Astrocytes (also, astroglia) consume huge amounts of glucose and produce lactate regardless of sufficient oxygen availability, indicating a high capacity for aerobic glycolysis. Glycolysis in ...astrocytes is activated in accordance with neuronal excitation and leads to increases in the release of lactate from astrocytes. Although the fate of this lactate remains somewhat controversial, it is believed to fuel neurons as an energy substrate. Besides providing lactate, astrocytic glycolysis plays an important role in neuroprotection. Among the minor pathways of glucose metabolism, glucose flux to the pentose-phosphate pathway (PPP), a major shunt pathway of glycolysis, is attracting research interest. In fact, PPP activity in astrocytes is five to seven times higher than that in neurons. The astrocytic PPP plays a key role in protecting neurons against oxidative stress by providing neurons with a reduced form of glutathione, which is necessary to eliminate reactive oxygen species. Therefore, enhancing astrocytic glycolysis might promote neuronal protection during acute ischemic stroke. Contrariwise, the dysfunction of astrocytic glycolysis and the PPP have been implicated in the pathogenesis of various neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, since mitochondrial dysfunction and oxidative stress trigger and accelerate disease progression.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Astroglia or astrocytes, the most abundant cells in the brain, are interposed between neuronal synapses and microvasculature in the brain gray matter. They play a pivotal role in brain metabolism as ...well as in the regulation of cerebral blood flow, taking advantage of their unique anatomical location. In particular, the astroglial cellular metabolic compartment exerts supportive roles in dedicating neurons to the generation of action potentials and protects them against oxidative stress associated with their high energy consumption. An impairment of normal astroglial function, therefore, can lead to numerous neurological disorders including stroke, neurodegenerative diseases, and neuroimmunological diseases, in which metabolic derangements accelerate neuronal damage. The neurovascular unit (NVU), the major components of which include neurons, microvessels, and astroglia, is a conceptual framework that was originally used to better understand the pathophysiology of cerebral ischemia. At present, the NVU is a tool for understanding normal brain physiology as well as the pathophysiology of numerous neurological disorders. The metabolic responses of astroglia in the NVU can be either protective or deleterious. This review focuses on three major metabolic compartments: (i) glucose and lactate; (ii) fatty acid and ketone bodies; and (iii) D‐ and L‐serine. Both the beneficial and the detrimental roles of compartmentalization between neurons and astroglia will be discussed. A better understanding of the astroglial metabolic response in the NVU is expected to lead to the development of novel therapeutic strategies for diverse neurological diseases.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The neurovascular unit (NVU) is a conceptual framework that has been proposed to better explain the relationships between the neural cells and blood vessels in the human brain, focused mainly on the ...brain gray matter. The major components of the NVU are the neurons, astrocytes (astroglia), microvessels, pericytes, and microglia. In addition, we believe that oligodendrocytes should also be included as an indispensable component of the NVU in the white matter. Of all these components, astrocytes in particular have attracted the interest of researchers because of their unique anatomical location; these cells are interposed between the neurons and the microvessels of the brain. Their location suggests that astrocytes might regulate the cerebral blood flow (CBF) in response to neuronal activity, so as to ensure an adequate supply of glucose and oxygen to meet the metabolic demands of the neurons. In fact, the adult human brain, which accounts for only 2% of the entire body weight, consumes approximately 20-25% of the total amount of glucose and oxygen consumed by the whole body. The brain needs a continuous supply of these essential energy sources through the CBF, because there are practically no stores of glucose or oxygen in the brain; both acute and chronic cessation of CBF can adversely affect brain functions. In addition, another important putative function of the NVU is the elimination of heat and waste materials produced by neuronal activity. Recent evidence suggests that astrocytes play pivotal roles not only in supplying glucose, but also fatty acids and amino acids to neurons. Loss of astrocytic support can be expected to lead to malfunction of the NVU as a whole, which underlies numerous neurological disorders. In this review, we shall focus on historical and recent findings with regard to the metabolic contributions of astrocytes in the NVU.
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Intracranial branch atheromatous disease (BAD) is a pathological condition characterized by the occlusion of a relatively large perforating branch (700–800 µm) near the orifice of a parent artery due ...to atherosclerotic plaque-based thrombus (microatheroma). BAD is refractory to treatment and follows a course of progressive exacerbation, especially motor paralysis. Uniform treatment for common atherothrombotic cerebral infarction or lacunar infarction does not prevent the progressive exacerbation of BAD, and consequently affects functional prognosis. To date, various combinations of treatments have been investigated and proposed to attenuate the worsening symptoms of BAD. However, no therapy with established efficacy is yet available for BAD. Since it is the most difficult condition to treat in the area of cerebral infarction, the establishment of optimal treatment methods for BAD is keenly awaited. This review presents an overview of the acute treatments available for BAD and discusses the prospects for optimal treatment.
Ropinirole, a New ALS Drug Candidate Developed Using iPSCs Okano, Hideyuki; Yasuda, Daisuke; Fujimori, Koki ...
Trends in pharmacological sciences (Regular ed.),
February 2020, 2020-Feb, 2020-02-00, 20200201, Volume:
41, Issue:
2
Journal Article
Peer reviewed
Open access
Induced pluripotent stem cells (iPSCs) are increasingly used in the study of disease mechanisms and the development of effective disease-modifying therapies for neurodegenerative diseases, including ...amyotrophic lateral sclerosis (ALS). Recently, three candidate anti-ALS drugs – ropinirole (ROPI), retigabine, and bosutinib – have been identified in iPSC-based drug screens and are now being evaluated in clinical trials for safety and effectiveness. We review the preclinical data, clinical research design, and rationale for ROPI as an anti-ALS drug candidate compared with those of the other two drugs. We also discuss the use of iPSCs for understanding and monitoring treatment response as well as for new insights into the development of new drugs and therapeutic interventions for major neurodegenerative diseases.
iPSC-based drug discovery is a promising technology for developing novel therapeutics for neurodegenerative diseases lacking useful disease models, such as amyotrophic lateral sclerosis (ALS).Ropinirole, retigabine, and bosutinib were identified as candidate therapeutic agents for ALS by the combination of iPSC-based drug discovery and drug repositioning.The potential anti-ALS mechanism of ropinirole is independent of antioxidant activity, rescue of mitochondria, reduction of stress granules, and abnormal proteins such as phosphorylated TDP-43 and FUS, and dopamine D2 receptor (D2R) agonism.Retigabine inhibits the hyperexcitability of motor neurons in ALS and bosutinib prompts autophagy and reduces abnormal proteins such as SOD-1 and phosphorylated TDP-43 via the Src/c-Abl pathway in motor neurons in ALS.Stratification of ALS, personalized medicine strategies, and the identification of common mechanisms with other neurodegenerative diseases are key aspects in the development of ALS therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Oxidative stress and neuroinflammation are common bases for disease onset and progression in many neurodegenerative diseases. In Parkinson disease, which is characterized by the degeneration of ...dopaminergic neurons resulting in dopamine depletion, the pathogenesis differs between hereditary and solitary disease forms and is often unclear. In addition to the pathogenicity of alpha-synuclein as a pathological disease marker, the involvement of dopamine itself and its interactions with glial cells (astrocyte or microglia) have attracted attention. Pacemaking activity, which is a hallmark of dopaminergic neurons, is essential for the homeostatic maintenance of adequate dopamine concentrations in the synaptic cleft, but it imposes a burden on mitochondrial oxidative glucose metabolism, leading to reactive oxygen species production. Astrocytes provide endogenous neuroprotection to the brain by producing and releasing antioxidants in response to oxidative stress. Additionally, the protective function of astrocytes can be modified by microglia. Some types of microglia themselves are thought to exacerbate Parkinson disease by releasing pro-inflammatory factors (M1 microglia). Although these inflammatory microglia may further trigger the inflammatory conversion of astrocytes, microglia may induce astrocytic neuroprotective effects (A2 astrocytes) simultaneously. Interestingly, both astrocytes and microglia express dopamine receptors, which are upregulated in the presence of neuroinflammation. The anti-inflammatory effects of dopamine receptor stimulation are also attracting attention because the functions of astrocytes and microglia are greatly affected by both dopamine depletion and therapeutic dopamine replacement in Parkinson disease. In this review article, we will focus on the antioxidative and anti-inflammatory effects of astrocytes and their synergism with microglia and dopamine.
Recent advances in pathophysiology suggest that a pathological atrial substrate can cause embolic stroke even in patients without atrial fibrillation (AF). This pathological condition is called ..."atrial cardiopathy", which indicates atrial structural and functional disorders that can precede AF. The objective of this narrative review was to provide a current overview of atrial cardiopathy and cryptogenic stroke. We searched the PubMed database and summarized the recent findings of the identified studies, including the pathogenesis of atrial cardiopathy, biomarkers of atrial cardiopathy, relationship between atrial cardiopathy and cryptogenic stroke, and therapeutic interventions for atrial cardiopathy. Abnormal atrial substrate (atrial cardiopathy) that leads to AF can result in embolic stroke before developing AF, and may explain the source of cryptogenic stroke in some patients. Although there are several potential biomarkers indicative of atrial cardiopathy, P-wave terminal force in lead V1 (>5,000 μV
ms), N-terminal pro-brain natriuretic peptide (>250 pg/ml), and left atrial enlargement are currently promising biomarkers for the diagnosis of atrial cardiopathy. Because the optimal combination and thresholds of biomarkers for diagnosing atrial cardiopathy remain uncertain, atrial cardiopathy represents a spectrum disorder. The concept of atrial cardiopathy appears to be most valuable as a starting point for therapeutic intervention to prevent stroke. Validation of the diagnosis of atrial cardiopathy and whether it can be used as a new therapeutic target for direct oral anticoagulants are currently being covered in the ARCADIA trial.
Objective Despite aggressive therapeutic interventions during the acute phase of branch atheromatous disease (BAD)-type cerebral infarction, many patients, even those with a mild condition at the ...onset, experience neurological deterioration after hospitalization and develop serious deficits. We compared the therapeutic efficacy of multiple antithrombotic therapies for BAD between patients who received a clopidogrel loading dose (loading group; LG) and those without loading (non-loading group; NLG). Patients Between January 2019 and May 2022, patients with BAD-type cerebral infarction in the lenticulostriate artery admitted within 24 h of the onset were recruited. This study included 95 consecutive patients who received combination argatroban and dual antiplatelet therapy (aspirin and clopidogrel). Methods Patients were classified into the LG and NLG according to whether or not a loading dose of clopidogrel (300 mg) had been administered on admission. Changes in neurological severity National Institutes of Health Stroke Scale (NIHSS) score during the acute phase were retrospectively evaluated. Results There were 34 (36%) and 61 (64%) patients in the LG and NLG, respectively. On admission, the median NIHSS score was similar between the groups LG: 2.5 (2-4) vs. NLG: 3 (2-4), p=0.771. At 48 h following admission, the median NIHSS scores were 1 (0.25-4), and 2 (1-5) in the LG and NLG, respectively (p=0.045). Early neurological deterioration (END; defined as worsening of the NIHSS score by ≥4 points at 48 h after admission) occurred in 3% of LG and 20% of NLG patients (p=0.028). Conclusion Administration of a clopidogrel loading dose with combination antithrombotic therapy for BAD reduced END.
Using patient-derived induced pluripotent stem cells, neurodegenerative disease phenotypes have been recapitulated and their pathogenesis analysed leading to significant progress in drug screening. ...In amyotrophic lateral sclerosis, high-throughput screening using induced pluripotent stem cells-derived motor neurons has identified candidate drugs. Owing to induced pluripotent stem cell-based drug evaluation/screening, three compounds, retigabine, ropinirole and bosutinib, have progressed to clinical trials. Retigabine blocks hyperexcitability and improves survival in amyotrophic lateral sclerosis patient-derived motor neurons. In a randomized clinical trial (n = 65), treatment with retigabine reduced neuronal excitability after 8 weeks. Ropinirole, identified in a high-throughput screening, attenuates pathological phenotypes in patient-derived motor neurons. In a trial limited by a small sample size (n = 20), ropinirole was tolerable and had clinical benefits on function and survival. A phase 1 study of bosutinib has reported safety and tolerability for 12 weeks. Thus, these clinical trials show safety and positive effects and confirm the reliability of stem cell-based drug discovery. This novel strategy leads to reduced costs and time when compared to animal testing and opens new avenues for therapy in intractable diseases.
Aims: Mechanical thrombectomy using a standard device has been effective for acute cerebral large-vessel occlusions, particularly those due to cardiogenic embolism. However, evidence for those with ...underlying atherosclerotic lesions is lacking. In this study, we evaluated the predictive factors, treatment details, and outcomes of acute cerebral large-vessel occlusions with underlying atherosclerotic lesions in patients who underwent mechanical thrombectomy.Methods: We retrospectively analyzed consecutive patients with acute large-vessel occlusions who underwent mechanical thrombectomy at our institution between August 2014 and May 2021. Predictive factors of underlying atherosclerotic lesions were evaluated using univariate and multivariate analyses. In addition, treatment details and outcomes were evaluated and compared with those of other etiologies.Results: Among 322 included patients, 202 (62.7%) were males and 65 (20.2%) had underlying atherosclerotic lesions. Multivariate analysis identified dyslipidemia, lack of arterial fibrillation documented on admission, smoking, internal carotid artery lesions, and stenosis ≥ 25% in non-occluded large vessels as predictive factors of underlying atherosclerotic lesions. Regarding treatment for underlying atherosclerotic lesions, the need for percutaneous transluminal angioplasty, stent placement, medical therapy, and longer procedure time were observed, while successful reperfusion rates, favorable outcomes, and mortality rates showed no significant differences with those of other etiologies.Conclusion: Coexisting diseases and radiological findings were useful for predicting underlying atherosclerotic lesions. Further understanding these characteristics may lead to the early detection of underlying atherosclerotic lesions, optimal treatment strategies, and better outcomes.
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