CNS Drug Delivery in Stroke: Improving Therapeutic Translation From the Bench to the Bedside.

Drug development for ischemic stroke is challenging as evidenced by the paucity of therapeutics that have advanced beyond a phase III trial. There are many reasons for this lack of clinical translation including factors related to the experimental design of preclinical studies. Often overlooked in therapeutic development for ischemic stroke is the requirement of effective drug delivery to the brain, which is critical for neuroprotective efficacy of several small and large molecule drugs. Advancing central nervous system drug delivery technologies implies a need for detailed comprehension of the blood-brain barrier (BBB) and neurovascular unit. Such knowledge will permit the innate biology of the BBB/neurovascular unit to be leveraged for improved bench-to-bedside translation of novel stroke therapeutics. In this review, we will highlight key aspects of BBB/neurovascular unit pathophysiology and describe state-of-the-art approaches for optimization of central nervous system drug delivery (ie, passive diffusion, mechanical opening of the BBB, liposomes/nanoparticles, transcytosis, intranasal drug administration). Additionally, we will discuss how endogenous BBB transporters represent the next frontier of drug delivery strategies for stroke. Overall, this review will provide cutting edge perspective on how central nervous system drug delivery must be considered for the advancement of new stroke drugs toward human trials.

ß-glucan, a specific immuno-stimulant, produces rapid antidepressant effects by stimulating ERK1/2-dependent synthesis of BDNF in the hippocampus.

A decline in microglia in the dentate gyrus of the hippocampus has recently been described as an important mechanism for the progression of depression. Reversal of this decline by innate immune system stimulants may represent a novel strategy to ameliorate the depressive phenotype in chronically stressed animals. ß-glucan is a polysaccharide from Saccharomyces cerevisiae. It can efficiently stimulate microglia without inducing the production of pro-inflammatory cytokines. Therefore, ß-glucan could be an ideal drug to ameliorate depressive phenotypes. In the present study, we found that a single injection of ß-glucan reversed depression-like behaviors in mice induced by chronic unpredictable stress (CUS) in a dose-dependent manner, which was accompanied by a reversal of the CUS-induced decrease in brain-derived neurotrophic factor (BDNF) protein levels in the dentate gyrus. The crucial role of BDNF signaling in the antidepressant effect of ß-glucan was demonstrated by experiments showing that infusion of an anti-BDNF antibody into dentate gyrus, construction of BDNF-Val68Met allele knock-in mice, or treatment with the BDNF receptor antagonist K252a abolished the antidepressant effect of ß-glucan. The increased BDNF signaling induced by ß-glucan was mediated by extracellular signal-regulated kinase1/2 (ERK1/2)-mediated BDNF synthesis, and inhibition of ERK1/2 by SL327 was able to abolish the antidepressant effect of ß-glucan. Moreover, inhibition or depletion of microglia by minocycline or PLX3397 abolished the reversal effect of ß-glucan on CUS-induced depression-like behaviors and CUS-induced impairment of ERK1/2-BDNF signaling. These results suggest that ß-glucan exhibits antidepressant effects by stimulating microglia-mediated activation of ERK1/2 and synthesis of BDNF in the hippocampus.

Recent Update on Pharmacokinetics and Drug Metabolism in CNS-based Drug Discovery.

Despite significant advancements in CNS research, CNS illnesses are the most important and serious cause of mental disability worldwide. These facts show a tremendous unmet demand for effective CNS medications and pharmacotherapy since it accounts for more hospitalizations and extended care than practically all other disorders combined. The site-targeted kinetics of the brain and, pharmacodynamics of CNS effects are determined/regulated by various mechanisms after the dose, including blood-brain barrier (BBB) transport and many other processes. These processes are condition-dependent in terms of their rate and extent because they are dynamically controlled. For effective therapy, drugs should access the CNS "at the right place, time, and concentration". Details on inter-species and inter-condition variances are required to translate target site pharmacokinetics and associated CNS effects between species and illness states, improving CNS therapeutics and drug development. The present review encircles a short discussion about the barriers that affect effective CNS treatment and precisely focuses on the pharmacokinetics aspects of efficient CNS therapeutics.

Targeted to neuronal organelles for CNS drug development.

Significant evidences indicate that sub-cellular organelle dynamics is critical for both physiological and pathological events and therefore may be attractive drug targets displaying great therapeutic potential. Although the basic biological mechanism underlying the dynamics of intracellular organelles has been extensively studied, relative drug development is still limited. In the present review, we show that due to the development of technical advanced imaging tools, especially live cell imaging methods, intracellular organelle dynamics (including mitochondrial dynamics and membrane contact sites) can be dissected at the molecular level. Based on these identified molecular targets, we review and discuss the potential of drug development to target organelle dynamics, especially mitochondria dynamics and ER-organelle membrane contact dynamics, in the central nervous system for treating human diseases, including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

Aporphines: A privileged scaffold in CNS drug discovery.

Aporphine alkaloids embedded in 4H-dibenzo[de,g]quinoline four-ring structures belong to one of the largest subclasses of isoquinoline alkaloids. Aporphine is a privileged scaffold in the field of organic synthesis and medicinal chemistry for the discovery of new therapeutic agents for central nervous system (CNS) diseases, cancer, metabolic syndrome, and other diseases. In the past few decades, aporphine has attracted continuing interest to be widely used to develop selective or multitarget directed ligands (MTDLs) targeting the CNS (e.g., dopamine D1/2/5, serotonin 5-HT1A/2A/2C and 5-HT7, adrenergic α/ß receptors, and cholinesterase enzymes), thereby serving as valuable pharmacological probes for mechanism studies or as potential leads for CNS drug discovery. The aims of the present review are to highlight the diverse CNS activities of aporphines, discuss their SAR, and briefly summarize general synthetic routes, which will pave the way for the design and development of new aporphine derivatives as promising CNS active drugs in the future.

Explaining Blood-Brain Barrier Permeability of Small Molecules by Integrated Analysis of Different Transport Mechanisms.

The blood-brain barrier (BBB) represents a major obstacle to delivering drugs to the central nervous system (CNS), resulting in the lack of effective treatment for many CNS diseases including brain cancer. To accelerate CNS drug development, computational prediction models could save the time and effort needed for experimental evaluation. Here, we studied BBB permeability focusing on active transport (influx and efflux) as well as passive diffusion using previously published and self-curated data sets. We created prediction models based on physicochemical properties, molecular substructures, or their combination to understand which mechanisms contribute to BBB permeability. Our results show that features that predicted passive diffusion over membranes overlap with features that explain endothelial permeation of approved CNS-active drugs. We also identified physical properties and molecular substructures that positively or negatively predicted BBB transport. These findings provide guidance toward identifying BBB-permeable compounds by optimally matching physicochemical and molecular properties to BBB transport mechanisms.

Endocannabinoid-dependent decrease of GABAergic transmission on dopaminergic neurons is associated with susceptibility to cocaine stimulant effects in pre-adolescent male MAOA hypomorphic mice exposed to early life stress.

Vulnerability to cocaine use disorder depends upon a combination of genetic and environmental risk factors. While early life adversity is a critical environmental vulnerability factor for drug misuse, allelic variants of the monoamine oxidase A (MAOA) gene have been shown to moderate its influence on the risk of drug-related problems. However, data on the interactions between MAOA variants and early life stress (ES) with respect to predisposition to cocaine abuse are limited. Here, we show that a mouse model capturing the interaction of genetic (low-activity alleles of the Maoa gene; MAOANeo) and environmental (i.e., ES) vulnerability factors displays an increased sensitivity to repeated in vivo cocaine psychomotor stimulant actions associated with a reduction of GABAA receptor-mediated inhibition of dopamine neurons of the ventral tegmental area (VTA). Depolarization-induced suppression of inhibition (DSI), a 2-arachidonoylglycerol (2AG)-dependent form of short-term plasticity, also becomes readily expressed by dopamine neurons from male MAOANeo ES mice repeatedly treated with cocaine. The activation of either dopamine D2 or CB1 receptors contributes to cocaine-induced DSI expression, decreased GABA synaptic efficacy, and hyperlocomotion. Next, in vivo pharmacological enhancement of 2AG signaling during repeated cocaine exposure occludes its actions both in vivo and ex vivo. This data extends our knowledge of the multifaceted sequelae imposed by this gene-environment interaction in VTA dopamine neurons of male pre-adolescent mice and contributes to our understanding of neural mechanisms of vulnerability for early onset cocaine use.

Synthesis, Computational and Pharmacological Evaluation of 7-(2-(2- (3- (Substituted Phenyl) Acryloyl) Phenoxy) Ethoxy)-4-Methyl-2H-Chromen- 2-Ones as CNS Agents.

BACKGROUND: Motivated by the exciting biological potential for the use of hybrid molecules in medicine and therapy. It is anticipated that the coumarin-chalcone hybrids for skeletal muscle and antianxiety action will be investigated using a chemical hybridization technique. OBJECTIVE: Due to its numerous benefits, including high effectiveness, mode of action at receptors, minimal adverse effects, and improved pharmacokinetic features, naturally occurring and synthesized hybrid compounds are prospective sources for novel drug development techniques. In opinion of these applications, we here designed some coumarin-chalcone hybrids and explored them for skeletal muscle and antianxiety potential. METHODS: Using a chemical hybridization strategy, coumarin-chalcone hybrids have been synthesized and evaluated for skeletal muscle and antianxiety activity. The target compounds were synthesized by reaction of 7-hydroxy-4-methylcoumarion with haloalkane to afford 7-(2- bromoethoxy)-4-methyl-2H-chromen-2-one which was further treated with hydroxychalcones. The structures of target compounds were confirmed on the basis of their Melting Point, Thin Layer Chromatography, IR, 1HNMR and Mass studies. The computational properties of target compounds were also determined through online software. Skeletal muscle and antianxiety potential were performed in Swiss albino mice. RESULTS: The coumarin-chalcones hybrids showed skeletal muscle and antianxiety potential in Swiss albino mice and computational properties of the target compounds were also showed similarity as compared with diazepam. CONCLUSION: Among the target compounds, the fluoro group containing compound was found to be more potent as compared to the standard drug diazepam.

Recent Advances in the Development of Pyrimidine-based CNS Agents.

BACKGROUND: In the past few decades, considerable progress has been made in CNS drug discovery, and various new CNS agents have been developed. Pyrimidine is an important scaffold in the area of medicinal chemistry. Recently, pyrimidine-containing compounds have been successfully designed as potent CNS agents. Substantial research has been carried out on pyrimidine-bearing compounds to treat different disorders of CNS in various animal models. METHODS: Utilizing various databases, including Google Scholar, PubMed, Science Direct, and Web of Science, the literature review was conducted. The specifics of significant articles were discussed with an emphasis on the potency of pyrimidines derivatives possessing CNS activity. RESULTS: Recent papers indicating pyrimidine derivatives with CNS activity were incorporated into the manuscript. (46) to (50) papers included different pyrimidine derivatives as 5-HT agonist/antagonists, (62) to (67) as adenosine agonist/antagonist, (70) to (75) as anticonvulsant agents, (80) to (83) as cannabinoid receptor agonists, (102) to (103) as nicotinic and (110) as muscarinic receptor agonists. The remaining papers (113) to (114) represented pyrimidine-based molecular imaging agents. CONCLUSION: Pyrimidine and its derivatives have been studied in detail to evaluate their efficacy in overcoming multiple central nervous system disorders. The article covers the current updates on pyrimidine-based compounds as potent CNS and molecular imaging agents and will definitely provide a better platform for the development of potent pyrimidine-based CNS drugs in the near future.

Recent Scaffold Hopping Applications in Central Nervous System Drug Discovery.

The concept of bioisosterism and the implementation of bioisosteric replacement is fundamental to medicinal chemistry. The exploration of bioisosteres is often used to probe key structural features of candidate pharmacophores and enhance pharmacokinetic properties. As the understanding of bioisosterism has evolved, capabilities to undertake more ambitious bioisosteric replacements have emerged. Scaffold hopping is a broadly used term in the literature referring to a variety of different bioisosteric replacement strategies, ranging from simple heterocyclic replacements to topological structural overhauls. In this work, we have highlighted recent applications of scaffold hopping in the central nervous system drug discovery space. While we have highlighted the benefits of using scaffold hopping approaches in central nervous system drug discovery, these are also widely applicable to other medicinal chemistry fields. We also recommend a shift toward the use of more refined and meaningful terminology within the realm of scaffold hopping.

Recent Advancements in CNS Acting Drugs: A Step Towards End of Illness.

Progressive degeneration in the morphology and functions of neuronal cells leads to multifactorial pathogenesis conditions of oxidative stress, mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity, and neuro-inflammation to mediate heterogeneous types of neurodegenerative diseases, such as Epilepsy, Alzheimer's (AD) and Parkinson's (PD), more prominently among aging populations. In this editorial, complex mechanisms, challenges, and advancements made in the discovery of new neurotherapeutics, as well as designing approaches being adopted to fabricate brain-targeted delivery systems, are discussed.

A merged molecular representation deep learning method for blood-brain barrier permeability prediction.

The ability of a compound to permeate across the blood-brain barrier (BBB) is a significant factor for central nervous system drug development. Thus, for speeding up the drug discovery process, it is crucial to perform high-throughput screenings to predict the BBB permeability of the candidate compounds. Although experimental methods are capable of determining BBB permeability, they are still cost-ineffective and time-consuming. To complement the shortcomings of existing methods, we present a deep learning-based multi-model framework model, called Deep-B3, to predict the BBB permeability of candidate compounds. In Deep-B3, the samples are encoded in three kinds of features, namely molecular descriptors and fingerprints, molecular graph and simplified molecular input line entry system (SMILES) text notation. The pre-trained models were built to extract latent features from the molecular graph and SMILES. These features depicted the compounds in terms of tabular data, image and text, respectively. The validation results yielded from the independent dataset demonstrated that the performance of Deep-B3 is superior to that of the state-of-the-art models. Hence, Deep-B3 holds the potential to become a useful tool for drug development. A freely available online web-server for Deep-B3 was established at http://cbcb.cdutcm.edu.cn/deepb3/, and the source code and dataset of Deep-B3 are available at https://github.com/GreatChenLab/Deep-B3.

Intranasal oxytocin attenuates the effects of monetary feedback on procedural learning.

Procedural learning is a vital brain function that allows us to acquire motor skills during development or re-learn them after lesions affecting the motor system. Procedural learning can be improved by feedback of different valence, e.g., monetary or social, mediated by dopaminergic circuits. While processing motivationally relevant stimuli, dopamine interacts closely with oxytocin, whose effects on procedural learning, particularly feedback-based approaches, remain poorly understood. In a randomized, double-blind, placebo-controlled trial, we investigated whether oxytocin modulates the differential effects of monetary and social feedback on procedural learning. Sixty-one healthy male participants were randomized to receive a placebo or oxytocin intranasally. The participants then performed a modified serial reaction time task. Oxytocin plasma concentrations were measured before and after applying the placebo or verum. Groups did not differ regarding general reaction times or measures of procedural learning. For the placebo group, monetary feedback improved procedural learning compared to a neutral control condition. In contrast, the oxytocin group did not show a differential effect of monetary or social feedback despite a significant increase in oxytocin plasma levels after intranasal application. The data suggest that oxytocin does not influence procedural learning per se. Instead, oxytocin seems to attenuate the effects of monetary feedback on procedural learning specifically.

Neurobiology of Dream Activity and Effects of Stimulants on Dream.

The sleep-wake cycle is the result of the activity of multiple neurobiological network interactions. The dreaming feature is one interesting sleep on that represents sensorial components, mostly visual perceptions, accompaniedby intense emotions. Further complexity has been added to the topic of the neurobiological mechanism of dream generation by the current data suggesting drugs' influence on dream generation. Here, we discuss the review of some of the neurobiological mechanisms of the regulation of dream activity, with special emphasis on the effects of stimulants on dreaming.

In Silico Approaches for Addressing Challenges in CNS Radiopharmaceutical Design.

Positron emission tomography (PET) is a highly sensitive and versatile molecular imaging modality that leverages radiolabeled molecules, known as radiotracers, to interrogate biochemical processes such as metabolism, enzymatic activity, and receptor expression. The ability to probe specific molecular and cellular events longitudinally in a noninvasive manner makes PET imaging a particularly powerful technique for studying the central nervous system (CNS) in both health and disease. Unfortunately, developing and translating a single CNS PET tracer for clinical use is typically an extremely resource-intensive endeavor, often requiring synthesis and evaluation of numerous candidate molecules. While existing in vitro methods are beginning to address the challenge of derisking molecules prior to costly in vivo PET studies, most require a significant investment of resources and possess substantial limitations. In the context of CNS drug development, significant time and resources have been invested into the development and optimization of computational methods, particularly involving machine learning, to streamline the design of better CNS therapeutics. However, analogous efforts developed and validated for CNS radiotracer design are conspicuously limited. In this Perspective, we overview the requirements and challenges of CNS PET tracer design, survey the most promising computational methods for in silico CNS drug design, and bridge these two areas by discussing the potential applications and impact of computational design tools in CNS radiotracer design.

Bioactive properties of the aromatic molecules of spearmint (Mentha spicata L.) essential oil: a review.

Spearmint belongs to the genus Mentha in the family Labiatae (Lamiaceae), which is cultivated worldwide for its remarkable aroma and commercial value. The aromatic molecules of spearmint essential oil, including carvone, carveol, dihydrocarvone, dihydrocarveol and dihydrocarvyl acetate, have been widely used in the flavors and fragrances industry. Besides their traditional use, these aromatic molecules have attracted great interest in other application fields (e.g., medicine, agriculture, food, and beverages) especially due to their antimicrobial, antioxidant, insecticidal, antitumor, anti-inflammatory and antidiabetic activities. This review presents the sources, properties, synthesis and application of spearmint aromatic molecules. Furthermore, this review focuses on the biological properties so far described for these compounds, their therapeutic effect on some diseases, and future directions of research. This review will, therefore, contribute to the rational and economic exploration of spearmint aromatic molecules as natural and safe alternative therapeutics.

Transient Opening of the Blood-Brain Barrier by Vasoactive Peptides to Increase CNS Drug Delivery: Reality Versus Wishful Thinking?

BACKGROUND: The blood-brain barrier inhibits the central nervous system penetration of 98% of small molecule drugs and virtually all biologic agents, which has limited progress in treating neurologic disease. Vasoactive peptides have been shown in animal studies to transiently disrupt the blood-brain barrier and regadenoson is currently being studied in humans to determine if it can improve drug delivery to the brain. However, many other vasoactive peptides could potentially be used for this purpose. METHODS: We performed a review of the literature evaluating the physiologic effects of vasoactive peptides on the vasculature of the brain and systemic organs. To assess the likelihood that a vasoactive peptide might transiently disrupt the blood-brain barrier, we devised a four-tier classification system to organize the available evidence. RESULTS: We identified 32 vasoactive peptides with potential blood-brain barrier permeabilityaltering properties. To date, none of these are shown to open the blood-brain barrier in humans. Twelve vasoactive peptides increased blood-brain barrier permeability in rodents. The remaining 20 had favorable physiologic effects on blood vessels but lacked specific information on permeability changes to the blood-brain barrier. CONCLUSION: Vasoactive peptides remain an understudied class of drugs with the potential to increase drug delivery and improve treatment in patients with brain tumors and other neurologic diseases. Dozens of vasoactive peptides have yet to be formally evaluated for this important clinical effect. This narrative review summarizes the available data on vasoactive peptides, highlighting agents that deserve further in vitro and in vivo investigations.

Coronavirus Disease 2019 (COVID-19) and Its Neuroinvasive Capacity: Is It Time for Melatonin?

The world faces an exceptional new public health concern caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), subsequently termed the coronavirus disease 2019 (COVID-19) by the World Health Organization (WHO). Although the clinical symptoms mostly have been characterized, the scientific community still doesn´t know how SARS-CoV-2 successfully reaches and spreads throughout the central nervous system (CNS) inducing brain damage. The recent detection of SARS-CoV-2 in the cerebrospinal fluid (CSF) and in frontal lobe sections from postmortem examination has confirmed the presence of the virus in neural tissue. This finding reveals a new direction in the search for a neurotherapeutic strategy in the COVID-19 patients with underlying diseases. Here, we discuss the COVID-19 outbreak in a neuroinvasiveness context and suggest the therapeutic use of high doses of melatonin, which may favorably modulate the immune response and neuroinflammation caused by SARS-CoV-2. However, clinical trials elucidating the efficacy of melatonin in the prevention and clinical management in the COVID-19 patients should be actively encouraged.

Injectable and Self-Healing Hydrogels with Double-Dynamic Bond Tunable Mechanical, Gel-Sol Transition and Drug Delivery Properties for Promoting Periodontium Regeneration in Periodontitis.

Injection of a hydrogel loaded with drugs with simultaneous anti-inflammatory and tissue regenerating properties can be an effective treatment for promoting periodontal regeneration in periodontitis. Nevertheless, the design and preparation of an injectable hydrogel with self-healing properties for tunable sustained drug release is still highly desired. In this work, polysaccharide-based hydrogels were formed by a dynamic cross-linked network of dynamic Schiff base bonds and dynamic coordination bonds. The hydrogels showed a quick gelation process, injectability, and excellent self-healing properties. In particular, the hydrogels formed by a double-dynamic network would undergo a gel-sol transition process without external stimuli. And the gel-sol transition time could be tuned by the double-dynamic network structure for in situ stimuli involving a change in its own molecular structure. Moreover, the drug delivery properties were also tunable owing to the gel-sol transition process. Sustained drug release characteristics, which were ascribed to a diffusion process, were observed during the first stage of drug release, and complete drug release owing to the gel-sol transition process was achieved. The sustained drug release time could be tuned according to the double-dynamic bonds in the hydrogel. The CCK-8 assay was used to evaluate the cytotoxicity, and the result showed no cytotoxicity, indicating that the injectable and self-healing hydrogels with double-dynamic bond tunable gel-sol transition could be safely used in controlled drug delivery for periodontal disease therapy. Finally, the promotion of periodontal regeneration in periodontitis in vivo was investigated using hydrogels loaded with ginsenoside Rg1 and amelogenin. Micro-CT and histological analyses indicated that the hydrogels were promising candidates for addressing the practical needs of a tunable drug delivery method for promoting periodontal regeneration in periodontitis.