Current Neuropharmacology - Volume 20, Issue 7, 2022

Background: Absence epilepsy is characterized by the presence of spike-and-wave discharges (SWDs) at the EEG generated within the cortico-thalamo-cortical circuit. The molecular mechanisms involved in the pathophysiology of absence epilepsy are only partially known. WAG/Rij rats older than 2-3 months develop spontaneous SWDs, and they are sensitive to anti- absence medications. Hence, WAG/Rij rats are extensively used as a model for absence epilepsy with predictive validity. Objective: The aim of the study was to examine the possibility that the orexin system, which supports the wake status in experimental animals and humans, plays a role in the pathophysiology of absence seizures. Methods: The perspective grounds its method from recent literature along with measurements of orexin receptor type-1 (OX1) protein levels in the thalamus and somatosensory cortex of WAG/Rij rats and non-epileptic Wistar control rats at two ages (25 days and 6-7 months). OX1 protein levels were measured by immunoblotting. Results: The analysis of the current literature suggests that the orexin system might be involved in the pathophysiology of absence epilepsy and might be targeted by therapeutic intervention. Experimental data are in line with this hypothesis, showing that OX1 protein levels were reduced in the thalamus and somatosensory cortex of symptomatic WAG/Rij rats (6-7 months of age) with respect to non-epileptic controls, whereas these differences were not seen in pre-symptomatic, 25 days-old WAG/Rij rats. Conclusion: This perspective might pave the way for future studies on the involvement of the orexinergic system in the pathophysiology of SWDs associated with absence epilepsy and its comorbidities.

Major depressive disorder (MDD) is a disease associated with many factors; specifically, environmental, genetic, psychological, and biological factors play critical roles. Recent studies have demonstrated that histone modification may occur in the human brain in response to severely stressful events, resulting in transcriptional changes and the development of MDD. In this review, we discuss five different histone modifications, histone methylation, histone acetylation, histone phosphorylation, histone crotonylation and histone β-hydroxybutyrylation, and their relationships with MDD. The utility of histone deacetylase (HDAC) inhibitors (HDACis) for MDD treatment is also discussed. As a large number of MDD patients in China have been treated with traditional Chineses medicine (TCM), we also discuss some TCM therapies, such as Xiaoyaosan (XYS), and their effects on histone modification. In summary, targeting histone modification may be a new strategy for elucidating the mechanism of MDD and a new direction for MDD treatment.

Spontaneous subarachnoid hemorrhage (SAH) accounts for 5-10% of all strokes and is a subtype of hemorrhagic stroke that places a heavy burden on health care. Despite great progress in surgical clipping and endovascular treatment for ruptured aneurysms, cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) threaten the long-term outcomes of patients with SAH. Moreover, there are limited drugs available to reduce the risk of DCI and adverse outcomes in SAH patients. New insight suggests that early brain injury (EBI), which occurs within 72 h after the onset of SAH, may lay the foundation for further DCI development and poor outcomes. The mechanisms of EBI mainly include excitotoxicity, oxidative stress, neuroinflammation, blood-brain barrier (BBB) destruction, and cellular death. Mitochondria are a double-membrane organelle, and they play an important role in energy production, cell growth, differentiation, apoptosis, and survival. Mitochondrial dysfunction, which can lead to mitochondrial membrane potential (Δψm) collapse, overproduction of reactive oxygen species (ROS), release of apoptogenic proteins, disorders of mitochondrial dynamics, and activation of mitochondria-related inflammation, is considered a novel mechanism of EBI related to DCI as well as post-SAH outcomes. In addition, mitophagy is activated after SAH. In this review, we discuss the latest perspectives on the role of mitochondria in EBI and DCI after SAH. We emphasize the potential of mitochondria as therapeutic targets and summarize the promising therapeutic strategies targeting mitochondria for SAH.

Nowadays, neurodegenerative diseases (NDs), such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), represent a great challenge in different scientific fields, such as neuropharmacology, medicinal chemistry, molecular biology and medicine, as all these pathologies remain incurable, with high socioeconomic impacts and high costs for governmental health services. Due to their severity and multifactorial pathophysiological complexity, the available approved drugs for clinic have not yet shown adequate effectiveness and exhibited very restricted options in the therapeutic arsenal; this highlights the need for continued drug discovery efforts in the academia and industry. In this context, natural products, such as curcumin (1), resveratrol (2) and cannabidiol (CBD, 3) have been recognized as important sources, with promising chemical entities, prototype models and starting materials for medicinal organic chemistry, as their molecular architecture, multifunctional properties and single chemical diversity could facilitate the discovery, optimization and development of innovative drug candidates with improved pharmacodynamics and pharmacokinetics compared to the known drugs and, perhaps, provide a chance for discovering novel effective drugs to combat NDs. In this review, we report the most recent efforts of medicinal chemists worldwide devoted to the exploration of curcumin (1), resveratrol (2) and cannabidiol (CBD, 3) as starting materials or privileged scaffolds in the design of multi-target directed ligands (MTDLs) with potential therapeutic properties against NDs, which have been published in the scientific literature during the last 10 years of research and are available in PubMed, SCOPUS and Web of Science databases.

Depression is one of the major disorders of the central nervous system worldwide and causes disability and functional impairment. According to the World Health Organization, around 265 million people worldwide are affected by depression. Currently marketed antidepressant drugs take weeks or even months to show anticipated clinical efficacy but remain ineffective in treating suicidal thoughts and cognitive impairment. Due to the multifactorial complexity of the disease, single-target drugs do not always produce satisfactory results and lack the desired level of therapeutic efficacy. Recent literature reports have revealed improved therapeutic potential of multi-target directed ligands due to their synergistic potency and better safety. Medicinal chemists have gone to great extents to design multitarget ligands by generating structural hybrids of different key pharmacophores with improved binding affinities and potency towards different receptors or enzymes. This article has compiled the design strategies of recently published multi-target directed ligands as antidepressant agents. Their biological evaluation, structural-activity relationships, mechanistic and in silico studies have also been described. This article will prove to be highly useful for the researchers to design and develop multi-target ligands as antidepressants with high potency and therapeutic efficacy.

Background: A variety of emerging medical imaging technologies based on artificial intelligence have been widely applied in many diseases, but they are still limitedly used in the cerebrovascular field even though the diseases can lead to catastrophic consequences. Objective: This work aims to discuss the current challenges and future directions of artificial intelligence technology in cerebrovascular diseases through reviewing the existing literature related to applications in terms of computer-aided detection, prediction and treatment of cerebrovascular diseases. Methods: Based on artificial intelligence applications in four representative cerebrovascular diseases including intracranial aneurysm, arteriovenous malformation, arteriosclerosis and moyamoya disease, this paper systematically reviews studies published between 2006 and 2021 in five databases: National Center for Biotechnology Information, Elsevier Science Direct, IEEE Xplore Digital Library, Web of Science and Springer Link. And three refinement steps were further conducted after identifying relevant literature from these databases. Results: For the popular research topic, most of the included publications involved computer-aided detection and prediction of aneurysms, while studies about arteriovenous malformation, arteriosclerosis and moyamoya disease showed an upward trend in recent years. Both conventional machine learning and deep learning algorithms were utilized in these publications, but machine learning techniques accounted for a larger proportion. Conclusion: Algorithms related to artificial intelligence, especially deep learning, are promising tools for medical imaging analysis and will enhance the performance of computer-aided detection, prediction and treatment of cerebrovascular diseases.

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.

The central nervous system (CNS) is enriched with important classes of lipids, in which cholesterol is known to make up a major portion of myelin sheaths, besides being a structural and functional unit of CNS cell membranes. Unlike in the adult brain, where the cholesterol pool is relatively stable, cholesterol is synthesized and accumulated at the highest rate in the developing brain to meet the needs of rapid brain growth at this stage, which is also a critical period for neuroplasticity. In addition to its biophysical role in membrane organization, cholesterol is crucial for brain development due to its involvement in brain patterning, myelination, neuronal differentiation, and synaptogenesis. Thus any injuries to the immature brain that affect cholesterol homeostasis may have long-term adverse neurological consequences. In this review, we describe the unique features of brain cholesterol biosynthesis and metabolism, cholesterol trafficking between different cell types, and highlight cholesterol-dependent biological processes during brain maturation. We also discuss the association of impaired cholesterol homeostasis with several forms of perinatal brain disorders in term and preterm newborns, including hypoxic-ischemic encephalopathy. Strategies targeting the cholesterol pathways may open new avenues for the diagnosis and treatment of developmental brain injury.

The role of gut microbiota in health and diseases has been receiving increased attention recently. Emerging evidence from previous studies on gut-microbiota-brain axis highlighted the importance of gut microbiota in neurological disorders. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) resulting from T-cell-driven, myelin-directed autoimmunity. The dysbiosis of gut microbiota in MS patients has been reported in published research studies, indicating that gut microbiota plays an important role in the pathogenesis of MS. Gut microbiota have also been reported to influence the initiation of disease and severity of experimental autoimmune encephalomyelitis, which is the animal model of MS. However, the underlying mechanisms of gut microbiota involvement in the pathogenesis of MS remain unclear. Therefore, in this review, we summerized the potential mechanisms for gut microbiota involvement in the pathogenesis of MS, including increasing the permeability of the intestinal barrier, initiating an autoimmune response, disrupting the blood-brain barrier integrity, and contributing to chronic inflammation. The possibility for gut microbiota as a target for MS therapy has also been discussed. This review provides new insight into understanding the role of gut microbiota in neurological and inflammatory diseases.

Background: Despite increasing worldwide incidence of Parkinson’s disease, the therapy is still suboptimal due to the diversified clinical manifestations, lack of sufficient treatment, the poor adherence in advanced patients, and varied response. Proper intake of medications regarding food and managing drug-food interactions may optimize Parkinson’s disease treatment. Objectives: We investigated potential effects that food, beverages, and dietary supplements may have on the pharmacokinetics and pharmacodynamics of drugs used by parkinsonian patients; identified the most probable interactions; and shaped recommendations for the optimal intake of drugs regarding food. Methods: We performed a systematic review in adherence to PRISMA guidelines, and included a total of 81 studies in the qualitative synthesis. Results and Conclusion: We found evidence for levodopa positive interaction with coffee, fiber and vitamin C, as well as for the potential beneficial impact of low-fat and protein redistribution diet. Contrastingly, high-protein diet and ferrous sulfate supplements can negatively affect levodopa pharmacokinetics and effectiveness. For other drugs, the data of food impact are scarce. Based on the available limited evidence, all dopamine agonists (bromocriptine, cabergoline, ropinirole), tolcapone, rasagiline, selegiline in tablets, safinamide, amantadine and pimavanserin can be taken with or without a meal. Opicapone and orally disintegrating selegiline tablets should be administered on an empty stomach. Of monoamine oxidase B inhibitors, safinamide is the least susceptible for interaction with the tyramine-rich food, whereas selegiline and rasagiline may lose selectivity to monoamine oxidase B when administered in supratherapeutic doses. The level of presented evidence is low due to the poor studies design, their insufficient actuality, and missing data.