Pharmacological Reviews最新文献

The blood-brain barrier (BBB) is a specialized vascular interface that safeguards central nervous system homeostasis by tightly regulating molecular exchange between blood and the brain. While essential for neuroprotection, its restrictive permeability limits therapeutic access, and its dysfunction is increasingly recognized as a driver of pathology across neurodegenerative, inflammatory, cerebrovascular, traumatic, and rare genetic disorders. In this review, we provide a comprehensive overview of pharmacological strategies to modulate BBB function, linking mechanistic insights into tight junction dynamics, transporter networks, endothelial-pericyte interactions, and immune crosstalk to emerging therapeutic approaches. We discuss interventions ranging from small molecules, peptides, and biologics to nanocarriers, noninvasive technologies, gene therapy, and stem cell-based strategies, highlighting their applications in 2 key translational contexts: transient enhancement of drug delivery and restoration of barrier integrity in disease. Ongoing challenges include ensuring safety, accounting for patient heterogeneity, and addressing the limitations of current experimental models. Finally, we consider how advances in BBB-on-chip systems, patient-specific induced pluripotent stem cell-derived models, and novel molecular targets are accelerating translation. Collectively, pharmacological modulation of the BBB, whether by reversible opening to enhance delivery or by reinforcing its protective function, represents a transformative frontier in central nervous system therapy. SIGNIFICANCE STATEMENT: The blood-brain barrier (BBB) is both a vital safeguard of neural homeostasis and a central obstacle to drug development in the central nervous system. This review integrates mechanistic insights into BBB regulation with translational advances in pharmacology and biotechnology, highlighting strategies that restore barrier integrity in disease and enhance therapeutic delivery. Emerging approaches, including gene therapy, nanotechnology, stem cell-based interventions, and next-generation human-relevant BBB models, illustrate how pharmacological innovation can overcome longstanding challenges and expand therapeutic access to the brain.

Bile acids (BAs) are mainly synthesized in the liver as end products of cholesterol catabolism through the classic (neutral) and alternative (acidic) pathways. BA synthesis requires a coordinated series of enzymes, in which CYP7A1 catalyzes the rate-limiting step, whereas CYP8B1 determines the proportion of the 2 primary BAs-cholic acid and chenodeoxycholic acid. Enterohepatic circulation of BAs is essential not only for nutrient absorption but also for maintaining systemic metabolic homeostasis. The expanding catalog of BA-responsive receptors throughout the gastrointestinal tract and peripheral metabolic tissues underscores the hormone-like nature of BAs in metabolic regulation. Moreover, dynamic and bidirectional interactions between BAs and the gut microbiota introduce an additional layer of complexity that shapes physiological and pathological metabolic processes. Targeting BA synthesis and microbial modification offers substantial therapeutic potential for a wide spectrum of metabolism-related diseases. SIGNIFICANCE STATEMENT: Bile acids (BAs) comprise a large family of endogenous steroid metabolites with diverse chemical structures. They can activate or inhibit a panel of BA-responsive receptors to elicit distinct cellular signaling programs integral to metabolic regulation. Their reciprocal interactions with gut microbiota further amplify the complexity of host metabolic control. Therapeutic strategies that modulate BA synthesis and microbial BA transformation, leveraging both BA synthesis enzymes and microbial partners, hold great promise for treating metabolic disorders.

Neurological diseases often lead to life-altering consequences, underscoring the urgent need for therapies that can reverse or mitigate their effects. Effective management of neurological disorders necessitates a thorough understanding of the common pathological mechanisms driving their onset and progression. Mitochondrial dysfunction and oxidative stress stand out as critical contributors to neuronal damage, implicated in traumatic brain injury, stroke, and amyotrophic lateral sclerosis. Disruptions in energy metabolism lead to the accumulation of reactive oxygen species and elevate the level of neural injury. Moreover, these imbalances disrupt cellular homeostasis and activate apoptotic pathways, further exacerbating neuronal loss and ultimately worsening the clinical prognosis. In this context, edaravone (Eda), a Food and Drug Administration-approved free radical scavenger, has emerged as a compelling candidate for the treatment of neuropathologies. This review provides a comprehensive overview of Eda, detailing its chemical structure and pharmacokinetic profile, with a focus on strategies to enhance its delivery to the central nervous system by modulating blood-brain barrier permeability or employing delivery systems that facilitate central nervous system penetration. Moreover, the review examines Eda's pharmacodynamic properties, including the signaling pathways it influences. The neurotherapeutic potential of Eda is further examined through in vitro and in vivo models of neurological disease. Insights from clinical trials are discussed to bridge the gap between preclinical findings and patient outcomes. Finally, the review highlights the synergistic effects of combining Eda with other pharmacological agents or therapeutic interventions, underscoring its promise as a versatile and indispensable treatment for neurological disorders. SIGNIFICANCE STATEMENT: Edaravone, a Food and Drug Administration-approved free radical scavenger, shows broad neuroprotective potential by mitigating oxidative stress and mitochondrial dysfunction across diverse neurological disorders, including stroke, amyotrophic lateral sclerosis, and traumatic brain injury. By synthesizing preclinical and clinical evidence, this review highlights edaravone's pleiotropic therapeutic actions, identifies translational challenges, and underscores its promise as a versatile treatment strategy for neurodegenerative and acute and chronic brain conditions.

Often, gene therapy reviews concentrate upon specific therapeutic modalities-particularly either viral vector-mediated or a nonviral approach. Here, we draw together a comprehensive array of knowledge across the field of genetic therapy for genetic neurological disease. The sections on preclinical and clinical application of viral vectors are followed by sections on RNA-based therapies and then by antisense oligonucleotide approaches also in preclinical and clinical settings. We present a separate section on gene editing strategies and conclude with a section elaborating on the neurosurgical techniques and the expertise required for clinical application of many of these technologies. SIGNIFICANCE STATEMENT: Genetic therapies have significant potential to treat life-limiting neurological diseases. This review examines the different approaches, clinical successes, and considerations on how to deploy them.

Sleep disturbance is increasingly recognized as a viable prevention target that could lower dementia risk. While a wide range of pharmacological options exist to manage sleep disturbance in people living with dementia, their use often does not adherent to the quality use of medicine. The complex nature of dementia as a syndrome often requires drugs that target multiple complaints (eg, sleep, cognition, and mood) and thus could produce psychological and physiological side effects that have the potential to do more harm than confer benefits. Therefore, this review first provides an expert narration of the pharmacology of sleep and the mechanisms of agents used to treat sleep disturbance. Then, a systematic scoping review was conducted to analyze evidence from studies over the past 10 years, which examined various pharmacological agents used for sleep disturbance in people living with dementia. SIGNIFICANCE STATEMENT: Sleep disturbances are a common consequence of the neurodegenerative changes occurring in dementia syndromes. They may also be etiologically linked to its development and progression. This review summarizes the pharmacological basis of sleep and collates the impact of medications used for dementia or sedatives on sleep and cognition outcomes. The review highlights gaps in research and will provide clinicians with key information required to make decisions about the quality use of medications to improve sleep health in those with dementia.

Cancer treatments have dramatically improved because of advances in surgery, radiotherapy, and chemotherapy. Although the duration of remission has steadily increased in recent years, preventing metastasis and achieving complete remission is still beyond reach for various types of cancers. However, recent advancements in immunology have facilitated the development of immunotherapies aimed at enhancing the specificity and efficacy of natural anticancer immune responses while impairing the inhibitory effects of immune checkpoints. Although immunotherapies combined with other treatment modalities have already produced remarkable results in previously untreatable tumors, many patients still do not achieve complete remission. In this review, we explore the effects of miR-155, a microRNA that plays a critical role in initiation and resolution of both innate and adaptive immunity. Among the many target transcripts of miR-155 are those encoding immune checkpoints, cell cycle regulators, epigenetics regulators, transcription factors, DNA repairs factors, and factors involved in various signaling pathways. The inhibitory effects of miR-155 on its target transcripts are likely to be context- and dose-dependent. As certain miR-155 targets can have opposing effects based on their dose and activity, therapies aimed at increasing or decreasing miR-155 levels can potentially backfire, inhibiting the beneficial effects of widely used anticancer drugs. Precise monitoring and adjustment of miR-155 levels, depending on the type and stage of tumors, should enhance the effectiveness of immunotherapies and increase the percentage of patients achieving complete remission in the future, particularly when immunotherapies are combined with chemotherapies. SIGNIFICANCE STATEMENT: Although immunotherapies developed the last decade have brought hope and improved cancer treatments, prevented metastasis, and increased the rate of complete remission, many aspects of the anticancer immune response are controlled by miR-155, a microRNA whose activity is both context- and dose-dependent. Therefore, it is essential to determine the optimal levels of miR-155 activity according to the type and stage of tumors, in order to fully unlock the potential of immunotherapies in combination with surgery, radiotherapies, or chemotherapies.

Generative drug design has emerged as a transformative approach in pharmaceutical research, leveraging deep learning models to create novel molecules with targeted properties. This systematic review analyzes the current landscape of computational approaches across 3 critical dimensions: molecular representation strategies (1-dimensional, 2-dimensional, and 3-dimensional), generative architectural frameworks (including variational autoencoders, generative adversarial networks, reinforcement learning systems, and diffusion models), and evaluation methodologies. We provide a comprehensive categorization of these approaches, critically assessing their relative advantages and limitations. Additionally, we examine the datasets driving development in this field and the metrics employed to evaluate model performance. Through structured analysis of these interconnected components, we identify significant research gaps and propose promising future directions for advancing artificial intelligence-driven drug discovery. This review offers researchers a unified framework for understanding the complex interplay between representation choices, generative mechanisms, and evaluation paradigms in computational drug design. SIGNIFICANCE STATEMENT: This review provides a unique framework for generative drug design by categorizing methods first by drug representation and then by generative model type. This novel taxonomy clarifies which models are best suited for specific molecular data types, offering practical guidance for researchers. We also critically discuss the advantages, disadvantages, key datasets, and evaluation metrics, delivering a comprehensive and actionable resource for the field.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most widespread neurodevelopmental disorders globally, marked by chronic symptoms of inattention and/or hyperactivity-impulsivity. Its multifactorial origin and phenotypic heterogeneity make it a complex condition, and despite substantial research, the precise causes of ADHD remain poorly understood. A significant challenge in advancing ADHD research is the lack of a unified resource that consolidates animal models across different species and considers the diversity of ADHD subtypes and associated coexisting conditions. This lack of standardization of the models delays progress in developing a deeper understanding of the neuronal and molecular mechanisms behind the disorder, which is essential to advance its treatment. This review aims to bridge this gap by offering a comprehensive compilation of available animal models used in ADHD research, accompanied by an evaluation of their validity. It is essential for researchers to have access to a range of models, each selected based on the specific scientific objectives and hypotheses of their studies. The review highlights that an extensive approach to studying ADHD, including its various dimensions and associated conditions, requires the use of multiple animal models. Moreover, it emphasizes the importance of assessing the mechanisms and broader effects of current pharmacological treatments while also exploring novel therapeutic possibilities. By providing a clearer and more structured resource, this work pursues to assist researchers in selecting the most appropriate models for their investigations. Additionally, it aims to contribute to the broader understanding of ADHD neurobiology, offering new perspectives for new models and the potential for more targeted therapeutic strategies. SIGNIFICANT STATEMENT: Attention-deficit/hyperactivity disorder (ADHD), one of the most prevalent neurodevelopmental disorders globally, is marked by inattention and/or hyperactivity-impulsivity. This review evaluates animal models for ADHD and its coexisting conditions, emphasizing the need for diverse models to reflect its complexity. It underscores the importance of selecting appropriate models to address specific research goals and investigates current and potential pharmacological treatments, providing a vital resource for advancing ADHD research and improving therapeutic approaches.

Enhanced de novo lipogenesis is a hallmark of cancer cells, enabling their proliferation, metastasis, and resistance to therapy. Among key lipogenic enzymes, fatty acid synthase (FASN) is frequently overexpressed in cancer but minimally expressed in most normal adult tissues, making it an appealing drug target. Human FASN is the sole cytosolic type I enzyme responsible for the de novo synthesis of palmitate. It is a homodimer of 270 kDa multidomain protein, functioning like an automatic assembly line. Its acyl carrier protein domain serves as a flexible arm, transporting the elongating acyl chain through other enzymatic domains responsible for chain elongation and modification, including malonyl/acetyltransferase, β-ketoacyl synthase, enoyl reductase, β-ketoacyl reductase, dehydrase, and thioesterase. The process begins at the malonyl/acetyltransferase domain, where the acetyl and malonyl groups from acetyl-CoA and malonyl-CoA, respectively, are transferred to the acyl carrier protein. FASN has been validated to play vital roles in promoting cancer progression, supporting cancer cell survival, reprogramming lipid metabolism, modulating oncogenic signaling pathways, and inducing drug resistance. Over the past 2 decades, significant progress has been made in developing inhibitors targeting different domains of FASN, including structure-based drug design, repurposing existing drugs, and nature-derived compounds with FASN-inhibitory properties. Despite these efforts, only a handful of inhibitors have entered clinical trials, such as 3-V Biosciences-2640 (denifanstat) and repurposed omeprazole, and none have received regulatory approval to date. In this review, we critically evaluate FASN-targeting strategies, highlight domain-specific targeting challenges, and discuss emerging insights that may help overcome current limitations, aiming to guide future discovery and optimization of FASN-targeted therapeutics. SIGNIFICANCE STATEMENT: Enhanced lipogenesis and fatty acid synthase overexpression in cancer make this multidomain enzyme an attractive target for therapy and overcoming drug resistance. Despite progress with novel and repurposed inhibitors, none have gained approval. This review critically examines past efforts, current challenges, and offers insights to guide future development of effective fatty acid synthase-targeting cancer therapeutics.

New chemical entities (NCEs) that act on the central nervous system are synthesized in pharmaceutical drug development programs for investigational purposes or by clandestine laboratories for illicit purposes. One component in the regulatory evaluation process of any NCE is abuse potential assessment, which involves both preclinical and human laboratory experiments to compare a NCE with an established and validated positive control that has known abuse potential in humans. Although multiple procedures are available in both preclinical and human laboratories, this review has focused on preclinical drug self-administration procedures because these results are heavily weighted in the regulatory evaluation process. Preclinical drug self-administration procedures have demonstrated high predictive validity for human abuse potential, and procedures that use simple fixed-ratio schedules of reinforcement, as recommended by the current U.S. Food and Drug Administration guidance, have good sensitivity for detecting drug reinforcement and abuse potential. However, these procedures have displayed poor resolution for ranking NCEs along an abuse-potential continuum that may inform controlled substance schedule placement. This review discusses the utility of behavioral economic/demand-curve experimental designs as a method to improve the resolution for differentiating relative reinforcing strength across drugs and ranking abuse potential for considerations of regulatory control. Theoretical benefits of demand-curve analysis are considered, and experimental parameters that optimize those benefits are reviewed. The influence of chronic drug exposure and history on demand-curve metrics of drug reinforcing strength and abuse potential is also reviewed. Future directions are highlighted toward empirically determining the utility of behavioral economic approaches for preclinical abuse potential assessment. SIGNIFICANCE STATEMENT: Simple fixed-ratio schedules of reinforcement have good sensitivity for detecting drug reinforcement and abuse potential but have poor resolution for ranking chemical entities along an abuse-potential continuum. Behavioral economic/demand-curve approaches maybe a method to increase resolution for abuse potential assessment. Accordingly, a preclinical abuse potential algorithm incorporating both simple fixed-ratio schedules and behavioral economic/demand-curve methods is described. Finally, the manuscript describes how individual subject traits and state variables, including chronic drug exposure and history, impact behavioral economic metrics of drug abuse potential.