Oral l-Citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection

Yabuki, Yasushi; Shioda, Norifumi; Yamamoto, Yoshiyuki; Shigano, Miyuki; Kumagai, Kota; Murakami, Masahiko; Fukunaga, Kohji

doi:10.1016/j.brainres.2013.05.011

Cited by 41 publications

(27 citation statements)

References 44 publications

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“…For instance, Cit increases neuronal expression of NO synthase (Yabuki et al . ), which recent research shows to be an important regulator of blood pressure and vascular resistance in humans (Shabeeh et al . ).…”

Section: Discussionmentioning

confidence: 99%

“…Although we attribute improved blood pressure and exercise blood flow after Cit in men to elevated endothelial NO bioavailability, consistent with other researchers (Bailey et al 2015(Bailey et al , 2016Figueroa et al 2017), we appreciate that there may be other pathways by which Cit might impart benefits to vascular function. For instance, Cit increases neuronal expression of NO synthase (Yabuki et al 2013), which recent research shows to be an important regulator of blood pressure and vascular resistance in humans (Shabeeh et al 2017). This central effect may be augmented by Arg-induced elevations in neuronal cyclic AMP levels (Sidorov et al 1999) that can subsequently trigger adenosine-stimulated NO synthesis (Dubey et al 1998).…”

Section: Limitationsmentioning

confidence: 99%

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Does l‐citrulline supplementation improve exercise blood flow in older adults?

Gonzales

Raymond

Ashley

et al. 2017

Experimental Physiology

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New Findings r What is the central question of this study?Does short-term supplementation with l-citrulline in order to increase l-arginine improve exercise blood flow and peripheral dilatation responses to exercise in older adults? r What is the main finding and its importance? l-Citrulline increased femoral blood flow by 11% and vascular conductance by 14% during lower-limb exercise in older men, whereas no changes were observed in older women. This modest improvement in bulk muscle blood flow in older men has implications for altering muscle metabolism that may result in enhanced exercise tolerance in older adults.l-Citrulline (Cit) increases l-arginine (Arg), the primary substrate for nitric oxide biosynthesis. We tested the hypothesis that muscle blood flow during exercise would be enhanced by Cit supplementation in older adults. Femoral artery blood flow was measured during calf exercise using Doppler ultrasound, and vascular conductance (FVC) was calculated in 25 older adults (13 women and 12 men) before and after 14 days of Cit (6 g day −1 ) and placebo (maltodextrin) in a randomized, double-blind, crossover study. Plasma [Arg] and resting blood pressure were also measured before and after each condition. Women and men were analysed separately because of significant sex-by-condition interactions for the change in exercise blood flow and FVC. Plasma [Arg] was increased by 30 and 35% after Cit (P < 0.01) in women and men, respectively, with no change after placebo. Citrulline lowered diastolic blood pressure in men (75 ± 9 versus 71 ± 6 mmHg, P = 0.02), but this variable remained unchanged in women. Blood flow and FVC during exercise at higher workloads were increased after Cit in men (flow, 521 ± 134 versus 584 ± 166 ml min −1 , P = 0.04; FVC, 5.0 ± 1.5 versus 5.8 ± 1.7 m, min mmHg −1 , P = 0.01) but were not different after placebo. These variables were not altered by Cit in women. Adjusting for baseline diastolic blood pressure removed (P = 0.10) the difference in FBF and FVC following Cit in men. These results indicate that l-citrulline has a modest effect of improving muscle blood flow during submaximal exercise in older men.

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Section: Discussionmentioning

confidence: 99%

Section: Limitationsmentioning

confidence: 99%

Does l‐citrulline supplementation improve exercise blood flow in older adults?

Gonzales

Raymond

Ashley

et al. 2017

Experimental Physiology

View full text Add to dashboard Cite

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“…Moreover, NO regulates Ca 2+ influx into the neurons via inhibition of NMDA receptors at glutamatergic synapses, protecting the cells from overstimulation and, subsequently, excitotoxicity (Ditlevsen et al 2007). Additionally, L-Citrulline, which is a byproduct of the reaction, catalyzed by NOS, was shown to possess neuroprotective properties (Yabuki et al 2013).…”

Section: Introductionmentioning

confidence: 99%

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

Polis

Srikanth

Elliott

et al. 2018

Preprint

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The urea cycle plays a role in the pathogenesis of Alzheimer's disease (AD). Arginase-I accumulation at sites of amyloid-beta deposition is associated with L-arginine deprivation and neurodegeneration. Moreover, a positive interaction between the arginase-II and mTOR-S6K1 pathways promote inflammation and oxidative stress. In this study, we treated 3xTg-AD mice exhibiting increased ribosomal protein S6 kinase beta-1 (S6K1) activity and wild-type (WT) mice with L-norvaline. The substance combines unique properties of arginase and S6K1 inhibition. The treated 3xTg-AD mice demonstrated significantly improved acquisition of spatial memory, associated with a substantial reduction of microgliosis and shift from activated to resting phenotype. Moreover, an increase of dendritic spines density and escalation of the expression rates of neuroplasticity related proteins were followed by a decline in the levels of amyloid-beta toxic oligomeric and fibrillar species in the hippocampus. Our findings associate local amyloid-beta-driven and immune-mediated response with altered L-arginine metabolism and suggest that arginase and S6K1 inhibition by L-norvaline can delay progression of AD.

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“…Abnormal elevation of NO causes brain damage following cerebral ischemia during the subacute phase [11, 12]. Recently, the neuroprotective effect of L -citrulline on CNS disorders such as brain ischemia has been investigated [13]. Previous studies have shown that L -citrulline not only prevented neuronal cell death but it also prevented capillary loss in the hippocampal region by cerebral ischemia.…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have shown that L -citrulline not only prevented neuronal cell death but it also prevented capillary loss in the hippocampal region by cerebral ischemia. The cerebrovascular protective effect of L -citrulline was associated with the restoration of endothelial nitric oxide synthase (eNOS) expression in the hippocampus [13]. Thus, L -citrulline administration may offer a potential therapeutic strategy not only for patients with impaired arginine metabolism and deficiencies but also for controlling NO metabolism disorders and cell death in the CNS [3, 13].…”

Section: Introductionmentioning

confidence: 99%

Characteristics of L-citrulline transport through blood-brain barrier in the brain capillary endothelial cell line (TR-BBB cells)

Lee

Kang

2017

J Biomed Sci

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Background L-Citrulline is a neutral amino acid and a major precursor of L-arginine in the nitric oxide (NO) cycle. Recently it has been reported that L-citrulline prevents neuronal cell death and protects cerebrovascular injury, therefore, L-citrulline may have a neuroprotective effect to improve cerebrovascular dysfunction. Therefore, we aimed to clarify the brain transport mechanism of L-citrulline through blood-brain barrier (BBB) using the conditionally immortalized rat brain capillary endothelial cell line (TR-BBB cells), as an in vitro model of the BBB.MethodsThe uptake study of [14C] L-citrulline, quantitative real-time polymerase chain reaction (PCR) analysis, and rLAT1, system b0,+, and CAT1 small interfering RNA study were performed in TR-BBB cells.ResultsThe uptake of [14C] L-citrulline was a time-dependent, but ion-independent manner in TR-BBB cells. The transport process involved two saturable components with a Michaelis–Menten constant of 30.9 ± 1.0 μM (Km1) and 1.69 ± 0.43 mM (Km2). The uptake of [14C] L-citrulline in TR-BBB cells was significantly inhibited by neutral and cationic amino acids, but not by anionic amino acids. In addition, [14C]L-citrulline uptake in the cells was markedly inhibited by 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH), which is the inhibitor of the large neutral amino acid transporter 1 (LAT1), B0, B0,+ and harmaline, the inhibitor of system b0,+. Gabapentin and L-dopa as the substrates of LAT1 competitively inhibited the uptake of [14C] L-citrulline. IC50 values for L-dopa, gabapentin, L-phenylalanine and L-arginine were 501 μM, 223 μM, 68.9 μM and 33.4 mM, respectively. The expression of mRNA for LAT1 was predominantly increased 187-fold in comparison with that of system b0,+ in TR-BBB cells. In the studies of LAT1, system b0,+ and CAT1 knockdown via siRNA transfection into TR-BBB cells, the transcript level of LAT1 and [14C] L-citrulline uptake by LAT1 siRNA were significantly reduced compared with those by control siRNA in TR-BBB cells.ConclusionsOur results suggest that transport of L-citrulline is mainly mediated by LAT1 in TR-BBB cells. Delivery strategy for LAT1-mediated transport and supply of L-citrulline to the brain may serve as therapeutic approaches to improve its neuroprotective effect in patients with cerebrovascular disease.

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Oral l-Citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection

Cited by 41 publications

References 44 publications

Does l‐citrulline supplementation improve exercise blood flow in older adults?

Does l‐citrulline supplementation improve exercise blood flow in older adults?

L-norvaline reverses cognitive decline and synaptic loss in a murine model of Alzheimer’s disease

Characteristics of L-citrulline transport through blood-brain barrier in the brain capillary endothelial cell line (TR-BBB cells)

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