Pharmacological Reviews最新文献

{"title":"Cathepsin B Gene Knockout Improves Behavioral Deficits and Reduces Pathology in Models of Neurologic Disorders.","authors":"Gregory Hook, Thomas Reinheckel, Junjun Ni, Zhou Wu, Mark Kindy, Christoph Peters, Vivian Hook","doi":"10.1124/pharmrev.121.000527","DOIUrl":"10.1124/pharmrev.121.000527","url":null,"abstract":"<p><p>Cathepsin B (CTSB) is a powerful lysosomal protease. This review evaluated <i>CTSB</i> gene knockout (KO) outcomes for amelioration of brain dysfunctions in neurologic diseases and aging animal models. Deletion of the <i>CTSB</i> gene resulted in significant improvements in behavioral deficits, neuropathology, and/or biomarkers in traumatic brain injury, ischemia, inflammatory pain, opiate tolerance, epilepsy, aging, transgenic Alzheimer's disease (AD), and periodontitis AD models as shown in 12 studies. One study found beneficial effects for double <i>CTSB</i> and cathepsin S KO mice in a multiple sclerosis model. Transgenic AD models using amyloid precursor protein (APP) mimicking common sporadic AD in three studies showed that <i>CTSB</i> KO improved memory, neuropathology, and biomarkers; two studies used APP representing rare familial AD and found no <i>CTSB</i> KO effect, and two studies used highly engineered APP constructs and reported slight increases in a biomarker. In clinical studies, all reports found that CTSB enzyme was upregulated in diverse neurologic disorders, including AD in which elevated CTSB was positively correlated with cognitive dysfunction. In a wide range of neurologic animal models, CTSB was also upregulated and not downregulated. Further, human genetic mutation data provided precedence for CTSB upregulation causing disease. Thus, the consilience of data is that <i>CTSB</i> gene KO results in improved brain dysfunction and reduced pathology through blockade of CTSB enzyme upregulation that causes human neurologic disease phenotypes. The overall findings provide strong support for CTSB as a rational drug target and for CTSB inhibitors as therapeutic candidates for a wide range of neurologic disorders. SIGNIFICANCE STATEMENT: This review provides a comprehensive compilation of the extensive data on the effects of deleting the cathepsin B (<i>CTSB</i>) gene in neurological and aging mouse models of brain disorders. Mice lacking the <i>CTSB</i> gene display improved neurobehavioral deficits, reduced neuropathology, and amelioration of neuronal cell death and inflammatory biomarkers. The significance of the compelling CTSB evidence is that the data consilience validates CTSB as a drug target for discovery of CTSB inhibitors as potential therapeutics for treating numerous neurological diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9553114/pdf/pharmrev.121.000527.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9217353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantitative Proteomics in Translational Absorption, Distribution, Metabolism, and Excretion and Precision Medicine.","authors":"Deepak Ahire,&nbsp;Laken Kruger,&nbsp;Sheena Sharma,&nbsp;Vijaya Saradhi Mettu,&nbsp;Abdul Basit,&nbsp;Bhagwat Prasad","doi":"10.1124/pharmrev.121.000449","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000449","url":null,"abstract":"<p><p>A reliable translation of in vitro and preclinical data on drug absorption, distribution, metabolism, and excretion (ADME) to humans is important for safe and effective drug development. Precision medicine that is expected to provide the right clinical dose for the right patient at the right time requires a comprehensive understanding of population factors affecting drug disposition and response. Characterization of drug-metabolizing enzymes and transporters for the protein abundance and their interindividual as well as differential tissue and cross-species variabilities is important for translational ADME and precision medicine. This review first provides a brief overview of quantitative proteomics principles including liquid chromatography-tandem mass spectrometry tools, data acquisition approaches, proteomics sample preparation techniques, and quality controls for ensuring rigor and reproducibility in protein quantification data. Then, potential applications of quantitative proteomics in the translation of in vitro and preclinical data as well as prediction of interindividual variability are discussed in detail with tabulated examples. The applications of quantitative proteomics data in physiologically based pharmacokinetic modeling for ADME prediction are discussed with representative case examples. Finally, various considerations for reliable quantitative proteomics analysis for translational ADME and precision medicine and the future directions are discussed. SIGNIFICANCE STATEMENT: Quantitative proteomics analysis of drug-metabolizing enzymes and transporters in humans and preclinical species provides key physiological information that assists in the translation of in vitro and preclinical data to humans. This review provides the principles and applications of quantitative proteomics in characterizing in vitro, ex vivo, and preclinical models for translational research and interindividual variability prediction. Integration of these data into physiologically based pharmacokinetic modeling is proving to be critical for safe, effective, timely, and cost-effective drug development.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9553121/pdf/pharmrev.121.000449.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9786781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carbon Monoxide Signaling: Examining Its Engagement with Various Molecular Targets in the Context of Binding Affinity, Concentration, and Biologic Response.","authors":"Zhengnan Yuan,&nbsp;Ladie Kimberly De La Cruz,&nbsp;Xiaoxiao Yang,&nbsp;Binghe Wang","doi":"10.1124/pharmrev.121.000564","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000564","url":null,"abstract":"<p><p>Carbon monoxide (CO) has been firmly established as an endogenous signaling molecule with a variety of pathophysiological and pharmacological functions, including immunomodulation, organ protection, and circadian clock regulation, among many others. In terms of its molecular mechanism(s) of action, CO is known to bind to a large number of hemoproteins with at least 25 identified targets, including hemoglobin, myoglobin, neuroglobin, cytochrome c oxidase, cytochrome P450, soluble guanylyl cyclase, myeloperoxidase, and some ion channels with dissociation constant values spanning the range of sub-nM to high <i>μ</i>M. Although CO's binding affinity with a large number of targets has been extensively studied and firmly established, there is a pressing need to incorporate such binding information into the analysis of CO's biologic response in the context of affinity and dosage. Especially important is to understand the reservoir role of hemoglobin in CO storage, transport, distribution, and transfer. We critically review the literature and inject a sense of quantitative assessment into our analyses of the various relationships among binding affinity, CO concentration, target occupancy level, and anticipated pharmacological actions. We hope that this review presents a picture of the overall landscape of CO's engagement with various targets, stimulates additional research, and helps to move the CO field in the direction of examining individual targets in the context of all of the targets and the concentration of available CO. We believe that such work will help the further understanding of the relationship of CO concentration and its pathophysiological functions and the eventual development of CO-based therapeutics. SIGNIFICANCE STATEMENT: The further development of carbon monoxide (CO) as a therapeutic agent will significantly rely on the understanding of CO's engagement with therapeutically relevant targets of varying affinity. This review critically examines the literature by quantitatively analyzing the intricate relationships among targets, target affinity for CO, CO level, and the affinity state of carboxyhemoglobin and provide a holistic approach to examining the molecular mechanism(s) of action for CO.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9553107/pdf/pharmrev.121.000564.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9722272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Matrix Metalloproteinases: From Molecular Mechanisms to Physiology, Pathophysiology, and Pharmacology.","authors":"Luiz G N de Almeida,&nbsp;Hayley Thode,&nbsp;Yekta Eslambolchi,&nbsp;Sameeksha Chopra,&nbsp;Daniel Young,&nbsp;Sean Gill,&nbsp;Laurent Devel,&nbsp;Antoine Dufour","doi":"10.1124/pharmrev.121.000349","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000349","url":null,"abstract":"<p><p>The first matrix metalloproteinase (MMP) was discovered in 1962 from the tail of a tadpole by its ability to degrade collagen. As their name suggests, matrix metalloproteinases are proteases capable of remodeling the extracellular matrix. More recently, MMPs have been demonstrated to play numerous additional biologic roles in cell signaling, immune regulation, and transcriptional control, all of which are unrelated to the degradation of the extracellular matrix. In this review, we will present milestones and major discoveries of MMP research, including various clinical trials for the use of MMP inhibitors. We will discuss the reasons behind the failures of most MMP inhibitors for the treatment of cancer and inflammatory diseases. There are still misconceptions about the pathophysiological roles of MMPs and the best strategies to inhibit their detrimental functions. This review aims to discuss MMPs in preclinical models and human pathologies. We will discuss new biochemical tools to track their proteolytic activity in vivo and ex vivo, in addition to future pharmacological alternatives to inhibit their detrimental functions in diseases. SIGNIFICANCE STATEMENT: Matrix metalloproteinases (MMPs) have been implicated in most inflammatory, autoimmune, cancers, and pathogen-mediated diseases. Initially overlooked, MMP contributions can be both beneficial and detrimental in disease progression and resolution. Thousands of MMP substrates have been suggested, and a few hundred have been validated. After more than 60 years of MMP research, there remain intriguing enigmas to solve regarding their biological functions in diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40332540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Technologies Bloom Together for Bettering Cancer Drug Conjugates.","authors":"Yiming Jin, Shahab Edalatian Zakeri, Raman Bahal, Andrew J Wiemer","doi":"10.1124/pharmrev.121.000499","DOIUrl":"10.1124/pharmrev.121.000499","url":null,"abstract":"<p><p>Drug conjugates, including antibody-drug conjugates, are a step toward realizing Paul Ehrlich's idea from over 100 years ago of a \"magic bullet\" for cancer treatment. Through balancing selective targeting molecules with highly potent payloads, drug conjugates can target specific tumor microenvironments and kill tumor cells. A drug conjugate consists of three parts: a targeting agent, a linker, and a payload. In some conjugates, monoclonal antibodies act as the targeting agent, but new strategies for targeting include antibody derivatives, peptides, and even small molecules. Linkers are responsible for connecting the payload to the targeting agent. Payloads impact vital cellular processes to kill tumor cells. At present, there are 12 antibody-drug conjugates on the market for different types of cancers. Research on drug conjugates is increasing year by year to solve problems encountered in conjugate design, such as tumor heterogeneity, poor circulation, low drug loading, low tumor uptake, and heterogenous expression of target antigens. This review highlights some important preclinical research on drug conjugates in recent years. We focus on three significant areas: improvement of antibody-drug conjugates, identification of new conjugate targets, and development of new types of drug conjugates, including nanotechnology. We close by highlighting the critical barriers to clinical translation and the open questions going forward. SIGNIFICANCE STATEMENT: The development of anticancer drug conjugates is now focused in three broad areas: improvements to existing antibody drug conjugates, identification of new targets, and development of new conjugate forms. This article focuses on the exciting preclinical studies in these three areas and advances in the technology that improves preclinical development.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2022-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/cf/24/pharmrev.121.000499.PMC9553120.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9786759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acylcarnitines: Nomenclature, Biomarkers, Therapeutic Potential, Drug Targets, and Clinical Trials","authors":"M. Dambrova, M. Makrecka-Kuka, J. Kuka, R. Vilskersts, Didi O. T. Nordberg, M. Attwood, S. Smesny, Z. Sen, Anchi Guo, Eponine Oler, Siyang Tian, Jiamin Zheng, D. Wishart, E. Liepinsh, H. Schiöth","doi":"10.1124/pharmrev.121.000408","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000408","url":null,"abstract":"Acylcarnitines are fatty acid metabolites that play important roles in many cellular energy metabolism pathways. They have historically been used as important diagnostic markers for inborn errors of fatty acid oxidation and are being intensively studied as markers of energy metabolism, deficits in mitochondrial and peroxisomal β-oxidation activity, insulin resistance, and physical activity. Acylcarnitines are increasingly being identified as important indicators in metabolic studies of many diseases, including metabolic disorders, cardiovascular diseases, diabetes, depression, neurologic disorders, and certain cancers. The US Food and Drug Administration-approved drug L-carnitine, along with short-chain acylcarnitines (acetylcarnitine and propionylcarnitine), is now widely used as a dietary supplement. In light of their growing importance, we have undertaken an extensive review of acylcarnitines and provided a detailed description of their identity, nomenclature, classification, biochemistry, pathophysiology, supplementary use, potential drug targets, and clinical trials. We also summarize these updates in the Human Metabolome Database, which now includes information on the structures, chemical formulae, chemical/spectral properties, descriptions, and pathways for 1240 acylcarnitines. This work lays a solid foundation for identifying, characterizing, and understanding acylcarnitines in human biosamples. We also discuss the emerging opportunities for using acylcarnitines as biomarkers and as dietary interventions or supplements for many wide-ranging indications. The opportunity to identify new drug targets involved in controlling acylcarnitine levels is also discussed. Significance Statement This review provides a comprehensive overview of acylcarnitines, including their nomenclature, structure and biochemistry, and use as disease biomarkers and pharmaceutical agents. We present updated information contained in the Human Metabolome Database website as well as substantial mapping of the known biochemical pathways associated with acylcarnitines, thereby providing a strong foundation for further clarification of their physiological roles.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48006213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Allosteric Modulators of Metabotropic Glutamate Receptors as Novel Therapeutics for Neuropsychiatric Disease","authors":"D. Luessen, P. Conn","doi":"10.1124/pharmrev.121.000540","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000540","url":null,"abstract":"Metabotropic glutamate (mGlu) receptors, a family of G-protein-coupled receptors, have been identified as novel therapeutic targets based on extensive research supporting their diverse contributions to cell signaling and physiology throughout the nervous system and important roles in regulating complex behaviors, such as cognition, reward, and movement. Thus, targeting mGlu receptors may be a promising strategy for the treatment of several brain disorders. Ongoing advances in the discovery of subtype-selective allosteric modulators for mGlu receptors has provided an unprecedented opportunity for highly specific modulation of signaling by individual mGlu receptor subtypes in the brain by targeting sites distinct from orthosteric or endogenous ligand binding sites on mGlu receptors. These pharmacological agents provide the unparalleled opportunity to selectively regulate neuronal excitability, synaptic transmission, and subsequent behavioral output pertinent to many brain disorders. Here, we review preclinical and clinical evidence supporting the utility of mGlu receptor allosteric modulators as novel therapeutic approaches to treat neuropsychiatric diseases, such as schizophrenia, substance use disorders, and stress-related disorders. Significance Statement Allosteric modulation of metabotropic glutamate (mGlu) receptors represents a promising therapeutic strategy to normalize dysregulated cellular physiology associated with neuropsychiatric disease. This review summarizes preclinical and clinical studies using mGlu receptor allosteric modulators as experimental tools and potential therapeutic approaches for the treatment of neuropsychiatric diseases, including schizophrenia, stress, and substance use disorders.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43333612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the Adaptive Immune System in Depression: Focus on T Helper 17 Cells.","authors":"Eléonore Beurel, Eva M Medina-Rodriguez, Richard S Jope","doi":"10.1124/pharmrev.120.000256","DOIUrl":"10.1124/pharmrev.120.000256","url":null,"abstract":"<p><p>There is a vital need to understand mechanisms contributing to susceptibility to depression to improve treatments for the 11% of Americans who currently suffer from this debilitating disease. The adaptive immune system, comprising T and B cells, has emerged as a potential contributor to depression, as demonstrated in the context of lymphopenic mice. Overall, patients with depression have reduced circulating T and regulatory B cells, \"immunosuppressed\" T cells, and alterations in the relative abundance of T cell subtypes. T helper (Th) cells have the capacity to differentiate to various lineages depending on the cytokine environment, antigen stimulation, and costimulation. Regulatory T cells are decreased, and the Th1/Th2 ratio and the Th17 cells are increased in patients with depression. Evidence for changes in each Th lineage has been reported to some extent in patients with depression. However, the evidence is strongest for the association of depression with changes in Th17 cells. Th17 cells produce the inflammatory cytokine interleukin (IL)-17A, and the discovery of Th17 cell involvement in depression evolved from the well established link that IL-6, which is required for Th17 cell differentiation, contributes to the onset, and possibly maintenance, of depression. One intriguing action of Th17 cells is their participation in the gut-brain axis to mediate stress responses. Although the mechanisms of action of Th17 cells in depression remain unclear, neutralization of IL-17A by anti-IL-17A antibodies, blocking stress-induced production, or release of gut Th17 cells represent feasible therapeutic approaches and might provide a new avenue to improve depression symptoms. SIGNIFICANCE STATEMENT: Th17 cells appear as a promising therapeutic target for depression, for which efficacious therapeutic options are limited. The use of neutralizing antibodies targeting Th17 cells has provided encouraging results in depressed patients with comorbid autoimmune diseases.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973514/pdf/pharmrev.120.000256.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9596052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"International Union of Basic and Clinical Pharmacology. CXII: Adenosine Receptors: A Further Update.","authors":"Adriaan P IJzerman, Kenneth A Jacobson, Christa E Müller, Bruce N Cronstein, Rodrigo A Cunha","doi":"10.1124/pharmrev.121.000445","DOIUrl":"10.1124/pharmrev.121.000445","url":null,"abstract":"<p><p>Our previous International Union of Basic and Clinical Pharmacology report on the nomenclature and classification of adenosine receptors (2011) contained a number of emerging developments with respect to this G protein-coupled receptor subfamily, including protein structure, protein oligomerization, protein diversity, and allosteric modulation by small molecules. Since then, a wealth of new data and results has been added, allowing us to explore novel concepts such as target binding kinetics and biased signaling of adenosine receptors, to examine a multitude of receptor structures and novel ligands, to gauge new pharmacology, and to evaluate clinical trials with adenosine receptor ligands. This review should therefore be considered a further update of our previous reports from 2001 and 2011. SIGNIFICANCE STATEMENT: Adenosine receptors (ARs) are of continuing interest for future treatment of chronic and acute disease conditions, including inflammatory diseases, neurodegenerative afflictions, and cancer. The design of AR agonists (\"biased\" or not) and antagonists is largely structure based now, thanks to the tremendous progress in AR structural biology. The A_2A- and A_2BAR appear to modulate the immune response in tumor biology. Many clinical trials for this indication are ongoing, whereas an A_2AAR antagonist (istradefylline) has been approved as an anti-Parkinson agent.</p>","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":19.3,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic Opportunities and Delivery Strategies for Brain Revascularization in Stroke, Neurodegeneration, and Aging","authors":"Idoia Gallego, Ilia Villate-Beitia, L. Saenz-del-Burgo, G. Puras, J. Pedraz","doi":"10.1124/pharmrev.121.000418","DOIUrl":"https://doi.org/10.1124/pharmrev.121.000418","url":null,"abstract":"Central nervous system (CNS) diseases, especially acute ischemic events and neurodegenerative disorders, constitute a public health problem with no effective treatments to allow a persistent solution. Failed therapies targeting neuronal recovery have revealed the multifactorial and intricate pathophysiology underlying such CNS disorders as ischemic stroke, Alzheimeŕs disease, amyotrophic lateral sclerosis, vascular Parkisonism, vascular dementia, and aging, in which cerebral microvasculature impairment seems to play a key role. In fact, a reduction in vessel density and cerebral blood flow occurs in these scenarios, contributing to neuronal dysfunction and leading to loss of cognitive function. In this review, we provide an overview of healthy brain microvasculature structure and function in health and the effect of the aforementioned cerebral CNS diseases. We discuss the emerging new therapeutic opportunities, and their delivery approaches, aimed at recovering brain vascularization in this context. Significance Statement The lack of effective treatments, mainly focused on neuron recovery, has prompted the search of other therapies to treat cerebral central nervous system diseases. The disruption and degeneration of cerebral microvasculature has been evidenced in neurodegenerative diseases, stroke, and aging, constituting a potential target for restoring vascularization, neuronal functioning, and cognitive capacities by the development of therapeutic pro-angiogenic strategies.","PeriodicalId":19780,"journal":{"name":"Pharmacological Reviews","volume":null,"pages":null},"PeriodicalIF":21.1,"publicationDate":"2022-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46366496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}