Neurochemical Research最新文献

{"title":"Dopamine D1-Like Receptor Stimulation Induces CREB, Arc, and BDNF Dynamic Changes in Differentiated SH-SY5Y Cells","authors":"Omar B. Rivera-Maya,&nbsp;Christian D. Ortiz-Robles,&nbsp;José R. Palacios-Valladares,&nbsp;Emma S. Calderón-Aranda","doi":"10.1007/s11064-024-04293-8","DOIUrl":"10.1007/s11064-024-04293-8","url":null,"abstract":"<div><p>The dopamine D1-like receptor is a dopamine (DA) receptor regulating diverse brain functions. Once the dopamine D1-like receptor is activated, it induces activation of the Protein Kinase A (PKA) that phosphorylates the cAMP Response Element-Binding (CREB) transcription factor, which once active elicits the expression of the critical synaptic elements Activity-regulated cytoskeleton-associated (Arc) and the Brain-Derived Neurotrophic Factor (BDNF). The temporality and subcellular localization of proteins impact brain function. However, there is no information about the temporality of CREB activation and Arc and BDNF levels induced through dopamine D1-like receptor activation. In this study, we aimed to assess the specific effect of dopamine D1-like receptor activation on the temporality of CREB-phosphorylation (p-CREB^S133) and the spatiotemporal induction of Arc and BDNF. Using SY-SY5Y cells differentiated with Retinoic Acid (RA), the dopamine D1-like receptor activation with a specific agonist transiently increased p-CREB^S133 at 30 min of stimulation. It induced two spikes of Arc protein at 15 min and 6 h, forming clusters near the cell membrane. BDNF secretion temporarily increased, reaching a maximum at 6 h, while secretion was lower at 24 h compared to the unstimulated group. Our results provide new insight into the role of dopamine D1-like receptor activation on CREB activation, Arc, and BDNF increase, showing that these effects occur temporally and for Arc in subcellular specific sites. This study highlights the dopaminergic system as a critical regulator of subcellular events relevant to neuron plasticity. Future research should address the study of the implications for brain function and behavior.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-024-04293-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Doxophylline, a Non-Selective Phosphodiesterase Inhibitor, Protects Against Chronic Fatigue-Induced Neurobehavioral, Biochemical, and Mitochondrial Alterations","authors":"Anushka Vashishth,&nbsp;Garima Sharma,&nbsp;Ankan Sarkar,&nbsp;Monika Kadian,&nbsp;Manish Jain,&nbsp;Anil Kumar","doi":"10.1007/s11064-024-04295-6","DOIUrl":"10.1007/s11064-024-04295-6","url":null,"abstract":"<div><p>Chronic fatigue stress (CFS) is a multisystem disorder which exhibits multiple signs of neurological complications like brain fog, cognitive deficits and oxidative stress with no specific treatment. Doxophylline, a non-selective phosphodiesterase inhibitor (PDEI), has anti-inflammatory properties with enhanced blood-brain barrier penetration and tissue specificity. We have evaluated the neuroprotective potential of doxophylline in a murine model of forced swim test (FST) induced CFS and in H₂O₂ (hydrogen peroxide) induced oxidative stress in PC12 cells. An FST model to induce a state of CFS in mice was induced by forcing them to swim daily for 6 min for 15 days. The drug was administered daily 30 min prior to FST. The immobility period was compared for day 1 and day 15. Animals were sacrificed on day 16 for biochemical, mitochondrial, and histopathological estimations in the brain. Cytotoxicity assay, reactive oxygen species (ROS) and nuclear morphology determination were carried out in PC12 cells. A significant increase in immobility has been observed on the 15th day in CFS-induced mice compared to doxophylline treated group. Neurobehavioral studies revealed hypo locomotion, anxiety, motor incoordination, and memory deficit. Biochemical analysis showed a significant change in oxidative stress markers (superoxide dismutase (SOD), reduced glutathione (GSH), catalase, lipid peroxidation (LPO) and nitrite levels) and acetylcholinesterase enzyme activity (AChE) in brain homogenates. Doxophylline pre-treatment protects against these impairments. In PC12 cell lines, doxophylline exhibits alleviation against H₂O₂-induced oxidative stress, intracellular ROS generation, and changes in nuclear morphology. Doxophylline could be promising and possess therapeutic potential in CFS treatment. Further research is needed to test if doxophylline can be repurposed for neurological disorders.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis in the Substantia Nigra Pars Compacta of Mice: Triggering Role of Ultrafine Diesel Exhaust Particles and Mitigation by α-Lipoic Acid","authors":"Ji Young Kim,&nbsp;Aryun Kim,&nbsp;Jin-Hee Kim,&nbsp;Young-Chun Gil,&nbsp;Yong-Dae Kim,&nbsp;Dong-Ick Shin,&nbsp;Je Hoon Seo","doi":"10.1007/s11064-024-04278-7","DOIUrl":"10.1007/s11064-024-04278-7","url":null,"abstract":"<div><p>Recent epidemiological and experimental studies have increasingly highlighted the association between environmental pollution, especially ultrafine particulate matter (PM), and the risk of neurodegenerative diseases, such as Parkinson’s disease (PD). These previous studies suggest a potential mechanism by which ultrafine PM contributes to neuronal damage through processes, such as iron accumulation and oxidative stress. In this study, we aimed to elucidate the effects of ultrafine PM on ferroptosis, an iron-dependent form of cell death, in the mouse substantia nigra pars compacta (SNc) and to evaluate the protective role of α-lipoic acid (ALA). Mice were exposed to ultrafine diesel exhaust particles (ufDEP), a type of ultrafine PM, intranasally and injected ALA intraperitoneally for seven consecutive days. Iron accumulation and lipid peroxidation were significantly increased, and antioxidant capacity was significantly decreased in the SNc after ufDEP exposure, highlighting the deleterious effects of ufDEP on tyrosine hydroxylase (TH)-positive neurons. In contrast, ALA treatment effectively mitigated these effects by reducing iron accumulation, decreasing lipid peroxidation, and restoring antioxidant levels, resulting in the protection of TH-positive neurons from ferroptotic damage. Our results provide evidence that ufDEP can induce ferroptosis in dopaminergic neurons in the SNc, potentially contributing to PD pathogenesis. Furthermore, ALA showed protective effects against ufDEP-induced ferroptotic damage, suggesting its potential as a therapeutic intervention for PD.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Piezo1 Modulates Neuronal Autophagy and Apoptosis in Cerebral Ischemia–Reperfusion Injury Through the AMPK-mTOR Signaling Pathway","authors":"Yingjie Yue,&nbsp;Pingping Chen,&nbsp;Chongwen Ren","doi":"10.1007/s11064-024-04291-w","DOIUrl":"10.1007/s11064-024-04291-w","url":null,"abstract":"<div><p>Cerebral ischemia–reperfusion (I/R) injury is a complex pathophysiological process involving multiple mechanisms, including apoptosis and autophagy, which can lead to significant neuronal damage. PIEZO1, a stretch-activated ion channel, has recently emerged as a potential regulator of cellular responses to ischemic conditions. However, its role in neuronal cell survival and death during ischemic events is not well elucidated. This study aimed to ascertain the regulatory function of PIEZO1 in neuronal cell apoptosis and autophagy in an in vitro model of hypoxia-reoxygenation and an in vivo model of brain I/R injury. HT22 hippocampal neuronal cells were subjected to oxygen–glucose deprivation/reoxygenation (OGD/R) to simulate ischemic conditions, with subsequent reoxygenation. In vitro, PIEZO1 expression was silenced using small interfering RNA (si-RNA) transfection. The effects on cell viability, apoptosis, and autophagy were assessed using CCK-8 assays, PI-Annexin/V staining combined with flow cytometry, and Western blot analysis. Additionally, intracellular Ca²⁺ levels in HT22 cells were measured using a Ca²⁺ probe. The involvement of the AMPK-mTOR pathway was investigated using rapamycin. For in vivo validation, middle cerebral artery occlusion/reperfusion (MCAO/R) in rats was employed. To determine the neuroprotective role of PIEZO1 silencing, sh-PIEZO1 adeno-associated virus was stereotaxically injected into the cerebral ventricle, and neurological and histological outcomes were assessed using neurological scoring, TTC staining, H&amp;E staining, Nissl staining, and immunofluorescence. In HT22 cells, OGD/R injury notably upregulated PIEZO1 expression and intracellular Ca²⁺ levels. Silencing PIEZO1 significantly diminished OGD/R-induced Ca²⁺ influx, apoptosis, and autophagy, as indicated by lower levels of pro-apoptotic and autophagy-related proteins and improved cell viability. Additionally, PIEZO1 modulated the AMPK-mTOR signaling pathway, an effect that was counteracted by rapamycin treatment, implying its regulatory role. In vivo, PIEZO1 silencing ameliorated brain I/R injury in MCAO/R rats, demonstrated by improved neurological function scores and reduced neuronal apoptosis and autophagy. However, these neuroprotective effects were reversed through rapamycin treatment. Our findings indicate that PIEZO1 is upregulated following ischemic injury and facilitates Ca²⁺ influx, apoptosis, and autophagy via the AMPK-mTOR pathway. Silencing PIEZO1 confers neuroprotection against I/R injury both in vitro and in vivo, highlighting its potential as a therapeutic target for stroke management.</p><h3>Graphical Abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebrolysin Induces Motor Recovery Along with Plastic Changes in Motoneurons and an Increase in GAP43 Protein in the Ventral Spinal Cord Following a Kainic Acid Excitotoxic Lesion in the Rat Motor Cortex","authors":"Nestor I. Martínez-Torres,&nbsp;Jhonathan Cárdenas-Bedoya,&nbsp;Blanca Miriam Torres-Mendoza","doi":"10.1007/s11064-024-04288-5","DOIUrl":"10.1007/s11064-024-04288-5","url":null,"abstract":"<div><p>Lesions in the motor cortex induced by contusions or pathological insults can exert the degeneration of afferent neurons lying distal to these lesions. Axon degeneration and demyelination are hallmarks of several diseases sharing pathophysiological and clinical characteristics. These conditions are very disabling due to the disruption of motor abilities, with lesions that affect this area proving to be a therapeutic challenge, which has driven increasing efforts to search for treatments. Cerebrolysin (CBL) contains a mix of pig brain-derived peptides with activity similar to neurotrophic factors. Here, the effect of cerebrolysin administration on the motor impairment produced by kainic acid (KA) lesion of the motor cortex was evaluated in Sprague–Dawley female rats (n = 27), defining its effect on motoneurons dendritic tree changes, dendritic spine density and GAP43 presence in the ventral thoracolumbar regions of the spinal cord. Ten days after the KA lesion of the motor cortex, rats were administered cerebrolysin, and their motor performance was evaluated using the “Basso, Beattie, and Bresnahan” (BBB) and Bederson scores. Cerebrolysin administration improved motor activity according to the BBB and Bederson scales, along with increased dendritic intersections and dendritic spine density on motoneurons. There was also a significant increase in GAP43 protein, suggesting that CBL may promote plastic changes through this protein, among others. Hence, this study proposes that cerebrolysin could promote motor recovery following motor cortex lesions by driving neuronal changes and dendritic spine plasticity on motoneurons and an increase in GAP43 protein, along with other mechanisms.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chaperone-Mediated Autophagy Alleviates Cerebral Ischemia–Reperfusion Injury by Inhibiting P53-Mediated Mitochondria-Associated Apoptosis","authors":"Shaonan Yang,&nbsp;Lu Jiang,&nbsp;Ling Deng,&nbsp;Jingjing Luo,&nbsp;Xiaoling Zhang,&nbsp;Sha Chen,&nbsp;Zhi Dong","doi":"10.1007/s11064-024-04266-x","DOIUrl":"10.1007/s11064-024-04266-x","url":null,"abstract":"<div><p>Ischemia–reperfusion is a complex brain disease involving multiple biological processes, including autophagy, oxidative stress, and mitochondria-associated apoptosis. Chaperone-mediated autophagy (CMA), a selective autophagy, is involved in the development of various neurodegenerative diseases and acute nerve injury, but its role in ischemia–reperfusion is unclear. Here, we used middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen–glucose deprivation/reoxygenation (OGD/R) models to simulate cerebral ischemic stroke in vivo and in vitro, respectively. LAMP2A (lysosome-associated membrane protein 2A), a key molecule of CMA, was dramatically downregulated in ischemia–reperfusion. Enhancement of CMA activity by LAMP2A overexpression reduced the neurological deficit, brain infarct volume, pathological features, and neuronal apoptosis of the cortex in vivo. Concomitantly, enhanced CMA activity alleviated OGD/R-induced apoptosis and mitochondrial membrane potential decline in vitro. In addition, we found that CMA inhibited the P53(Tumor protein p53) signaling pathway and reduced P53 translocation to mitochondria. The P53 activator, Nutlin-3, not only reversed the inhibitory effect of CMA on apoptosis, but also significantly weakened the protective effect of CMA on OGD/R and MCAO/R. Taken together, these results indicate that inhibition of P53-mediated mitochondria-associated apoptosis is essential for the neuroprotective effect of CMA against ischemia–reperfusion.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective Effect of Maresin-1 in Rotenone-Induced Parkinson’s Disease in Rats: The Putative Role of the JAK/STAT Pathway","authors":"Suzan A. Khodir,&nbsp;Eman M. Sweed,&nbsp;Manar A. Faried,&nbsp;Doaa M. Abo Elkhair,&nbsp;Marwa M. Khalil,&nbsp;Khaled Hatem Afifi,&nbsp;Dalia Fathy El Agamy","doi":"10.1007/s11064-024-04282-x","DOIUrl":"10.1007/s11064-024-04282-x","url":null,"abstract":"<div><p>Exposure to rotenone results in similar pathophysiological features as Parkinson’s disease. Inflammation and oxidative stress are essential to PD pathogenesis. Maresin-1 has potent anti-inflammatory properties and promotes the regression of inflammation function. The current study aimed to evaluate the protective effects of Maresin-1 (MaR1) in rotenone (ROT)-induced PD and whether this protective role is associated with the initiation of the Janus kinase (JAK)-signal transducers and activator of transcription (STAT) signaling pathway. Thirty male Wister rats were classified into control, ROT-treated, and ROT + MaR1-treated groups. Rats underwent rotarod, open field, grip strength, and stepping tests as part of their motor behavioral evaluation. Serum glial cell-derived neurotrophic factor (GDNF) and striatal dopamine, acetylcholine, malondialdehyde (MDA), reduced glutathione (GSH), TNF-α, IL-6, and IL-1β were evaluated. Expression of JAK1 and STAT3 genes was assessed in striatum. Then, the tissue was subjected to histological and immunohistochemical evaluation for caspase-3, GFAP, and NF-kB. The administrated group with rotenone showed significant motor behavioral impairment. This was accompanied by reduced levels of GDNF and dopamine and increased levels of acetylcholine, as well as augmented oxidative stress and inflammatory biomarkers and reduced antioxidant activity. Inflammatory pathways (JAK1/STAT3, caspase-3, and NF-kB) were upregulated. Histopathological changes and upregulation in GFAP immunopositive reaction were observed. Remarkably, MaR1 treatment effectively alleviated behavior, histopathological changes, and biochemical alterations induced by ROT. MaR1 exerts protective effects against ROT-induced PD by its anti-inflammatory, antiapoptotic, and antioxidant properties. MaR1 mechanisms of action may involve modulation of pathways such as JAK/STAT.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-024-04282-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dimethyl Fumarate Reduces Methylglyoxal-derived Carbonyl Stress Through Nrf2/GSH Activation in SH-SY5Y Cells","authors":"Shin Koike,&nbsp;Satori Tsurudome,&nbsp;Saki Okano,&nbsp;Atsushi Kishida,&nbsp;Yuki Ogasawara","doi":"10.1007/s11064-024-04255-0","DOIUrl":"10.1007/s11064-024-04255-0","url":null,"abstract":"<div><p>Carbonyl stress refers to the excessive accumulation of advanced glycation end products (AGEs) in mammalian tissues. This phenomenon plays a significant role in the pathogenesis of various diseases, including diabetes, chronic renal failure, arteriosclerosis, and central nervous system (CNS) disorders. We have previously demonstrated that an increase in glutathione concentration, dependent on the nuclear factor erythroid 2–related factor 2 (Nrf2) system, provides a potent cytoprotective effect against Methylglyoxal (MGO)-induced carbonyl stress. Meanwhile, dimethyl fumarate (DMF), known for its Nrf2-activating effects, was recently approved as a treatment for multiple sclerosis (MS), a neurodegenerative disease. DMF is a first line therapy for relapsing–remitting MS and may also be effective for other neurodegenerative conditions. However, the detailed mechanisms by which DMF mitigates neurodegenerative pathologies remain unclear. This study investigates the impact of DMF on anticarbonyl activity and its underlying mechanism focusing on the accumulation of carbonyl protein in the cell. MGO, a glucose metabolite, was used to induce carbonylation in the neuronal cell line. MGO is a typical carbonyl compound that readily reacts with arginine and lysine residues to form AGE-modified proteins. Methylglyoxal-derived hydroimidazolone 1 (MG-H1) often forms uncharged, hydrophobic residues on the protein surface, which can affect protein distribution and lead to misfolding. Our findings indicate that DMF increases levels of glutathione (GSH), glutamate cysteine ligase modifier subunit (GCLM), and nuclear Nrf2 in SH-SY5Y cells. Importantly, DMF pretreatment significantly reduced the accumulation of MG-H1-modified proteins. Furthermore, this effect of DMF was diminished when Nrf2 expression was suppressed and when GCL, a rate-limiting enzyme in GSH synthesis, was inhibited. Thus, the increase in GSH levels, leading to the activation of the Nrf2 pathway, a key factor in DMF’s ability to suppress the accumulation of MG-H1-modified proteins. This study is the first to demonstrate that DMF possesses strong anticarbonyl stress activity in neuronal cells. Therefore, future research may extend the application of DMF to other CNS diseases associated with carbonyl stress, such as Alzheimer’s and Parkinson’s disease.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dopamine D1 and NMDA Receptor Co-Regulation of Protein Translation in Cultured Nucleus Accumbens Neurons","authors":"Alexa R. Zimbelman,&nbsp;Benjamin Wong,&nbsp;Conor H. Murray,&nbsp;Marina E. Wolf,&nbsp;Michael T. Stefanik","doi":"10.1007/s11064-024-04283-w","DOIUrl":"10.1007/s11064-024-04283-w","url":null,"abstract":"<div><p>Protein translation is essential for some forms of synaptic plasticity. Here we used fluorescent noncanonical amino acid tagging (FUNCAT) to examine whether dopamine modulates protein translation in cultured nucleus accumbens (NAc) medium spiny neurons (MSN). These neurons were co-cultured with cortical neurons to restore excitatory synapses. We measured translation in MSNs under basal conditions and after disinhibiting excitatory transmission using the GABA_A receptor antagonist bicuculline (2 h). Under basal conditions, translation was not altered by the D1-class receptor (D1R) agonist SKF81297 or the D2-class receptor (D2R) agonist quinpirole. Bicuculline alone robustly increased translation. This was reversed by quinpirole but not SKF81297. It was also reversed by co-incubation with the D1R antagonist SCH23390, but not the D2R antagonist eticlopride, suggesting dopaminergic tone at D1Rs. This was surprising because no dopamine neurons are present. An alternative explanation is that bicuculline activates translation by increasing glutamate tone at NMDA receptors (NMDAR) within D1R/NMDAR heteromers. Supporting this, immunocytochemistry and proximity ligation assays revealed D1R/NMDAR heteromers on NAc cells both in vitro and in vivo, confirming previous results. Furthermore, bicuculline’s effect was reversed to the same extent by SCH23390 alone, the NMDAR antagonist APV alone, or SCH23390 + APV. These results suggest that: (1) excitatory transmission stimulates translation in NAc MSNs, (2) this is opposed when glutamate activates D1R/NMDAR heteromers, even in the absence of dopamine, and (3) antagonist occupation of D1Rs within the heteromers prevents their activation. Our study is the first to suggest a role for D2 receptors and D1R/NMDAR heteromers in regulating protein translation.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Effects of Itaconate and its Esters on the Glutathione and Glucose Metabolism of Cultured Primary Rat Astrocytes","authors":"Patrick Watermann,&nbsp;Gurleen K. Kalsi,&nbsp;Ralf Dringen,&nbsp;Christian Arend","doi":"10.1007/s11064-024-04263-0","DOIUrl":"10.1007/s11064-024-04263-0","url":null,"abstract":"<div><p>Itaconate is produced as endogenous metabolite by decarboxylation of the citric acid cycle intermediate <i>cis</i>-aconitate. As itaconate has anti-microbial and anti-inflammatory properties, this substance is considered as potential therapeutic drug for the treatment of inflammation in various diseases including traumatic brain injury and stroke. To test for potential adverse effects of itaconate on the viability and metabolism of brain cells, we investigated whether itaconate or its membrane permeable derivatives dimethyl itaconate (DI) and 4-octyl itaconate (OI) may affect the basal glucose and glutathione (GSH) metabolism of cultured primary astrocytes. Acute exposure of astrocytes to itaconate, DI or OI in concentrations of up to 300 µM for up to 6 h did not compromise cell viability. Of the tested substances, only OI stimulated aerobic glycolysis as shown by a time- and concentration-dependent increase in glucose-consumption and lactate release. None of the tested itaconates affected the pentose-phosphate pathway-dependent reduction of the water-soluble tetrazolium salt 1 (WST1). In contrast, both DI and OI, but not itaconate, depleted cellular GSH in a time- and concentration-dependent manner. For OI this depletion was accompanied by a matching increase in the extracellular GSH content that was completely prevented in the presence of the multidrug resistance protein 1 (Mrp1)-inhibitor MK571, while in DI-treated cultures GSH was depleted both in cells and medium. These data suggest that OI stimulates Mrp1-mediated astrocytic GSH export, while DI reacts with GSH to a conjugate that is not detectable by the GSH assay applied. The data presented demonstrate that itaconate, DI and OI differ strongly in their effects on the GSH and glucose metabolism of cultured astrocytes. Such results should be considered in the context of the discussed potential use of such compounds as therapeutic agents.</p></div>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":"50 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s11064-024-04263-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142672409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}