Brain Regions Involved in Fatigue Sensation: Reduced Acetylcarnitine Uptake into the Brain

Kuratsune, Hirohiko; Yamaguti, Kouzi; Lindh, Gudrun; Evengård, Birgitta; Hagberg, Gisela E.; Matsumura, Kiyoshi; Iwase, Masao; Onoe, Hirotaka; Takahashi, Mamoru; Machii, Takashi; Kanakura, Yuzuru; Kitani, Teruo; Långström, Bengt; Watanabe, Yasuyoshi

doi:10.1006/nimg.2002.1260

Cited by 100 publications

(76 citation statements)

References 30 publications

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“…Not only carnitine plays an important role in transfer of long chain fatty acids from cytosol into mitochondria for β-oxidation, but also it has been recently shown that carnitine prevents injury of normal cells caused by a anti-caner drug, cisplatin [19] and inhibits hepatocarcinogenesis via protection of mitochondria [20]. Acetylcarnitine, on the other hand, has been attracting much attention because of its pharmacological effects on various neurological disorders such as age-dependent memory loss [6,7], Alzheimer-type dementia [8,9], and chronic fatigue syndrome [5]. Therefore, OCTN2 could be a therapeutic target for cancers and neurological diseases, and since cartregulin up-regulates the expression of OCTN2 as shown here, it could be an alternative therapeutic target for these diseases through enhancement of OCTN2…”

Section: Discussionmentioning

confidence: 99%

“…[1-14 C] Acetyl-L-carnitine (30 Ci/mol) was synthesized as described [5]. COS-7 and CHO cells were cultured in Dulbecco's modified Eagle's medium containing 10% fetal calf serum, penicillin (100 U/ml), and streptomycin (100 μg/ml) at 37 °C under 5% CO 2 .…”

Section: Methodsmentioning

confidence: 99%

“…Carnitine is also the precursor of acetylcarnitine, which is the major constituent of blood acylcarnitine [3]. A study using positron emission tomography has demonstrated that the blood acetylcarnitine is taken up into specific regions of the human brain [4] and the uptake in some of the regions is impaired in the brain of patients with chronic fatigue syndrome [5]. It has recently been reported in mice that the acetyl group of acetylcarnitine is used mainly for synthesis of neurotransmitters such as glutamate and aspartate in the brain [5].…”

Section: Introductionmentioning

confidence: 99%

“…A study using positron emission tomography has demonstrated that the blood acetylcarnitine is taken up into specific regions of the human brain [4] and the uptake in some of the regions is impaired in the brain of patients with chronic fatigue syndrome [5]. It has recently been reported in mice that the acetyl group of acetylcarnitine is used mainly for synthesis of neurotransmitters such as glutamate and aspartate in the brain [5]. Thus acetylcarnitine appears to play a role in the brain which is distinct from carnitine: this notion is consistent with the observations that acetylcarnitine but not carnitine possesses therapeutic potentials in the treatment of a wide variety of neurological disorders including chronic fatigue syndrome [27], age-dependent memory loss [6,7] and Alzheimer-type dementia [8,9].…”

Section: Introductionmentioning

confidence: 99%

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Cloning and functional characterization of a novel up-regulator, cartregulin, of carnitine transporter, OCTN2

Nagai

Takikawa

Kawakami

et al. 2006

Archives of Biochemistry and Biophysics

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The abbreviations used are: OCTN, novel organic cation transporter; RT-PCR, reverse transcription-polymerase chain reaction; PGS, protein G-Sepharose; GST, glutathione S-transferase; ER, endoplasmic reticulum; PBS, phosphate-buffered saline; RT, room temperature; GFP, green fluorescent protein; ET A R, endothelin type A receptor; Ab, antibody. The accession number of rat cartregulin cDNA in the GenBank database is DQ119106. 1 ABSTRACTAcetylcarnitine exerts therapeutic effects on some neurological disorders including Alzheimer's disease. OCTN2 is known as a transporter for acetylcarnitine, but its expression in the brain is very low. To examine a brain-specific transporter for acetylcarnitine, we screened a rat brain cDNA library by hybridization using a DNA probe conserved among an OCTN family. A cDNA homologous to OCTN2 cDNA was isolated. The cDNA encoded a novel 146-amino acid protein with one putative transmembrane domain. The mRNA was expressed not only in rat brain but also in some other tissues. The novel protein was localized in endoplasmic reticulum when expressed in COS-7 cells but exhibited no transport activity for acetylcarnitine. However, when co-expressed with OCTN2, it enhanced the OCTN2-mediated transport by about twofold. The enhancement was accompanied by an increase in the levels of mRNA and protein. When OCTN2 was expressed in Xenopus oocytes by injection of its cRNA, its transport activity was enhanced by co-expression of the novel protein. These data suggest that the novel protein increases OCTN2 by stabilizing the mRNA in endoplasmic reticulum. The protein may be an up-regulator of OCTN2 and is tentatively designated cartregulin.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cloning and functional characterization of a novel up-regulator, cartregulin, of carnitine transporter, OCTN2

Nagai

Takikawa

Kawakami

et al. 2006

Archives of Biochemistry and Biophysics

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“…Indeed, when we studied the brain function of patients with severe fatigue state, chronic fatigue syndrome (CFS) by using 15 O-labeled water (H 2 15 O) and positron-emission tomography, we found that the vast majority of patients with CFS showed decreased blood flow in the anterior cingulated cortex, which is well known to be related to the autonomic nerve functions [16].…”

Section: As Shown Inmentioning

confidence: 99%

Changes in reaction time, coefficient of variance of reaction time, and autonomic nerve function in the mental fatigue state caused by long-term computerized Kraepelin test workload in healthy volunteers

Kuratsune¹,

Tajima²,

Koizumi³

et al. 2012

WJNS

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Fatigue is a common sense caused by crushing labor, stressful social events and various illnesses. It is usually judged by their subjective symptoms, but it should be evaluated in an objective perspective. Here we show that the decrease of working efficiency and sympathetic hyperactivity are associated with mental fatigue state caused by prolonged mental workload. Recently we made a new mental fatigue model of healthy volunteers caused by long-term computerized Kraepelin test (CKT) workload. CKT is our new software for automatically checking the calculation capability, with which it is easy to determine the reaction time (RT), coefficient of variance of reaction time (CV), and accuracy of the answers (AC) during tasks. We put 24 healthy volunteers into the fatigue state by subjecting them to 120 minutes' CKT workload, and then studied the changes in fatigue sensation, RT, CV, and AC before and after the CKT workload. The fatigue sensation, RT, and CV were clearly increased by the fatigue-inducing task and recovered during the resting period. We also studied the changes in autonomic nerve activity by using heart rate variability analysis. The low/high frequency component ratio (LF/HF) was significantly increased by the fatigue-inducing task and decreased by resting, suggesting that mental stress causes a relatively sympathetic nerve activity-dominant state. Therefore, our new fatigue model involveing a long-term CKT workload is a good mental fatigue model to provide much information about the fatigue state simultaneously, and the increase of RT, CV, and proportion of sympathetic activity (LF/HF) are associated with mental fatigue state. These might be useful objective biomarkers or evaluating a mental fatigue state.

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Bioanalysis of acetylcarnitine in cerebrospinal fluid by HILIC–mass spectrometry

Holder

McNaney

Luchetti

et al. 2015

Biomedical Chromatography

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Acetyl-L-carnitine (ALCAR) is a potential biomarker for the modulation of brain neurotransmitter activity, but is also present in cerebrospinal fluid (CSF). Recent studies have utilized hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS) based assays to detect and quantify ALCAR within biofluids such as urine, plasma and serum, using various sample pretreatment procedures. In order to address the need to quantify ALCAR in CSF on a high-throughput scale, a new and simple HILIC-MS/MS assay has been successfully developed and validated. For rapid analysis, CSF sample pretreatment was performed via 'dilute and shoot' directly onto an advanced HILIC column prior to MS/MS detection. This newly developed HILIC-MS/MS assay shows good recoveries of ALCAR without the need for chemical derivatization and multistep sample extraction procedures. The employment of this assay is suitable for the high-throughput bioanalysis and quantification of ALCAR within the CSF of various animal models and human clinical studies.

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Brain Regions Involved in Fatigue Sensation: Reduced Acetylcarnitine Uptake into the Brain

Cited by 100 publications

References 30 publications

Cloning and functional characterization of a novel up-regulator, cartregulin, of carnitine transporter, OCTN2

Cloning and functional characterization of a novel up-regulator, cartregulin, of carnitine transporter, OCTN2

Changes in reaction time, coefficient of variance of reaction time, and autonomic nerve function in the mental fatigue state caused by long-term computerized Kraepelin test workload in healthy volunteers

Bioanalysis of acetylcarnitine in cerebrospinal fluid by HILIC–mass spectrometry

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