scholarly journals Imaging 6-Phosphogluconolactonase Activity in Brain Tumors In Vivo Using Hyperpolarized δ-[1-13C]gluconolactone

2021 ◽  
Vol 11 ◽  
Author(s):  
Georgios Batsios ◽  
Céline Taglang ◽  
Peng Cao ◽  
Anne Marie Gillespie ◽  
Chloé Najac ◽  
...  
Keyword(s):  
Redox Homeostasis ◽  
Pentose Phosphate ◽  
Response To Therapy ◽  
Live Cells ◽  
Normal Brain ◽  
Glioblastoma Cells ◽  
Non Invasive ◽  
Contralateral Normal Brain ◽  
Magnetic Resonance Imaging Mri

IntroductionThe pentose phosphate pathway (PPP) is essential for NADPH generation and redox homeostasis in cancer, including glioblastomas. However, the precise contribution to redox and tumor proliferation of the second PPP enzyme 6-phosphogluconolactonase (PGLS), which converts 6-phospho-δ-gluconolactone to 6-phosphogluconate (6PG), remains unclear. Furthermore, non-invasive methods of assessing PGLS activity are lacking. The goal of this study was to examine the role of PGLS in glioblastomas and assess the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive imaging.MethodsTo interrogate the function of PGLS in redox, PGLS expression was silenced in U87, U251 and GS2 glioblastoma cells by RNA interference and levels of NADPH and reduced glutathione (GSH) measured. Clonogenicity assays were used to assess the effect of PGLS silencing on glioblastoma proliferation. Hyperpolarized δ-[1-13C]gluconolactone metabolism to 6PG was assessed in live cells treated with the chemotherapeutic agent temozolomide (TMZ) or with vehicle control. 13C 2D echo-planar spectroscopic imaging (EPSI) studies of hyperpolarized δ-[1-13C]gluconolactone metabolism were performed on rats bearing orthotopic glioblastoma tumors or tumor-free controls on a 3T spectrometer. Longitudinal 2D EPSI studies of hyperpolarized δ-[1-13C]gluconolactone metabolism and T2-weighted magnetic resonance imaging (MRI) were performed in rats bearing orthotopic U251 tumors following treatment with TMZ to examine the ability of hyperpolarized δ-[1-13C]gluconolactone to report on treatment response.ResultsPGLS knockdown downregulated NADPH and GSH, elevated oxidative stress and inhibited clonogenicity in all models. Conversely, PGLS expression and activity and steady-state NADPH and GSH were higher in tumor tissues from rats bearing orthotopic glioblastoma xenografts relative to contralateral brain and tumor-free brain. Importantly, [1-13C]6PG production from hyperpolarized δ-[1-13C]gluconolactone was observed in live glioblastoma cells and was significantly reduced by treatment with TMZ. Furthermore, hyperpolarized δ-[1-13C]gluconolactone metabolism to [1-13C]6PG could differentiate tumor from contralateral normal brain in vivo. Notably, TMZ significantly reduced 6PG production from hyperpolarized δ-[1-13C]gluconolactone at an early timepoint prior to volumetric alterations as assessed by anatomical imaging.ConclusionsCollectively, we have, for the first time, identified a role for PGLS activity in glioblastoma proliferation and validated the utility of probing PGLS activity using hyperpolarized δ-[1-13C]gluconolactone for non-invasive in vivo imaging of glioblastomas and their response to therapy.

scholarly journals CBMT-08. IN VIVO EVALUATION OF PENTOSE PHOSPHATE PATHWAY ACTIVITY IN ORTHOTOPIC GLIOMA USING HYPERPOLARIZED δ-[1-13C]GLUCONOLACTONE

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi34-vi34
Author(s):  
Georgios Batsios ◽  
Pavithra Viswanath ◽  
Peng Cao ◽  
Celine Taglang ◽  
Elavarasan Subramani ◽  
...  
Keyword(s):  
Pentose Phosphate Pathway ◽  
Tumor Development ◽  
Pentose Phosphate ◽  
Response To Therapy ◽  
Metabolic Imaging ◽  
Normal Brain ◽  
In Vivo Evaluation ◽  
First Time ◽  
Orthotopic Glioma

Abstract The pentose phosphate pathway (PPP) generates NADPH and ribose 5-phosphate, which are involved in the scavenging of reactive oxygen species and the synthesis of nucleotides. As such, the PPP is typically upregulated in cancer cells to address the metabolic needs of rapid cell proliferation. Imaging PPP upregulation could therefore be useful in tumor assessment. One intermediate of the pathway is 6-phospho-δ-gluconolactone (6P-δ-GL), which is produced by phosphorylation of δ-gluconolactone. 6P-δ-GL is further metabolized to 6-phospho-gluconate (6PG). The goal of our study was to evaluate, for the first time, whether hyperpolarized (HP) δ-[1-13C]gluconolactone can be used to assess PPP flux and detect the presence of tumor in an orthotopic glioma rat model. Athymic nude rats bearing orthotropic U87 tumors or age-matched tumor-free controls were investigated. HP studies were performed following intravenous injection of HP δ-[1-13C]gluconolactone and metabolic images using a flyback spectral-spatial echo-planar spectroscopic imaging pulse were acquired. The data were processed using in-house Matlab code. 6P-δ-GL and 6-phospho-γ-[1-13C]gluconolactone were observed in all rats ~10 seconds after HP δ-[1-13C]gluconolactone injection, followed ~5 seconds later by production of 6PG observed at 179.3ppm. These data indicate that HP δ-[1-13C]gluconolactone likely crosses the blood-brain barrier, consistent with its transport via glucose transporters, and is rapidly metabolized. Importantly, 6PG was significantly higher in tumor voxels. The ratio of 6PG-to-6P-δ-GL was comparable in normal brain and in normal-appearing contralateral brain of tumor-bearing rats at 0.43±0.09 and 0.45±0.06 respectively (p=0.85), but significant higher in the tumor regions at 0.70±0.11 (p=0.04 and p=0.02 respectively), consistent with the elevated PPP flux that typically occurs in tumor cells. Our results indicate, to our knowledge for the first time, that metabolism of HP δ-[1-13C]gluconolactone can be assessed in the brain and that elevated 6PG production in glioma provides a potential metabolic imaging approach to probe tumor development, recurrence and response to therapy.

scholarly journals Non-invasive diagnostics in fossils - Magnetic Resonance Imaging of pathological belemnites

2005 ◽  
Vol 2 (2) ◽  
pp. 133-140 ◽  
Author(s):  
D. Mietchen ◽  
H. Keupp ◽  
B. Manz ◽  
F. Volke
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Soft Tissue ◽  
Clinical Diagnostics ◽  
Resonance Imaging ◽  
Non Invasive ◽  
Physiological Processes ◽  
Magnetic Resonance Imaging Mri ◽  
Invasive Diagnostics

Abstract. For more than a decade, Magnetic Resonance Imaging (MRI) has been routinely employed in clinical diagnostics because it allows non-invasive studies of anatomical structures and physiological processes in vivo and to differentiate between healthy and pathological states, particularly of soft tissue. Here, we demonstrate that MRI can likewise be applied to fossilized biological samples and help in elucidating paleopathological and paleoecological questions: Five anomalous guards of Jurassic and Cretaceous belemnites are presented along with putative paleopathological diagnoses directly derived from 3D MR images with microscopic resolution. Syn vivo deformities of both the mineralized internal rostrum and the surrounding former soft tissue can be traced back in part to traumatic events of predator-prey-interactions, and partly to parasitism. Besides, evidence is presented that the frequently observed anomalous apical collar might be indicative of an inflammatory disease. These findings highlight the potential of Magnetic Resonance techniques for further paleontological applications.

scholarly journals Study of Osteocyte Behavior by High-Resolution Intravital Imaging Following Photo-Induced Ischemia

Molecules ◽  
2018 ◽  
Vol 23 (11) ◽  
pp. 2874
Author(s):  
Hengfeng Yuan ◽  
Wen Jiang ◽  
Yuanxin Chen ◽  
Betty Kim
Keyword(s):  
Imaging Techniques ◽  
Avascular Osteonecrosis ◽  
Functional Changes ◽  
Cellular Processes ◽  
Non Invasive ◽  
Behavioral Dynamics ◽  
Bony Anatomy ◽  
Magnetic Resonance Imaging Mri

Ischemic injuries and local hypoxia can result in osteocytes dysfunction and play a key role in the pathogenesis of avascular osteonecrosis. Conventional imaging techniques including magnetic resonance imaging (MRI) and computed tomography (CT) can reveal structural and functional changes within bony anatomy; however, characterization of osteocyte behavioral dynamics in the setting of osteonecrosis at the single cell resolution is limited. Here, we demonstrate an optical approach to study real-time osteocyte functions in vivo. Using nicotinamide adenine dinucleotide (NADH) as a biomarker for metabolic dynamics in osteocytes, we showed that NADH level within osteocytes transiently increase significantly after local ischemia through non-invasive photo-induced thrombosis of afferent arterioles followed by a steady decline. Our study presents a non-invasive optical approach to study osteocyte behavior through the modulation of local environmental conditions. Thus it provides a powerful toolkit to study cellular processes involved in bone pathologies in vivo.

scholarly journals Quantitative PET imaging of PD-L1 expression in xenograft and syngeneic tumour models using a site-specifically labelled PD-L1 antibody

2019 ◽  
Vol 47 (5) ◽  
pp. 1302-1313 ◽  
Author(s):  
Camilla Christensen ◽  
Lotte K. Kristensen ◽  
Maria Z. Alfsen ◽  
Carsten H. Nielsen ◽  
Andreas Kjaer
Keyword(s):  
Pet Imaging ◽  
Predictive Value ◽  
Ex Vivo ◽  
Response To Therapy ◽  
Whole Body ◽  
Therapeutic Monitoring ◽  
Non Invasive ◽  
Tumour Bearing ◽  
Quantitative Pet

Abstract Purpose Despite remarkable clinical responses and prolonged survival across several cancers, not all patients benefit from PD-1/PD-L1 immune checkpoint blockade. Accordingly, assessment of tumour PD-L1 expression by immunohistochemistry (IHC) is increasingly applied to guide patient selection, therapeutic monitoring, and improve overall response rates. However, tissue-based methods are invasive and prone to sampling error. We therefore developed a PET radiotracer to specifically detect PD-L1 expression in a non-invasive manner, which could be of diagnostic and predictive value. Methods Anti-PD-L1 (clone 6E11, Genentech) was site-specifically conjugated with DIBO-DFO and radiolabelled with 89Zr (89Zr-DFO-6E11). 89Zr-DFO-6E11 was optimized in vivo by longitudinal PET imaging and dose escalation with excess unlabelled 6E11 in HCC827 tumour-bearing mice. Specificity of 89Zr-DFO-6E11 was evaluated in NSCLC xenografts and syngeneic tumour models with different levels of PD-L1 expression. In vivo imaging data was supported by ex vivo biodistribution, flow cytometry, and IHC. To evaluate the predictive value of 89Zr-DFO-6E11 PET imaging, CT26 tumour-bearing mice were subjected to external radiation therapy (XRT) in combination with PD-L1 blockade. Results 89Zr-DFO-6E11 was successfully labelled with a high radiochemical purity. The HCC827 tumours and lymphoid tissue were identified by 89Zr-DFO-6E11 PET imaging, and co-injection with 6E11 increased the relative tumour uptake and decreased the splenic uptake. 89Zr-DFO-6E11 detected the differences in PD-L1 expression among tumour models as evaluated by ex vivo methods. 89Zr-DFO-6E11 quantified the increase in PD-L1 expression in tumours and spleens of irradiated mice. XRT and anti-PD-L1 therapy effectively inhibited tumour growth in CT26 tumour-bearing mice (p < 0.01), and the maximum 89Zr-DFO-6E11 tumour-to-muscle ratio correlated with response to therapy (p = 0.0252). Conclusion PET imaging with 89Zr-DFO-6E11 is an attractive approach for specific, non-invasive, whole-body visualization of PD-L1 expression. PD-L1 expression can be modulated by radiotherapy regimens and 89Zr-DFO-6E11 PET is able to monitor these changes and predict the response to therapy in an immunocompetent tumour model.

scholarly journals Targeted Molecular Imaging Using Aptamers in Cancer

2018 ◽  
Vol 11 (3) ◽  
pp. 71 ◽  
Author(s):  
Sorah Yoon ◽  
John Rossi
Keyword(s):  
Wide Spectrum ◽  
Rna Aptamers ◽  
Tissue Imaging ◽  
Live Cells ◽  
Target Cells ◽  
New Class ◽  
Non Invasive ◽  
Resolution Imaging ◽  
Tissue Specimens

Imaging is not only seeing, but also believing. For targeted imaging modalities, nucleic acid aptamers have features such as superior recognition of structural epitopes and quick uptake in target cells. This explains the emergence of an evolved new class of aptamers into a wide spectrum of imaging applications over the last decade. Genetically encoded biosensors tagged with fluorescent RNA aptamers have been developed as intracellular imaging tools to understand cellular signaling and physiology in live cells. Cancer-specific aptamers labeled with fluorescence have been used for assessment of clinical tissue specimens. Aptamers conjugated with gold nanoparticles have been employed to develop innovative mass spectrometry tissue imaging. Also, use of chemically conjugated cancer-specific aptamers as probes for non-invasive and high-resolution imaging has been transformative for in vivo imaging in multiple cancers.

scholarly journals Imaging of microglial activation in MS using PET: Research use and potential future clinical application

2016 ◽  
Vol 23 (4) ◽  
pp. 496-504 ◽  
Author(s):  
Laura Airas ◽  
Eero Rissanen ◽  
Juha Rinne
Keyword(s):  
Complex Disease ◽  
Treatment Options ◽  
Quantitative Information ◽  
Imaging Biomarkers ◽  
In Vivo Evaluation ◽  
Non Invasive ◽  
Positron Emission ◽  
Magnetic Resonance Imaging Mri

Multiple sclerosis (MS) is a complex disease, where several processes can be selected as a target for positron emission topography (PET) imaging. Unlike magnetic resonance imaging (MRI), PET provides specific and quantitative information, and unlike neuropathology, it can be non-invasively applied to living patients, which enables longitudinal follow-up of the MS pathology. In the study of MS, PET can be useful for in vivo evaluation of specific pathological characteristics at various stages of the disease. Increased understanding of the progressive MS pathology will enhance the treatment options of this undertreated condition. The ultimate goal of developing and expanding PET in the study of MS is to have clinical non-invasive in vivo imaging biomarkers of neuroinflammation that will help to establish prognosis and accurately measure response to therapeutics. This topical review provides an overview of the promises and challenges of the use of PET in MS.

scholarly journals CBMT-41. IMAGING A HALLMARK OF CANCER: HYPERPOLARIZED 13C-MAGNETIC RESONANCE SPECTROSCOPY CAN NON-INVASIVELY MONITOR TERT EXPRESSION IN LOW-GRADE GLIOMAS IN VIVO

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi42-vi42
Author(s):  
Pavithra Viswanath ◽  
Georgios Batsios ◽  
Anne Marie Gillespie ◽  
Russell O Pieper ◽  
Sabrina Ronen
Keyword(s):  
Lactate Production ◽  
Metabolic Imaging ◽  
Imaging Biomarkers ◽  
Resonance Spectroscopy ◽  
Low Grade ◽  
Normal Brain ◽  
Non Invasive ◽  
Glucose Flux ◽  
Tert Expression

Abstract Telomerase reverse transcriptase (TERT) expression is a hallmark of cancer, including in primary glioblastomas and low-grade oligodendrogliomas. Since TERT is essential for glioma proliferation and is an attractive therapeutic target, metabolic imaging of TERT status can inform on tumor progression and response to therapy. To that end, the goal of this study was to identify non-invasive, translational, hyperpolarized 13C-magnetic resonance spectroscopy-detectable metabolic imaging biomarkers of TERT in low-grade oligodendrogliomas. Unbiased metabolomic analysis of immortalized normal human astrocytes without (NHAcontrol) and with TERT (NHAtert) indicated that TERT induced unique metabolic reprogramming. Notably, TERT increased NADPH and NADH levels. Glucose flux through the pentose phosphate pathway (PPP) is a major producer of NADPH. Non-invasive imaging of PPP flux using hyperpolarized [U-13C,U-2H]-glucose indicated that production of the PPP metabolite 6-phosphogluconate (6-PG) was elevated in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [U-13C,U-2H]-glucose flux to 6-PG clearly differentiated tumor from normal brain in orthotopic NHAtert tumor xenografts. Next, we exploited the observation that TERT expression increased NADH, which is essential for the metabolism of hyperpolarized [1-13C]-alanine to lactate. Lactate production from hyperpolarized [1-13C]-alanine was higher in NHAtert cells relative to NHAcontrol. Importantly, hyperpolarized [1-13C]-alanine imaging in orthotopic NHAtert tumors revealed pronounced differences in lactate production between tumor tissue and normal brain. Mechanistically, TERT increased expression of glucose-6-phosphate dehydrogenase (G6PDH), the rate-limiting enzyme for 6-PG and NADPH production, and of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme for NADH biosynthesis. Silencing TERT reversed G6PDH and NAMPT expression and normalized hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine metabolism, validating our imaging biomarkers. Finally, hyperpolarized [U-13C,U-2H]-glucose and [1-13C]-alanine could monitor TERT status in the clinically relevant, patient-derived BT54 oligodendroglioma model. In summary, we demonstrate, for the first time, non-invasive in vivo imaging of TERT status in gliomas that can enable longitudinal analysis of tumor burden and treatment response in the clinic.

Non-invasive monitoring of patient-derived orthotopic xenograft: An optimal system for rapid in vivotesting.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 235-235
Author(s):  
Mayrim V. Rios Perez ◽  
Michael Pratt ◽  
Ya'an Kang ◽  
Jason B. Fleming
Keyword(s):  
Tumor Growth ◽  
Mouse Models ◽  
Response To Therapy ◽  
Ductal Adenocarcinoma ◽  
In Vivo Models ◽  
Treatment Groups ◽  
Non Invasive ◽  
Orthotopic Xenograft ◽  
Metastatic Burden

235 Background: Heterotopic patient-derived xenografts (PDX) have been used to assess response to therapy however they underrepresent the role of tumor microenvironment and rarely develop metastasis, both of which are overcome by orthotopic models. Fluorescent orthotopic mouse models require invasive measures to determine tumor bioluminescence. Ultrasonography (US) is a cost-effective, non-invasive imaging technique that has been used in genetically engineered mouse models of pancreatic cancer for a three-dimensional (3D) acquisition of tumor volume, which allows rapid and safe in vivo drug testing. We intend to demonstrate that this technique allows real time monitoring of in vivo response to therapy using patient-derived orthotopic xenograft (PDOX) of pancreatic ductal adenocarcinoma (PDAC). Methods: A non-survival study using PDOX was designed with control (n = 5) and treatment (n = 5) groups. Weekly 3D US images were obtained pre and post-treatment over 4 weeks. Tumor growth curves were generated to monitor progression of disease. Metastatic burden was determined during necropsy. Results: One mouse was excluded from control and treatment groups due to baseline tumor size exceeding 300mm3 and drug toxicity, respectively. Pre-treatment average tumor volumes for control and treatment groups were (36±12)mm3 and (34±12)mm3, respectively. No difference was found in average tumor growth over time between groups (p = 0.9120). A 20% tumor regression was observed per group. Both groups exhibited gross metastasis to spleen, peritoneum, and omentum. Liver, periportal metastasis and local extension to the gastrointestinal and genitourinary system were present on the treatment group. Conclusions: This study describes a rapid technique for in vivo drug response by using 3D US to monitor PDOX; failure of response to therapy correlated with metastatic burden observed. PDOX regression could be explained by tumor heterogeneity. PDOX models, as challenging as they could be, remain to be necessary in vivo models to show therapeutic response to human PDAC, which could be easily monitored using 3D US imaging.

scholarly journals Sensitive detection of extremely small iron oxide nanoparticles in living mice using MP2RAGE with advanced image co-registration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joong H. Kim ◽  
Stephen Dodd ◽  
Frank Q. Ye ◽  
Andrew K. Knutsen ◽  
Duong Nguyen ◽  
...  
Keyword(s):  
Iron Oxide ◽  
Contrast Agents ◽  
Iron Oxide Nanoparticles ◽  
Mouse Brain ◽  
Oxide Nanoparticles ◽  
Non Invasive ◽  
T1 Map ◽  
Magnetic Resonance Imaging Mri ◽  
Molecular Contrast

AbstractMagnetic resonance imaging (MRI) is a widely used non-invasive methodology for both preclinical and clinical studies. However, MRI lacks molecular specificity. Molecular contrast agents for MRI would be highly beneficial for detecting specific pathological lesions and quantitatively evaluating therapeutic efficacy in vivo. In this study, an optimized Magnetization Prepared—RApid Gradient Echo (MP-RAGE) with 2 inversion times called MP2RAGE combined with advanced image co-registration is presented as an effective non-invasive methodology to quantitatively detect T1 MR contrast agents. The optimized MP2RAGE produced high quality in vivo mouse brain T1 (or R1 = 1/T1) map with high spatial resolution, 160 × 160 × 160 µm3 voxel at 9.4 T. Test–retest signal to noise was > 20 for most voxels. Extremely small iron oxide nanoparticles (ESIONPs) having 3 nm core size and 11 nm hydrodynamic radius after polyethylene glycol (PEG) coating were intracranially injected into mouse brain and detected as a proof-of-concept. Two independent MP2RAGE MR scans were performed pre- and post-injection of ESIONPs followed by advanced image co-registration. The comparison of two T1 (or R1) maps after image co-registration provided precise and quantitative assessment of the effects of the injected ESIONPs at each voxel. The proposed MR protocol has potential for future use in the detection of T1 molecular contrast agents.

scholarly journals The pentose phosphate pathway regulates chronic neuroinflammation and dopaminergic neurodegeneration

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Dezhen Tu ◽  
Yun Gao ◽  
Ru Yang ◽  
Tian Guan ◽  
Jau-Shyong Hong ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Pentose Phosphate Pathway ◽  
Microglial Activation ◽  
Redox Homeostasis ◽  
Pentose Phosphate ◽  
Transgenic Expression ◽  
Dopaminergic Neurodegeneration ◽  
Locomotor Impairment

Abstract Background Metabolic dysfunction and neuroinflammation are increasingly implicated in Parkinson’s disease (PD). The pentose phosphate pathway (PPP, a metabolic pathway parallel to glycolysis) converts glucose-6-phosphate into pentoses and generates ribose-5-phosphate and NADPH thereby governing anabolic biosynthesis and redox homeostasis. Brains and immune cells display high activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP. A postmortem study reveals dysregulation of G6PD enzyme in brains of PD patients. However, spatial and temporal changes in activity/expression of G6PD in PD remain undetermined. More importantly, it is unclear how dysfunction of G6PD and the PPP affects neuroinflammation and neurodegeneration in PD. Methods We examined expression/activity of G6PD and its association with microglial activation and dopaminergic neurodegeneration in multiple chronic PD models generated by an intranigral/intraperitoneal injection of LPS, daily subcutaneous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 6 days, or transgenic expression of A53T α-synuclein. Primary microglia were transfected with G6PD siRNAs and treated with lipopolysaccharide (LPS) to examine effects of G6PD knockdown on microglial activation and death of co-cultured neurons. LPS alone or with G6PD inhibitor(s) was administrated to mouse substantia nigra or midbrain neuron-glia cultures. While histological and biochemical analyses were conducted to examine microglial activation and dopaminergic neurodegeneration in vitro and in vivo, rotarod behavior test was performed to evaluate locomotor impairment in mice. Results Expression and activity of G6PD were elevated in LPS-treated midbrain neuron-glia cultures (an in vitro PD model) and the substantia nigra of four in vivo PD models. Such elevation was positively associated with microglial activation and dopaminergic neurodegeneration. Furthermore, inhibition of G6PD by 6-aminonicotinamide and dehydroepiandrosterone and knockdown of microglial G6PD attenuated LPS-elicited chronic dopaminergic neurodegeneration. Mechanistically, microglia with elevated G6PD activity/expression produced excessive NADPH and provided abundant substrate to over-activated NADPH oxidase (NOX2) leading to production of excessive reactive oxygen species (ROS). Knockdown and inhibition of G6PD ameliorated LPS-triggered production of ROS and activation of NF-кB thereby dampening microglial activation. Conclusions Our findings indicated that G6PD-mediated PPP dysfunction and neuroinflammation exacerbated each other mediating chronic dopaminergic neurodegeneration and locomotor impairment. Insight into metabolic-inflammatory interface suggests that G6PD and NOX2 are potential therapeutic targets for PD.

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