Metabolomic changes in the mouse retina after optic nerve injury

Sato, Kota; Saigusa, Daisuke; Saito, Ryosuke; Fujioka, Amane; Nakagawa, Yurika; Nishiguchi, Koji M.; Kokubun, Taiki; Motoike, Ikuko N.; Maruyama, Kouichi; Omodaka, Kazuko; Shiga, Yukihiro; Uruno, Akira; Koshiba, S.; Yamamoto, Masayuki; Nakazawa, Toru

doi:10.1038/s41598-018-30464-z

Cited by 18 publications

(13 citation statements)

References 65 publications

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“…In contrast, ONC significantly reduced both TUBB3-positive cells (1623.9 ± 91.2 cells/mm 2 ) and FG-labeled RGC densities (1549.0.2 ± 51.8 cells/mm 2 ) in the WT mouse retinas compared with those with sham operation ( n = 8, ANOVA with post hoc Bonferroni test p < 0.001; Fig. 4a – d ), which is in agreement with previous studies [ 40 , 41 ].…”

Section: Resultssupporting

confidence: 92%

“…An additional finding of interest in the present study is that Aqp9 KO mice that underwent both ONC and 4-CIN injection exhibited significant reductions of nSTR amplitude. It is presumed that nSTR originates from amacrine cells [ 37 , 41 ]. As mentioned above, it was catecholaminergic amacrine cells that were originally found to express AQP9 in the retina [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

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Aqp9 Gene Deletion Enhances Retinal Ganglion Cell (RGC) Death and Dysfunction Induced by Optic Nerve Crush: Evidence that Aquaporin 9 Acts as an Astrocyte-to-Neuron Lactate Shuttle in Concert with Monocarboxylate Transporters To Support RGC Function and Survival

et al. 2020

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Aquaporin 9 (AQP9) is an aquaglyceroporin that can transport lactate. Accumulating evidence suggests that astrocyte-to-neuron lactate shuttle (ANLS) plays a critical role in energy metabolism in neurons, including retinal ganglion cells (RGCs). To test the hypothesis that AQP9, in concert with monocarboxylate transporters (MCTs), participates in ANLS to maintain function and survival of RGCs, Aqp9-null mice and wild-type (WT) littermates were subjected to optic nerve crush (ONC) with or without intravitreal injection of an MCT2 inhibitor. RGC density was similar between the Aqp9-null mice and WT mice without ONC, while ONC resulted in significantly more RGC density reduction in the Aqp9-null mice than in the WT mice at day 7. Positive scotopic threshold response (pSTR) amplitude values were similar between the two groups without ONC, but were significantly more reduced in the Aqp9-null mice than in the WT mice 7days after ONC. MCT2 inhibitor injection accelerated RGC death and pSTR amplitude reduction only in the WT mice with ONC. Immunolabeling revealed that both RGCs and astrocytes expressed AQP9, that ONC predominantly reduced astrocytic AQP9 expression, and that MCTs 1, 2, and 4 were co-localized with AQP9 at the ganglion cell layer. These retinal MCTs were also co-immunoprecipitated with AQP9 in the WT mice. ONC decreased the co-immunoprecipitation of MCTs 1 and 4, but did not impact co-immunoprecipitation of MCT2. Retinal glucose transporter 1 expression was increased in Aqp9-null mice. Aqp9 gene deletion reduced and increased the intraretinal l-lactate and d-glucose concentrations, respectively. Results suggest that AQP9 acts as the ANLS to maintain function and survival of RGCs.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Aqp9 Gene Deletion Enhances Retinal Ganglion Cell (RGC) Death and Dysfunction Induced by Optic Nerve Crush: Evidence that Aquaporin 9 Acts as an Astrocyte-to-Neuron Lactate Shuttle in Concert with Monocarboxylate Transporters To Support RGC Function and Survival

et al. 2020

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“…Subsequently, solvent B was immediately set to 100% and maintained for 8 min. Finally, the mobile phase was returned to the initiated conditions and maintained for 7 min until the end of the run (84). The oven temperature was 45°C.…”

Section: Maldi-msimentioning

confidence: 99%

Nrf2 Suppresses Oxidative Stress and Inflammation inAppKnock-In Alzheimer’s Disease Model Mice

Uruno

Matsumaru

Ryoke

et al. 2020

Molecular and Cellular Biology

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131

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Nrf2 (NF-E2-related-factor 2) is a stress-responsive transcription factor that protects cells against oxidative stresses. To clarify whether Nrf2 prevents Alzheimer’s disease (AD), AD model AppNL-G-F/NL-G-F knock-in (AppNLGF) mice were studied in combination with genetic Nrf2 induction model Keap1FA/FA mice. While AppNLGF mice displayed shorter latency to escape than wild-type mice in the passive-avoidance task, the impairment was improved in AppNLGF::Keap1FA/FA mice. Matrix-assisted laser desorption ionization–mass spectrometry imaging revealed that reduced glutathione levels were elevated by Nrf2 induction in AppNLGF::Keap1FA/FA mouse brains compared to AppNLGF mouse brains. Genetic Nrf2 induction in AppNLGF mice markedly suppressed the elevation of the oxidative stress marker 8-OHdG and Iba1-positive microglial cell number. We also determined the plasmalogen-phosphatidylethanolamine (PlsPE) level as an AD biomarker. PlsPE containing polyunsaturated fatty acids was decreased in the AppNLGF mouse brain, but Nrf2 induction attenuated this decline. To evaluate whether pharmacological induction of Nrf2 elicits beneficial effects for AD treatment, we tested the natural compound 6-MSITC [6-(methylsulfinyl)hexyl isothiocyanate]. Administration of 6-MSITC improved the impaired cognition of AppNLGF mice in the passive-avoidance task. These results demonstrate that the induction of Nrf2 ameliorates cognitive impairment in the AD model mouse by suppressing oxidative stress and neuroinflammation, suggesting that Nrf2 is an important therapeutic target of AD.

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“…Tandem Mass spectrometry was performed as previously described 52 . The UHPLC-QTOF/MS analysis was performed on an Acquity Ultra Performance LC I-class system, equipped with a binary solvent manager, a sample manager, and a column heater (Waters Corp.).…”

Section: Lc-ftms and Uhplc-qtof/ms Analysesmentioning

confidence: 99%

“…The data analysis was performed as previously reported 52 . Features were selected based on their coefficient of variation (CV) with the SQC samples, which were injected after every 8 study samples; features with CV over 30% were eliminated.…”

Section: Data Analysis and Statistics And Compound Annotationmentioning

confidence: 99%

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

Rashad

Saigusa

Yamazaki

et al. 2020

Sci Rep

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Understanding the root causes of neuronal vulnerability to ischemia is paramount to the development of new therapies for stroke. Transient global cerebral ischemia (tGCI) leads to selective neuronal cell death in the CA1 sub-region of the hippocampus, while the neighboring CA3 sub-region is left largely intact. By studying factors pertaining to such selective vulnerability, we can develop therapies to enhance outcome after stroke. Using untargeted liquid chromatography-mass spectrometry, we analyzed temporal metabolomic changes in CA1 and CA3 hippocampal areas following tGCI in rats till the setting of neuronal apoptosis. 64 compounds in CA1 and 74 in CA3 were found to be enriched and statistically significant following tGCI. Pathway analysis showed that pyrimidine and purine metabolism pathways amongst several others to be enriched after tGCI in CA1 and CA3. Metabolomics analysis was able to capture very early changes following ischemia. We detected 6 metabolites to be upregulated and 6 to be downregulated 1 hour after tGCI in CA1 versus CA3. Several metabolites related to apoptosis and inflammation were differentially expressed in both regions after tGCI. We offer a new insight into the process of neuronal apoptosis, guided by metabolomic profiling that was not performed to such an extent previously.Metabolomics is the study of metabolite composition of cells, tissues or biological fluids. Recent technological advances in this field has allowed the discovery of new biomarkers of diseases such as coronary artery disease, septic shock and brain tumors as well as the discovery of new drugs 1-5 . Metabolomic analysis has also deepened our understanding of several disease models, leading to the discovery of new pathways or targets for drug therapies that could later be applied to the treatment of various diseases [6][7][8][9][10][11] . Indeed, metabolomics are closer to the phenotype of a given disease compared with transcriptomic or proteomic analysis, both of which are prone to downstream modifications and changes in activities 1,12 .Several techniques, tools and software platforms exist to study metabolomics, all of which complement each other 13 . The application of these tools has greatly enhanced our understanding of the pathophysiology of diseases in almost every field of research 14 . In the field of neuroscience, metabolomic analysis is used to study stroke 15 , brain tumors 16 , traumatic brain injury (TBI) 17,18 , neurodegenerative diseases 19 , hypoxic-ischemic encephalopathy 20 and depression 21 to name a few 22 . The application of metabolomic tools to study brain diseases have greatly enhanced our understanding of different pathologies, for example; we demonstrated the upregulation of the ceramide "Cer(d18:0/18:0)" and phosphocreatine following transient ischemia-reperfusion in mice using a mass spectrometric imaging approach 15 . Several studies have highlighted an array of small molecules, amino acids and lipids that were linked to stroke severity, progression or post-stroke cognitive deficits [23][...

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Metabolomic changes in the mouse retina after optic nerve injury

Cited by 18 publications

References 65 publications

Aqp9 Gene Deletion Enhances Retinal Ganglion Cell (RGC) Death and Dysfunction Induced by Optic Nerve Crush: Evidence that Aquaporin 9 Acts as an Astrocyte-to-Neuron Lactate Shuttle in Concert with Monocarboxylate Transporters To Support RGC Function and Survival

Aqp9 Gene Deletion Enhances Retinal Ganglion Cell (RGC) Death and Dysfunction Induced by Optic Nerve Crush: Evidence that Aquaporin 9 Acts as an Astrocyte-to-Neuron Lactate Shuttle in Concert with Monocarboxylate Transporters To Support RGC Function and Survival

Nrf2 Suppresses Oxidative Stress and Inflammation inAppKnock-In Alzheimer’s Disease Model Mice

Metabolic basis of neuronal vulnerability to ischemia; an in vivo untargeted metabolomics approach

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