosine. Values were expressed as mean ± SD (P < 0.01; one-way ANOVA with Bonferroni’s multiple comparison; n = 8 in each group)
Source publication
Carnosine, an endogenous dipeptide (β-alanyl-l-histidine), exerts multiple neuroprotective properties, but its role in intracerebral hemorrhage (ICH) remains unclear. This study investigates the effect of Carnosine on brain injury using the rat ICH model, which is established by type IV collagenase caudatum infusion. The results indicate that intra...
Citations
... Analogous results in animal studies show that activated microglia and astrocytes are inhibited by carnosine treatment in chronic cerebral hypoperfusion and subcortical ischemic vascular models of dementia (Ma et al., 2012;Ma et al., 2018;Xie et al., 2017). Astrocyte reactivity plays a pivotal role in connecting Aβ with initial tau pathology, with activated astrocytes make patients more susceptible to AD pathology (Bellaver et al., 2023). ...
The morbidity and mortality associated with type 2 diabetes mellitus (T2DM) have grown exponentially over the last 30 years. Together with its associated complications, the mortality rates have increased. One important complication in those living with T2DM is the acceleration of age‐related cognitive decline. T2DM‐induced cognitive impairment seriously affects memory, executive function, and quality of life. However, there is a lack of effective treatment for both diabetes and cognitive decline. Thus, finding novel treatments which are cheap, effective in both diabetes and cognitive impairment, are easily accessible, are needed to reduce impact on patients with diabetes and health‐care systems. Carnosine, a histidine containing dipeptide, plays a protective role in cognitive diseases due to its antioxidant, anti‐inflammation, and anti‐glycation properties, all of which may slow the development of neurodegenerative diseases and ischemic injury. Furthermore, carnosine is also involved in regulating glucose and insulin in diabetes. Herein, we discuss the neuroprotective role of carnosine and its mechanisms in T2DM‐induced cognitive impairment, which may provide a theoretical basis and evidence base to evaluate whether carnosine has therapeutic effects in alleviating cognitive dysfunction in T2DM patients.
... 56 In addition, 1000 mg/kg per day of carnosine administration for 1 month in rats decreased TNF-a and IL-6 levels. 57 Apart from the direct effects of carnosine on inflammatory cytokines, carnosine could inhibit AGE and ALE formation and further contribute to the amelioration of inflammation. 58 No effects on adiponectin were found; however, only 2 studies could be pooled in this analysis. ...
... Similarly, 2 other studies in rats reported decreased MDA levels and elevated GSH levels following carnosine supplementation of 1000 mg/kg daily for 1 month and 10 mg/kg twice a week for 1 month. 18,57 In vitro, carnosinol, a new carnosine analogue, was shown to increase the activities of SOD and CAT in L6 skeletal muscle cells. 15 The present data agree with the findings for CAT, showing improved CAT levels following carnosine consumption. ...
Context
Carnosine and histidine-containing dipeptides (HCDs) are suggested to have anti-inflammatory and antioxidative benefits, but their effects on circulating adipokines and inflammatory and oxidative stress biomarkers remain unclear.
Objectives
The aim of the present systematic review and meta-analysis was to determine the impact of HCD supplementation on inflammatory and oxidative stress biomarkers.
Data Sources
A systematic search was performed on Medline via Ovid, Scopus, Embase, ISI Web of Science, and the Cochrane Library databases from inception to 25 January 2023.
Data Extraction
Using relevant key words, trials investigating the effects of carnosine/HCD supplementation on markers of inflammation and oxidative stress, including C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), adiponectin, malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), total antioxidant capacity (TAC), and catalase (CAT) were identified. Meta-analyses were conducted using random-effects models to calculate the weighted mean differences (WMDs) and 95% confidence intervals (CIs).
Data Analysis
A total of 9 trials comprising 350 participants were included in the present meta-analysis. Carnosine/HCD supplementation led to a significant reduction in CRP (WMD: –0.97 mg/L; 95% CI: –1.59, –0.36), TNF-α (WMD: –3.60 pg/mL; 95% CI: –7.03, –0.18), and MDA (WMD: –0.34 μmol/L; 95% CI: –0.56, –0.12) and an elevation in CAT (WMD: 4.48 U/mL; 95% CI: 2.43, 6.53) compared with placebo. In contrast, carnosine/HCD supplementation had no effect on IL-6, adiponectin, GSH, SOD, and TAC levels.
Conclusion
Carnosine/HCD supplementation may reduce inflammatory and oxidative stress biomarkers, and potentially modulate the cardiometabolic risks associated with chronic low-grade inflammation and lipid peroxidation.
Systematic Review Registration
PROSPERO registration no. CRD42017075354.
... The higher scores depict a more severe brain damage according to the scoring criteria. 25 ...
Purpose
Intracerebral hemorrhage (ICH) is a fatal disease without effective treatment. The damage of the blood–brain barrier (BBB) is a key cause of brain edema and herniation after ICH. Omarigliptin (also known as MK3102) is a potent antidiabetic that inhibits dipeptidyl peptidase (DPP4); the latter has the ability to bind and degrade matrix metalloproteinases (MMPs). The present study aims to investigate the protective effects of omarigliptin against the destruction of BBB following ICH in mice.
Methods and Materials
Collagenase VII was used to induce ICH in C57BL/6 mice. MK3102 (7 mg/kg/day) was administered after ICH. The modified neurological severity scores (mNSS) were carried out to assess neurological functions. Nissl staining was applied to evaluate neuronal loss. Brain water content, Evans blue extravasation, Western blots, immunohistochemistry and immunofluorescence were used to study the protective effects of BBB with MK3102 at 3 days after ICH.
Results
MK3102 reduced DPP4 expression and decreased hematoma formation and neurobehavioral deficits of ICH mice. This was correspondent with lowered activation of microglia/macrophages and infiltration of neutrophils after ICH. Importantly, MK3102 protected the integrity of the BBB after ICH, associated with decreased expression of MMP-9, and preservation of the tight junction proteins ZO-1 and Occludin on endothelial cells through putative degradation of MMP-9, and inhibition of the expression of CX43 on astrocytes.
Conclusion
Omarigliptin protects the integrity of the BBB in mice after ICH injury.
... Among its different pleiotropic abilities (Cuzzocrea et al. 2007;Oppermann et al. 2019;Zhao et al. 2019;Corona et al. 2011;Spina-Purrello et al. 2010;Miceli et al. 2018;Caruso et al. 2019;Jain et al. 2020;Boakye et al. 2019;Attanasio et al. 2013Attanasio et al. , 2009Bellia et al. 2011;Greco et al. 2020), this dipeptide displays neuroprotective features, as attested by the reduced brain damage and improved functional outcomes observed in mouse models of focal ischaemic stroke (Rajanikant et al. 2007;Baek et al. 2014). Furthermore, l-carnosine is a good candidate for a successful and reliable agent for SCI models in rodents (Di Paola et al. 2011;Albayrak et al. 2015) due to its protective effects against inflammation (Kubota et al. 2020), brain oxidative stress, apoptosis and autophagy (Xie et al. 2017). However, the potential therapeutic action of Car is drastically hampered by its hydrolysis due to serum (Teufel et al. 2003;Bellia et al. 2014) and tissue (Lenney et al. 1985) carnosinase enzymes. ...
Spinal cord injury (SCI) leads to long-term and permanent motor dysfunctions, and nervous system abnormalities. Injury to the spinal cord triggers a signaling cascade that results in activation of the inflammatory cascade, apoptosis, and Zn(II) ion homeostasis. Trehalose (Tre), a nonreducing disaccharide, and l-carnosine (Car), (β-alanyl-l-histidine), one of the endogenous histidine dipeptides have been recognized to suppress early inflammatory effects, oxidative stress and to possess neuroprotective effects. We report on the effects of the conjugation of Tre with Car (Tre–car) in reducing inflammation in in vitro and in vivo models. The in vitro study was performed using rat pheochromocytoma cells (PC12 cell line). After 24 h, Tre–car, Car, Tre, and Tre + Car mixture treatments, cells were collected and used to investigate Zn²⁺ homeostasis. The in vivo model of SCI was induced by extradural compression of the spinal cord at the T6–T8 levels. After treatments with Tre, Car and Tre–Car conjugate 1 and 6 h after SCI, spinal cord tissue was collected for analysis. In vitro results demonstrated the ionophore effect and chelating features of l-carnosine and its conjugate. In vivo, the Tre–car conjugate treatment counteracted the activation of the early inflammatory cascade, oxidative stress and apoptosis after SCI. The Tre–car conjugate stimulated neurotrophic factors release, and influenced Zn²⁺ homeostasis. We demonstrated that Tre–car, Tre and Car treatments improved tissue recovery after SCI. Tre–car decreased proinflammatory, oxidative stress mediators release, upregulated neurotrophic factors and restored Zn²⁺ homeostasis, suggesting that Tre–car may represent a promising therapeutic agent for counteracting the consequences of SCI.
... Although our results appear to contradict the assumed anti-oxidant role of carnosine, they are in line with several studies on the effect of supplemented carnosine on oxidative stress markers, which showed no or only weak effects on MDA or protein carbonyl content in rodents under nonpathological conditions (Aydin et al. 2010;Ozel Turkzu et al. 2010;Kalaz et al. 2014). These and other studies, however, indicated that a significant anti-oxidant activity of supplied carnosine may be observed in animal models exhibiting elevated oxidative stress (Ozel Turkzu et al. 2010;Kalaz et al. 2014;Xie et al. 2017;and references in Boldyrev et al. 2013). This appears to be the case also for HCDs synthesized in tissues, as ischemia-reperfusion injury in heart muscle and HNE and acrolein adduct formation are significantly reduced in Carns1-transgenic mice (Zhao et al. 2020). ...
Carnosine and other histidine-containing dipeptides are expected to be important anti-oxidants in vertebrates based on various in vitro and in vivo studies with exogenously administered carnosine or its precursor β-alanine. To examine a possible anti-oxidant role of endogenous carnosine, mice lacking carnosine synthase (Carns1−/−) had been generated and were examined further in the present study. Protein carbonylation increased significantly between old (18 months) and aged (24 months) mice in brain and kidney but this was independent of the Carns1 genotype. Lipoxidation end products were not increased in 18-month-old Carns1−/− mice compared to controls. We also found no evidence for compensatory increase of anti-oxidant enzymes in Carns1−/− mice. To explore the effect of carnosine deficiency in a mouse model known to suffer from increased oxidative stress, Carns1 also was deleted in the type II diabetes model Leprdb/db mouse. In line with previous studies, malondialdehyde adducts were elevated in Leprdb/db mouse kidney, but there was no further increase by additional deficiency in Carns1. Furthermore, Leprdb/db mice lacking Carns1 were indistinguishable from conventional Leprdb/db mice with respect to fasting blood glucose and insulin levels. Taken together, Carns1 deficiency appears not to reinforce oxidative stress in old mice and there was no evidence for a compensatory upregulation of anti-oxidant enzymes. We conclude that the significance of the anti-oxidant activity of endogenously synthesized HCDs is limited in mice, suggesting that other functions of HCDs play a more important role.
... Carnosine can regulate extracellular glutamate levels and prevent neuronal cell death [277]. Furthermore, in a rat model of intracerebral haemorrhage, carnosine can reduce inflammation by inhibiting the microglia activation and attenuating the oxidative stress by increasing GPx and SOD activities [278]. GSH ( Figure 3) is found in Ulva spp. ...
Currently, there is no known cure for neurodegenerative disease. However, the available therapies aim to manage some of the symptoms of the disease. Human neurodegenerative diseases are a heterogeneous group of illnesses characterized by progressive loss of neuronal cells and nervous system dysfunction related to several mechanisms such as protein aggregation, neuroinflammation, oxidative stress, and neurotransmission dysfunction. Neuroprotective compounds are essential in the prevention and management of neurodegenerative diseases. This review will focus on the neurodegeneration mechanisms and the compounds (proteins, polyunsaturated fatty acids (PUFAs), polysaccharides, carotenoids, phycobiliproteins, phenolic compounds, among others) present in seaweeds that have shown in vivo and in vitro neuroprotective activity. Additionally, it will cover the recent findings on the neuroprotective effects of bioactive compounds from macroalgae, with a focus on their biological potential and possible mechanism of action, including microbiota modulation. Furthermore, gastrointestinal digestion, absorption, and bioavailability will be discussed. Moreover, the clinical trials using seaweed-based drugs or extracts to treat neurodegenerative disorders will be presented, showing the real potential and limitations that a specific metabolite or extract may have as a new therapeutic agent considering the recent approval of a seaweed-based drug to treat Alzheimer’s disease.
... Our data also suggest the contribution of TJ remodelling to liposomal entry into the brain both at 3-5 h and 48-50 h after ICH as indicated by the reduction in claudin-5 positive areas. Previous studies in rodent models of ICH reported a reduction in various TJ proteins 1-3 days after ICH [38][39][40][41] using immunohistochemistry, western blot or mRNA expression. Similarly, a clinical study in ICH patients showed elevated TJ protein levels in CSF samples measured on admission which indicate a role in TJ remodelling in BBB dysfunction very early after ICH [42]. ...
Haemorrhagic stroke represents a significant public health burden, yet our knowledge and ability to treat this type of stroke are lacking. Previously we showed that we can target ischaemic-stroke lesions by selective translocation of lipid nanoparticles through the site of blood-brain barrier (BBB) disruption. The data we presented in this study provide compelling evidence that haemorrhagic stroke in mice induces BBB injury that mimics key features of the human pathology and, more importantly, provides a gate for entry of lipid nanoparticles-based therapeutics selectively to the bleeding site.
Methods: Haemorrhagic stroke was induced in mice by intra-striatal collagenase injection. lipid nanoparticles were injected intravenously at 3 h, 24 h & 48 h post-haemorrhagic stroke and accumulation in the brain studied using in-vivo optical imaging and histology. BBB integrity, brain water content and iron accumulation were characterised using dynamic contrast-enhanced MRI, quantitative T1 mapping, and gradient echo MRI.
Results: Using in-vivo SPECT/CT imaging and optical imaging revealed biphasic lipid nanoparticles entry into the bleeding site, with an early phase of increased uptake at 3-24 h post-haemorrhagic stroke, followed by a second phase at 48-72 h. Lipid nanoparticles entry into the brain post-haemorrhage showed an identical entry pattern to the trans-BBB leakage rate (Ktrans [min⁻¹]) of Gd-DOTA, a biomarker for BBB disruption, measured using dynamic contrast-enhanced MRI.
Discussion: Our findings suggest that selective accumulation of liposomes into the lesion site is linked to a biphasic pattern of BBB hyper-permeability. This approach provides a unique opportunity to selectively and efficiently deliver therapeutic molecules across the BBB, an approach that has not been utilised for haemorrhagic stroke therapy and is not achievable using free small drug molecules.
... Our data also suggest the contribution of TJ remodelling to liposomal entry into the brain both at 3-5 h and 48-50 h after ICH as indicated by the reduction in claudin-5 positive areas. Previous studies in rodent models of ICH reported a reduction in various TJ proteins 1-3 days after ICH [38][39][40][41] using immunohistochemistry, western blot or mRNA expression. Similarly, a clinical study in ICH patients showed elevated TJ protein levels in CSF samples measured on admission which indicate a role in TJ remodelling in BBB dysfunction very early after ICH [42]. ...
... Most importantly, OS is also a primary mediator that results in secondary brain injury after ICH (19). Accumulating evidence have revealed that the level of ROS is increased accompanying antioxidant enzyme reduction in the brain after ICH (19,20). Anti-OS strategies improve neurological function, and attenuates inflammatory responses and blood brain barrier (BBB) damage caused by OS after ICH (21). ...
Intracerebral hemorrhage (ICH) is a highly fatal disease with mortality rate of approximately 50%. Oxidative stress (OS) is a prominent cause of brain injury in ICH. Important sources of reactive oxygen species after hemorrhage are mitochondria dysfunction, degradated products of erythrocytes, excitotoxic glutamate, activated microglia and infiltrated neutrophils. OS harms the central nervous system after ICH mainly through impacting inflammation, killing brain cells and exacerbating damage of the blood brain barrier. This review discusses the sources and the possible molecular mechanisms of OS in producing brain injury in ICH, and anti-OS strategies to ameliorate the devastation of ICH.
... L-carnosine in all of the used concentrations exerted a moderate/strong expression of SOD2 in the mentioned cell line. This association between carnosine administration and increased SOD2 expression could be explained by the antioxidant role of carnosine in free radical scavenging but also due to its effects on the regulation of mitochondrial functions (Xie et al., 2017). ...
Carnosine is known as a natural dipeptide, which inhibits the proliferation of tumor cells throughout its action on mitochondrial respiration and cell glycolysis. However, not much is known about its effects on the metabolism of healthy cells. We explored the effects of Karnozin EXTRA® capsule with different concentrations of L-carnosine, on the cell viability and the expressions of intermediate filament vimentin (VIM) and superoxide dismutase (SOD2) in normal fibroblasts BHK-21/C13. Furthermore, we investigated its action on the energy production of these cells. Cell viability was quantified by the MTT assay. The Clark oxygen electrode (Oxygraph, Hansatech Instruments, England) was used to measure the “intact cell respiration rate”, state 3 of ADP-stimulated oxidation, maximum oxidation capacity and the activities of complexes I, II and IV. Results showed that Karnozin EXTRA® capsule in concentrations of 2 and 5 mM of L-carnosine did not induce toxic effects and morphological changes in treated cells. Our data revealed a dose-dependent immunofluorescent signal amplification of VIM and SOD2 in the BHK-21/C13 cell line. This supplement substantially increased the recorded mitochondrial respiration rates in the examined cell line. Due to the stimulation of mitochondrial energy production in normal fibroblasts, our results suggested that Karnozin EXTRA® is a potentially protective dietary supplement in the prevention of diseases with altered mitochondrial function.
