PMCID string | Title string | Sentences string |
|---|---|---|
PMC12736548 | CC-90009, a Cereblon E3 Ligase Modulator, Exhibits Antiviral Efficacy Against JEV In Vitro and In Vivo via Targeted Degradation of GSPT1 and Viral NS5 Protein | Previous studies have also indicated that GSPT1 directly interacts with the viral polymerases of EBOV and LASV . |
PMC12736548 | CC-90009, a Cereblon E3 Ligase Modulator, Exhibits Antiviral Efficacy Against JEV In Vitro and In Vivo via Targeted Degradation of GSPT1 and Viral NS5 Protein | Therefore, decreased NS5 abundance is expected to cause a genome-wide decline in JEV RNA synthesis. |
PMC12736548 | CC-90009, a Cereblon E3 Ligase Modulator, Exhibits Antiviral Efficacy Against JEV In Vitro and In Vivo via Targeted Degradation of GSPT1 and Viral NS5 Protein | Viral replication is highly dependent on the host translational apparatus ; consequently, multiple factors involved in translation initiation, elongation, and termination have emerged as promising targets for antiviral therapeutic development . |
PMC12736548 | CC-90009, a Cereblon E3 Ligase Modulator, Exhibits Antiviral Efficacy Against JEV In Vitro and In Vivo via Targeted Degradation of GSPT1 and Viral NS5 Protein | Human GSPT1 was initially identified as a key regulator of the G1-to-S phase transition . |
PMC12736548 | CC-90009, a Cereblon E3 Ligase Modulator, Exhibits Antiviral Efficacy Against JEV In Vitro and In Vivo via Targeted Degradation of GSPT1 and Viral NS5 Protein | Subsequent studies confirmed that it encodes a core component of the eukaryotic translation termination machinery, specifically functioning as the peptide chain release factor 3a . |
PMC12736548 | CC-90009, a Cereblon E3 Ligase Modulator, Exhibits Antiviral Efficacy Against JEV In Vitro and In Vivo via Targeted Degradation of GSPT1 and Viral NS5 Protein | The antiviral activity of CC-90009 against JEV appears to be both dependent on and specific to the downregulation of GSPT1. |
PMC12736548 | CC-90009, a Cereblon E3 Ligase Modulator, Exhibits Antiviral Efficacy Against JEV In Vitro and In Vivo via Targeted Degradation of GSPT1 and Viral NS5 Protein | Similarly, compound 103, a targeted GSPT1 degrader, has been demonstrated to possess broad-spectrum antiviral activity . |
PMC12736548 | CC-90009, a Cereblon E3 Ligase Modulator, Exhibits Antiviral Efficacy Against JEV In Vitro and In Vivo via Targeted Degradation of GSPT1 and Viral NS5 Protein | Additionally, CC-90009 has entered clinical trials for the treatment of patients with acute myeloid leukaemia , which lays the groundwork for the application of GSPT1-deletion-based strategies in treating viral infections. |
PMC12736548 | CC-90009, a Cereblon E3 Ligase Modulator, Exhibits Antiviral Efficacy Against JEV In Vitro and In Vivo via Targeted Degradation of GSPT1 and Viral NS5 Protein | Further exploration and research are required to elucidate the pharmacological properties, safety profile, and efficacy across different viral models to advance the therapeutic potential of GSPT1 degraders as pan-antiviral agents. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The disparity in outcomes between preclinical and clinical studies supplementing coenzyme Q10 (CoQ10) in neurological disorders may be a reflection of the differences in the ability of supplemental CoQ10 to access the blood–brain barrier (BBB) in rodents and in humans, which is, in turn, a consequence of contrasting structures of the BBB. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The applicability of in vivo animal models to study access of CoQ10 across the BBB and subsequent neuronal metabolism has, therefore, been questioned, and there is an argument, perhaps surprisingly, that in vitro model systems (particularly 3D cellular systems) may be more appropriate. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In this article, we have, therefore, reviewed the role of model systems to study the access of CoQ10 across the BBB, as well as the role of such systems in studying the role of CoQ10 in aspects of neuronal metabolism, such as mitochondrial and lysosomal function. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In addition, the use of such model systems to study the interactions of CoQ10 with vitamin E and selenium has been reviewed. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Finally, the practical application of a neuronal model system to investigate the effect of CoQ10 supplementation on CoQ10 status and mitochondrial metabolism in a CoQ10 deficiency state has been described. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Clinical studies supplementing coenzyme Q10 (CoQ10) in disorders such as heart failure have reported significant benefit ; however, the outcomes of clinical trials supplementing CoQ10 in neurological disorders have, in general, been disappointing. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Thus, while promising results have been obtained from preclinical studies supplementing CoQ10 in animal models of Parkinson’s disease, Alzheimer’s disease, or amyotrophic lateral sclerosis, corresponding randomised controlled trials in these disorders have reported no significant benefit . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | This disparity in outcomes between preclinical and clinical studies may be a reflection of the disparity in the ability of supplemental CoQ10 to access the blood–brain barrier (BBB) in rodents and humans, which is, in turn, a consequence of corresponding structural differences. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | It is of note that in primary CoQ10 deficiency, patients affected in non-CNS tissues (particularly skeletal muscle and kidney) may respond well to supplementation with CoQ10, whereas, in contrast, patients with neurological symptoms in general do not respond well to treatment ; this, in turn, suggests that CoQ10 has difficulty crossing the BBB in humans. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The applicability of in vivo animal models to study access of CoQ10 across the BBB and subsequent neuronal metabolism has, therefore, been questioned, and there is an argument, perhaps surprisingly, that in vitro model systems (particularly 3D cellular systems) may be more appropriate. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In this article, we have therefore reviewed the role of model systems to study access of CoQ10 across the BBB, as well as the role of such systems in studying the role of CoQ10 in aspects of neuronal metabolism, such as mitochondrial and lysosomal function. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Relevant articles in the peer-reviewed literature were identified using the Medline database and the keywords listed in the abstract. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | BBB model systems comprise in vitro cell culture models and in vivo animal-based models. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In vitro BBB models include 2D and 3D cellular systems. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In the so-called Transwell 2D model, a monolayer of endothelial cells is cultured on a permeable membrane with a small semi-permeable insert, separating the system into upper (luminal or blood) compartment and lower (abluminal or parenchymal) compartments. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | While this model is useful for evaluating the permeability of medicinal drugs across the BBB, the monolayer of cells does not replicate the complex 3D structure of the BBB in vivo, and the static nature of the culture lacks the physiological shear stress from blood flow that is crucial for endothelial cell differentiation and maintenance of BBB properties. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The physiological relevance of this model system can be improved by including other cell types (e.g., astrocytes, neurons, or pericytes), as well as incorporating a system to perfuse the endothelium, thereby providing shear stress . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In the brain, the BBB is a tubular structure, which is not accurately replicated using 2D models; 3D models include the different cell types (brain endothelial cells, pericytes, and astrocytes) that form the neurovascular unit (NVU). |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Hydrogel-based models use a supporting collagen matrix to create a 3D environment in which cells can grow and self-assemble into tubular structures, similar to the in vivo microvasculature. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Microfluidic BBB-on-a-chip models are lab-on-a-chip platforms that integrate NVU cells within microchannels to create a perfusable network, allowing for dynamic studies of barrier function, fluid flow, and responses to external stimuli. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | These systems represent models of increasing complexity; 2D models are useful for initial screening and evaluating basic barrier integrity, whereas multicellular models provide a more comprehensive system to study BBB functions, including size-selective transport, the activity of P-glycoprotein (P-gp) efflux pumps, and the functionality of specific transport systems such as the transferrin receptor . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The only in vitro BBB model system used to date to investigate access by CoQ10 is the 2D porcine endothelial monolayer cell model described by Wainwright et al. (Figure 1). |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In this model system, CoQ10 is transported in the apical-to-basal direction (i.e., blood-to-brain side) via lipoprotein-associated transcytosis, interacting with the SR-B1 (Scavenger Receptor) and RAGE (Receptor for Advanced Glycation End products) receptors. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | However, it is simultaneously effluxed back to the blood side via the LDLR (low-density lipoprotein receptor) transporter, leading to no net accumulation of CoQ10 in the brain. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | When a deficiency of CoQ10 in the model BBB is induced using para-aminobenzoic acid (PABA), the BBB becomes leakier, with disrupted tight junctions and poorer integrity; this, in turn, results in increased net CoQ10 transport from the blood side to the brain side. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Some studies in BBB model systems have been reported using the CoQ10 analogues idebenone and mitoquinone . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | However, although these analogues have antioxidant activity in common with CoQ10, their other intracellular functions differ due to their varying chemical structures; for example, mitoquinone cannot transfer electrons from Complex I to Complex III in the mitochondrial electron transport chain (ETC) during oxidative phosphorylation. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The suitability of in vivo rodent-based BBB models to extrapolate data for BBB accessibility of CoQ10 in humans has been questioned because of the differences in the BBB structure and transporter expression, and there is some evidence that the BBB in rodents may be more permeable. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | For example, Uchida et al. reported that protein expression levels of transporters and receptors in the BBB of humans were remarkably smaller than those in the BBB of rats. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Similarly, supplementation with CoQ10 in mouse models of Alzheimer’s disease (AD) has been reported to exhibit beneficial effects in reduced oxidative stress and beta-amyloid plaque levels and improved cognitive function . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | However, in a randomised clinical trial in which 70 patients with mild-to-moderate AD were treated with CoQ10 (400 mg; three times/day) for 16 weeks, no clinical benefit or significant effect on the CSF biomarkers for AD (amyloid-beta and tau protein levels) was reported . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | These data suggest a disparity between BBB accessibility in rodents and in humans. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In another study, Matthews et al. reported a 30% increase in cerebral cortex CoQ10 and coenzyme Q9 (CoQ9, the predominant ubiquinone species in rats) following oral supplementation of 12-month-old Sprague-Dawley rats with CoQ10 (200 mg/kg) for 2 months. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In addition, Smith et al. reported significant (p < 0.01) increases in brain levels of CoQ10 and CoQ9 following supplementation with high-dose (1000–5000 mg/kg) CoQ10 in a mouse model of Huntington’s disease. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | However, it is uncertain from these studies whether the degree of cerebral uptake of CoQ10 would be sufficient to replenish cellular levels of this quinone in a CoQ10 deficiency state. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Given the suggested limited uptake of CoQ10 across the BBB, therapeutic strategies that may enhance this transport, such as the use of LDLR inhibitors, or interventions to stimulate luminal activity of SR-B1 transporters may be appropriate to ensure sufficient exogenous CoQ10 is available in the cerebral interstitial fluid for metabolically compromised neurons . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | CoQ10 is transported in the blood circulation and bound to low-density lipoprotein and very low-density lipoprotein–cholesterol, irrespective of the initial dietary form (ubiquinone or ubiquinol). |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Accordingly at some point, dietary CoQ10 in the oxidised ubiquinone form must, therefore, be reduced to the ubiquinol form, and this was thought to take place during the absorption process into enterocytes . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | It was, therefore, postulated that supplemental CoQ10 already in ubiquinol form would facilitate the absorption process, resulting in improved bioavailability. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | However, research carried out by the late Dr William Judy demonstrated that under conditions simulating the environment of the stomach and small intestine in vitro, supplemental ubiquinol is largely oxidised to ubiquinone prior to entry into enterocytes . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | A standard gelatine capsule dissolves in the stomach in approximately 10 min, releasing the ubiquinol into the stomach environment. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The time for ingested material to remain in the stomach can be quite variable, but a reasonable estimate would be about 4 h . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | If the capsule is taken with food, free ubiquinol will be distributed among other stomach contents by the churning action of the stomach. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The stomach represents an oxidising environment , so ubiquinol would be oxidised to ubiquinone during this period, before ever reaching the small intestine and subsequent enterocyte absorption. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In addition, in vivo studies supplementing ubiquinol in dogs similarly showed oxidation of the latter to ubiquinone prior to enterocyte absorption, with the subsequent conversion of ubiquinone back to ubiquinol following the passage from enterocytes into the lymphatic system . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | CoQ10 that has been subjected to a patented crystal modification process shows improved bioavailability . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In a clinical study, Lopez-Lluch and colleagues reported that the bioavailability of a ubiquinol form of a particular CoQ10 supplement was approximately twice that of ubiquinone that had not been subjected to thermal crystal modification, but was only 52% of that of ubiquinone that had been subjected to thermal crystal modification. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Based on the above, there is, therefore, no rationale why the bioavailability (i.e., access to the blood circulation) of the ubiquinol form of CoQ10 should be superior to that of the ubiquinone form, which is a common misconception. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | It has also been suggested that in human subjects, the reduced form of CoQ10 (ubiquinol) may be able to access the BBB, while the oxidised form of CoQ10 (ubiquinone) is not able to cross the BBB. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Thus, following oral supplementation with ubiquinol, Mitsui et al. reported increased levels of ubiquinol in the CSF of patients with multiple system atrophy (MSA). |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | There are essentially two barriers preventing access of CoQ10 into the human brain: the BBB and the brain CSF barrier (BCSFB). |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The BCSFB is relatively leaky compared to the BBB, and access of CoQ10 (in either ubiquinone or ubiquinol form) into the CSF via the BCSFB does not equate to access of CoQ10 into the brain parenchyma—another common misconception . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | To date there have been no clinical studies in which orally administered CoQ10 has been unambiguously shown to directly cross the BBB and access the human brain. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Whether CoQ10, in either ubiquinone or ubiquinol forms, can access the BBB in humans, and the mechanism by which CoQ10 is then distributed within brain cells, has yet to be elucidated. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In view of the potential limited transport of CoQ10 across the BBB, other strategies may be appropriate to restore cerebral CoQ10 status. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | It has recently been reported that the intermediates 4-hydroxymandelate and 4-hydroxybenzoate may have the potential to cross the BBB and restore cerebral CoQ10 status, serving as a potential treatment for primary CoQ10 deficiencies . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | These intermediates have been investigated in mouse models of mitochondrial disease and were reported to increase cerebral ubiquinone status (CoQ10 plus CoQ9), although no studies have yet investigated the effect of these precursor molecules on CoQ10-deficient human neuronal cells. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Currently, the level of plasma CoQ10 that may have therapeutic potential in the treatment of disease is uncertain. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In a study by Langsjoen and Langsjoen , a blood concentration of approximately 4.1 mM was required before any therapeutic benefit was identified in patients with congestive heart failure. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | No studies to date have assessed this parameter in patients with CoQ10 deficiency, although a study by Lopez and colleagues reported an improvement in bioenergetic status, as indicated by an increased ATP/ADP ratio and normalisation of cellular oxidative stress in CoQ10-deficient fibroblasts following 7 days of supplementation with 5 mM CoQ10. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Interestingly, a comparative circulatory level of CoQ10 was associated with a slowing in the progressive deterioration of function in Parkinson’s disease patients in a randomised, double-blind, placebo-controlled study by Shults and colleagues , which assessed the effect of CoQ10 supplementation in early-stage Parkinson’s disease patients. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Co-administration of CoQ10 and vitamin E has been reported to be of synergistic benefit in both preclinical and clinical studies of neurological disorders . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Such studies raise the question of how vitamin E accesses the brain in comparison to CoQ10. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Access of vitamin E across the BBB involves carrier-mediated transport, which is mediated via the SR-B1 receptor uptake of HDL complexed alpha tocopherol, together with the protein afamin; the inter- and intra-cellular distribution of vitamin E is then controlled by the tocopherol transfer protein. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | As the uptake of vitamin E across the BBB involves the same SR-B1 receptor as that involved in the uptake of CoQ10, one might question whether restricted brain access for either substance might occur as a result of competition for the same transporter. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Indeed, in the porcine in vitro BBB model, alpha tocopherol was found to increase basal-to-apical transport of CoQ10 in control conditions, i.e., towards the blood side. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In the presence of alpha-tocopherol, CoQ10 transport towards the blood side dominated in the PABA-induced CoQ10-deficient BBB model . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | If this translates to clinical CoQ10 deficiency, then alpha-tocopherol co-administration with CoQ10 supplements would tend to reduce CoQ10 delivery towards the brain, the opposite of the desired effect. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In this regard, it is of note that in a Phase II clinical study, CoQ10 in daily doses of 300 mg, 600 mg, or 1200 mg administered to Parkinson’s disease patients resulted in a significant slowing of functional decline . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | However, in a Phase III study, daily doses of CoQ10 (1200 mg or 2400 mg) administered to Parkinson’s disease patients, together with a daily dose of 1200 IU of vitamin E, had no significant symptomatic benefit, in contrast to the outcome of the Phase II study . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | These data therefore suggest the possibility that co-administration of a high dose of vitamin E could have inhibited access to the brain for CoQ10 via competition for a shared carrier. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | It is also possible that vitamin E may interfere with the absorption of co-administered CoQ10 from the digestive tract via competition for the same transporter (putatively the cholesterol transporter NPC1L1 (Niemann-Pick C1 Like 1) . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Model systems for studying the metabolism of CoQ10 in neurons typically use human SH-SY5Y neuronal cell lines in 2D or 3D culture systems. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Para-aminobenzoic acid (PABA), a competitive inhibitor of the COQ2 enzyme in the CoQ10 biosynthetic pathway, can be used to induce CoQ10 deficiency to study the effect of CoQ10 deficiency on neuronal metabolism. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | This type of model system has been used to elucidate the action of supplementary CoQ10 in neurological disorders of CoQ10 deficiency and phenylketonuria, as described below. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | At present, the concentration of plasma or cerebral spinal fluid CoQ10 that may have therapeutic potential in the treatment of neurological disorders associated with mitochondrial dysfunction and oxidative stress has yet to be determined. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In vitro studies utilising CoQ10-deficient human fibroblasts have reported an improvement in bioenergetic status and normalisation of cellular oxidative stress following treatment with CoQ10 at a concentration of 5 μM. However, it is uncertain whether this concentration of CoQ10 would be physiologically achievable in human neurons in vivo, i.e., whether CoQ10 is able to cross the human BBB, and have therapeutic potential in the treatment of the neurological symptoms associated with metabolic disease. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | To investigate this question at the biochemical level, we evaluated the effect of treatment with 5 μM CoQ10 on a human neuronal cell model of CoQ10 deficiency . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The human neuronal cell model of CoQ10 deficiency was established using human SH-SY5Y neuronal cells. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In the CoQ10-deficient neuronal cells, supplementing with 5 uM CoQ10 was effective at significantly reducing mitochondrial oxidative stress (p < 0.0005) to below control levels. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | In contrast, CoQ10 supplementation at concentrations of either 5 or 10 uM was only partially effective at restoring MRC enzyme activities to control levels, with complex II/III activity being significantly (p < 0.05) increased to 82.5%, complex I to 71.1%, and IV to 77.7% of control levels following treatment with 10 uM CoQ10. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Treatment with 5 uM CoQ10 was also found to decrease the lysosomal pH of the CoQ10-deficient neurons from 6.2 to 4.4, which is within the pH range of control cells . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The results of this study have indicated that although cellular and mitochondrial oxidative stress in a neuronal cell model of CoQ10 deficiency appear to be attenuated following CoQ10 supplementation with 5 uM CoQ10, MRC enzyme activities were partially refractory to treatment, and supplementation with doses of CoQ10 > 10 uM may be required to restore MRC enzyme activities to control levels. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | However, given the suggested limited uptake of CoQ10 across the human blood–brain barrier, therapeutic strategies that may enhance this transport such as the use of LDLR (low-density lipoprotein related protein −1 receptor) inhibitors, or interventions to stimulate luminal activity of SR-B1 (Scavenger Receptor B1) transporters may be appropriate to ensure sufficient exogenous CoQ10 is available within the interstitial fluid for metabolically compromised neurons . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | This study indicates the potential requirement for high-dose CoQ10 supplementation to treat the neurological presentations of CoQ10 deficiency, although whether this will be able to reach the CoQ10-deficient neurons is still uncertain. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Studies using this model system have demonstrated the key role of CoQ10 for maintaining the acidic pH (quantified via the fluorescent probes Lysotracker or LysoSensor) within neuronal lysosomes, which is essential for their role in the degradation of cellular waste products. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | CoQ10 acts as a proton carrier at the lysosomal membrane, and its deficiency disrupts this process, leading to an increase in lysosomal pH and potentially impairing lysosomal and autophagy functions. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Administration of CoQ10 results in restoration of normal lysosomal pH and neuronal lysosomal function . |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Neurons are particularly susceptible to a build-up of cellular waste products resulting from lysosomal dysfunction, in turn resulting in neurological lysosomal storage disorders including Niemann–Pick disease, mucopolysaccharidosis (MPS), Batten’s disease, Gaucher’s disease, and Krabbe’s disease. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | The potential role of supplementary CoQ10 in the treatment of patients with lysosomal storage disorders is an area in the early stages of clinical research. |
PMC12837543 | Blood–Brain Barrier and Neuronal Model Systems for Studying CoQ10 Metabolism | Model systems based on the human SH-SY5Y neuroblastoma cell line have also been used to elucidate the mechanism(s) of intracellular CoQ10 transport, as described in the following section of this article. |
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