Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder, with an unknown etiology and a multifactorial pathophysiology characterized by protein misfolding, neuroinflammation, and neuronal loss. There are three well-discussed main hypotheses for the pathophysiology of AD, which are related to i) the accumulation of amyloid β (Aβ) protein aggregates in the extracellular space, ii) deposition of hyperphosphorylated tau fragments as neurofibrillary tangles, and iii) dysregulation of hemostasis of some neurotransmitters involved in the disease, such as acetylcholine (ACh) and glutamate. The association of all these factors is responsible for installing oxidative stress and neuroinflammation, which contribute to progressive neuronal death in specific brain regions. More recently, other remarkable pathological characteristics have been described, involving changes in all levels of cellular components, especially in the action and function of protein kinases. These enzymes are crucial for cellular regulation since they play a pivotal role in the phosphorylation of protein substrates by transferring a phosphate group from the ATP molecule to threonine, serine, or tyrosine residues. In more recent studies, some kinases have been especially reported by their role in inflammatory and oxidative processes associated to AD, such as cAMP-dependent protein kinase A (PKA), cyclin-dependent protein kinase 5 (CDK5), glycogen synthase kinase 3β (GSK-3β), and the microtubule affinity regulatory kinases (MARKs). Under homeostatic conditions, protein kinases act as cellular signals, directing physiological responses, but in AD pathogenesis, these enzymes have an exacerbated activity in the brain, justifying the need for a better comprehension of their function and role, and how new kinase inhibitors could lead to innovative drugs. In this context, this brief review aimed to compile the literature data related to the most recent efforts and strategies in Medicinal Chemistry in the discovery of new kinase inhibitors, opening new ways to AD therapeutics.

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. The disease is characterized by the abnormal accumulation of amyloid β (Aβ) protein creating neuritic plaques, hyperphosphorylated tau (p-tau) protein forming intracellular tangles, and neuronal degeneration. Pathological changes related to abnormal Aβ and p-tau accumulation may begin more than fifteen years before the clinical diagnosis of AD is made. The glymphatic system is the brain’s waste clearance pathway that prevents the accumulation of these abnormal proteins and macromolecules. Glymphatic clearance is negatively affected by physiological conditions such as sleep deprivation, and pathological conditions such as traumatic brain injury and hemorrhagic strokes. These physiological and pathological conditions are strong risk factors for AD. In conclusion, impaired glymphatic clearance is an important pathogenetic mechanism for AD.

Alzheimer’s disease continuum has been described as the progressive stages of the disease over a long period. This progression can be categorized into three main stages: preclinical, mild cognitive impairment (MCI), and dementia. It has been suggested that there is a bidirectional relationship between the preclinical stage and MCI, but not between dementia and the earlier stages. The stage of MCI should be further analyzed, especially in cases where there is a reversion from MCI to a normal cognitive condition. The mechanisms behind this reversion deserve further investigation to differentiate true reversion from compensatory mechanisms. Analyzing reversion in greater detail could help identify potential therapies aimed at preventing or delaying the onset of dementia. As indicated, the primary focus has been on research indicating that MCI can revert to normal cognition. This reversion can occur by addressing risk factors through lifestyle changes, although a novel mechanism involving a transient functional compensation process in response to cognitive impairment should be also taken into account.

Excitotoxicity represents a neuropathological process, describing the toxic actions of excitatory neurotransmitters, where the excessive or prolonged activation of glutamate receptors triggers a cascade of events leading to neuronal injury or death. Under conditions of reduced energy availability and increased oxidative stress neurons become particularly vulnerable to excitotoxicity and a large body of available evidence indicates that excitotoxicity represents a central mechanism in the pathogenesis of acute and degenerative diseases of the central nervous system. Astrocytes represent key elements in the regulation of glutamate homeostasis by their opposing functions of glutamate uptake and release, and microglial cells play an important role in the response to damage. Depending on the phenotype they assume when activated, microglial cells can trigger immune defense or neuroprotective processes. To perform their functions both glial cell populations monitor the extracellular space through a panel of receptors. Furthermore, a variety of signaling pathways also contribute to the modulation of the glutamatergic transmission, acting on specific cell receptors expressed by neurons, astrocytes, and microglia. In the last decades, evidence has been provided that receptors of almost all families can establish structural receptor-receptor interactions, leading to the formation of heteroreceptor complexes at the cell membrane of neurons and glial cells. The cooperativity that emerges in the actions of ligands of the monomers forming these assemblies provides the cell decoding apparatus with flexible dynamics in terms of recognition and signal transduction and allows an integration of the incoming signals already at the membrane level. Available data on possible modulatory roles played by heteroreceptor complexes in excitotoxic processes will be here reviewed and discussed. From the pharmacological standpoint, these findings may offer possibilities to explore novel therapeutic strategies targeting receptor complexes to address disorders of the central nervous system associated with dysregulation of glutamatergic signaling.

The central nervous system (CNS) is one of the most complex physiological systems, and treatment of CNS disorders represents an area of major medical need. One critical aspect of the CNS is its lack of regeneration, such that damage is often permanent. The damage often leads to neurodegeneration, and so strategies for neuroprotection could lead to major medical advances. The G protein-coupled receptor (GPCR) family is one of the major receptor classes, and they have been successfully targeted clinically. One class of GPCRs is those activated by bioactive lysophospholipids as ligands, especially sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA). Research has been increasingly demonstrating the important roles that S1P and LPA, and their receptors, play in physiology and disease. In this review, I describe the role of S1P and LPA receptors in neurodegeneration and potential roles in neuroprotection. Much of our understanding of the role of S1P receptors has been through pharmacological tools. One such tool, fingolimod (also known as FTY720), which is a S1P receptor agonist but a functional antagonist in the immune system, is clinically efficacious in multiple sclerosis by producing a lymphopenia to reduce autoimmune attacks; however, there is evidence that fingolimod is also neuroprotective. Furthermore, fingolimod is neuroprotective in many other neuropathologies, including stroke, Parkinson’s disease, Huntington’s disease, Rett syndrome, Alzheimer’s disease, and others that are discussed here. LPA receptors also appear to be involved, being upregulated in a variety of neuropathologies. Antagonists or mutations of LPA receptors, especially LPA₁, are neuroprotective in a variety of conditions, including cortical development, traumatic brain injury, spinal cord injury, stroke and others discussed here. Finally, LPA receptors may interact with other receptors, including a functional interaction with plasticity related genes.

Neuroinflammation can be caused by disease, aging, infection, brain injury, toxicity, or stress. It is a contributory factor in the neuropathology of serious conditions that include multiple sclerosis (MS), Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and autoimmune encephalomyelitis (EAE). The neuroinflammatory response involves the activation of microglia, astrocytes, the endothelial cells of the blood-brain barrier, and peripherally-derived immune cells. The endocannabinoid system is composed of the natural cannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG), enzymes regulating their synthesis/catabolism, and the cannabinoid CB₁ and CB₂ receptors. It regulates multiple systems in the body including inflammation and endocannabinoid system dysregulation is involved in numerous inflammatory conditions. The Cannabis sativa plant produces over 100 phytocannabinoids, some of which interact with the endocannabinoid system. The major phytocannabinoids are delta-9-tetrahydrocannabinol (delta-9-THC), cannabidiol (CBD), and cannabigerol (CBG). Compelling evidence is emerging that many phytocannabinoids have anti-inflammatory and antioxidant properties. Phytocannabinoids including delta-9-THC, CBD, and CBG bind to a wide variety of targets in the endocannabinoid and/or other systems, which probably accounts for their diversity of effects in non-clinical and clinical studies. The benefits of certain phytocannabinoids have been proven by regulatory approval for medical use of CBD (Epidiolex^®), chemically synthesized delta-9-THC (Marinol^® and Syndros^®) and 1:1 delta-9-THC/CBD (Sativex^®). Furthermore, the widely recognized therapeutic properties of Cannabis have been a key driver in legalizing the medical use of Cannabis in 38 USA states. In this review, the potential of phytocannabinoids as effective treatments in neuroinflammatory disorders is discussed based on a critical evaluation of the non-clinical and clinical evidence. We focused on delta-9-THC, CBD, and CBG because they are the most abundant phytocannabinoids in Cannabis sativa and a substantial body of scientific data exists to describe their respective pharmacological mechanisms.

To quantitatively analyze the effects of acoustic neurostimulation on the symptoms of depression, anxiety, stress, and sleep quality in healthy workers. Eleven physiological and psychological variables (V1–V11) representing stress levels, sleep quality, and cortisol levels were acquired from a recent article (https://doi.org/10.37349/ent.2023.00064) that analyzed the effects of brainwave entrainment (BWE) techniques—binaural beats (BB), isochronic tones (IT), or a combination of the two (BB + IT). Principal component analysis (PCA) was used to create principal components to analyze the contribution of each variable to the efficacy. A thermodynamic cycle and equations based on a Venn diagram were used to understand the differences in treatment effectiveness in individual and combined auditory stimulations. PCA reduced the dimensionality of variables from eleven to three. PC1 represented auditory treatment efficacy, while neither PC2 nor PC3 did. All eleven variables had a negative correlation to PC1, with stress (V3) showing the most negative correlation and salivary cortisol level (V11) showing the least. Treatments using BB were more effective than treatments with IT or BB + IT. PCA successfully aided in the analysis of auditory treatment efficacies. All examined variables, especially the stress scale (V3), had a negative correlation in treatment efficacy, aligning with the results of the original paper. Analysis using the thermodynamic cycle and Venn diagram based on PCA provided an explanation why a combined treatment (BB + IT) was less effective than BB alone in the collective consideration of all eleven variables. This study demonstrates that the thermodynamic cycle and Venn diagram in conjunction with PCA are useful analytical tools for the quantitative analysis of multi-factor systems.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by both non-motor and motor symptoms, due to the loss of dopamine-producing neurons in the brain. Monoamine oxidase-B (MAO-B) inhibitors are essential in the treatment of PD, as they increase dopamine levels and could potentially slow down the progression of the disease. MAO-B inhibitors block the ability of the enzyme to degrade dopamine in the brain. MAO-B inhibitors work by inhibiting this enzyme, which raises dopamine levels and helps reduce motor symptoms, such as akinesia and stiffness in the muscles. In addition to their impact on dopamine levels, MAO-B inhibitors may possess neuroprotective properties. Research indicates that these inhibitors can shield neurons from the harmful byproducts of dopamine breakdown, such as dihydroxy acetaldehyde and hydrogen peroxide. This neuroprotective effect could potentially slow the progression of PD and protect against neuronal damage. MAO-B inhibitors are effective in treating both advanced and early stages of PD. They are recommended as initial treatments for individuals with early PD and can also be used as supplementary therapy in advanced PD to assist in managing motor complications. Additionally, MAO-B inhibitors have shown promise for the treatment of non-motor symptoms of PD, such as fatigue and sleep disturbances. MAO-B inhibitors are an important class of drugs for the treatment of PD, offering both symptomatic relief and potential disease-modifying effects. The goal of ongoing research and development of MAO-B inhibitors is to enhance their safety and selectivity profiles, which could lead to improved treatment approaches for PD and other neurodegenerative disorders.

A novel concept has been recently put forward in the mind/body interface (https://doi.org/10.37349/ent.2024.00074). The new concept has led to a new word: vitaction. Vitactions offer benefits to the brain and mind comparable to the advantages vitamins provide for the body’s overall health. The field of vitactions is as it was the vitamin field one century ago, i.e., without tools to make a complete classification. I propose to classify vitactions into five categories according to the behaviours necessary to maintain balanced brain functionality. A deficit of vitactions would contribute to the enormous prevalence in developed countries of diseases ranging from type 2 diabetes to neuropsychiatric diseases. The concept should help to identify which vitactions are deficient and to outline how they can be progressively implemented to improve the quality of life. The parallelism vitactions/vitamins also extends to overdosing; both hypervitaminosis and hypervitactinosis may be detrimental. This perspective article argues that vitactions should be considered at the practical and the scientific research levels, and that a balanced vitamin and vitaction supply is essential for a better life. In addition, reasons for proposing a synonym, “vitactin”, are given.

Peripheral nerve injuries (PNIs) constitute a significant concern as they predominantly affect young and productive age groups of the population, causing social and economic pressure on patients. PNIs are a global problem that can result in disability because of the disruption of nerve function. PNI leads to a reduction in nerve conduction velocity, which worsens or impairs the mobility of the innervated area. Managing PNI remains a major clinical challenge. Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant first identified in 1957. It is an important antioxidant necessary for the organs to maintain their normal function and the body’s chemical processes. It scavenges free radicals and reduces oxidative stress. Studies showed that antioxidants such as CoQ10 a potent antioxidant, help the regeneration of PNIs. It has been observed to increase the myelination process in nerve fibres and promote nerve regeneration in rats after injury. Therefore, this review handles the current positive effects of CoQ10 on peripheral nerve regeneration following injury.

Epilepsy, a complex neurological disorder, is influenced by intricate interactions within cortical, hippocampal, or thalamocortical neuronal networks, presenting a genetically complex condition with non-Mendelian inheritance patterns. This complexity is underscored by the involvement of numerous “susceptibilities” or “modifier” genes, complicating the assessment of risk and therapy outcomes. A critical inquiry in epilepsy treatment involves understanding how genetic diversity impacts treatment strategies and efficacy. Pharmacogenomic advancements have elaborated the connection between genetic variants and antiseizure medication (ASM) safety and response, marking a shift towards precision medicine in epilepsy care. Notably, genetic screening for variants such as HLA-B*1502 and HLA-A*3101 has demonstrated significant efficacy in preventing severe hypersensitivity reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), particularly among specific ethnic populations. However, putting pharmacogenomic discoveries into clinical practice faces numerous challenges, including educational, legal, and economic barriers, emphasizing the need for broader acceptance and integration of pharmacogenomic data. This review synthesizes recent studies on pharmacogenomics in epilepsy, highlighting the current advances and prospects for personalizing epilepsy treatment through genetic insights, aiming to enhance ASM safety, reduce adverse effects, and improve treatment outcomes. Through a comprehensive examination of the genetic basis of epilepsy and its influence on pharmacotherapy, this review endeavors to contribute to the evolving landscape of precision medicine in epilepsy care, advocating for a more individualized and effective treatment approach.

Transmethylation in the context of psychiatry has historically referred to the enzymatic transfer of a methyl group from one biochemical to another, whose resulting function can change so dramatically that a biochemical like tryptamine, for example, is converted into the hallucinogen dimethyltryptamine. Central to endogenous methylation activity is the folate cycle, which generates the primary transferable methyl groups in mammalian biochemistry. The relevance of this cycle to mental health becomes clear when the cycle is dysregulated, often leading to a buildup of both homocysteine and S-adenosylhomocysteine (SAH), while accompanied by a transient reduction in the intended physiologic target, S-adenosylmethionine (SAM). This paper includes an in-depth review of the causes of folate cycle perturbations associated with psychotic symptoms, expounding on alternative downstream pathways which are activated and pointing toward potential etiologic agents of the associated psychosis, the methylated tertiary amines N-methyl-salsolinol, N-methyl-norsalsolinol, and adrenochrome, which appear in scientific reports concerning their association with hallucinogenic and/or neurotoxic outcomes. Electrotopological state (E-state) data has been generated for these compounds, illustrating a strong similarity with hallucinogens, particularly in terms of the E-state of the nitrogen in their tertiary amine moieties. In light of the role the folate cycle plays in transmethylation, neuroprotective strategies to prevent the transition to psychosis are suggested, including the advisory that folate supplementation can be harmful depending on the status of other relevant biochemicals.

Stroke, one of the leading causes of global morbidity and mortality, results from disrupted cerebral blood circulation, leads to cellular damage or death. Ischemic stroke, the predominant subtype, relies mainly on recombinant tissue plasminogen activator (rtPA) and endovascular thrombectomy for the treatment. Neurological impairments following ischemic stroke highlight the importance of understanding the interplay between neuroinflammation and neurogenesis in brain repair. Research reveals a complex relationship, where inflammation both promotes and hinders neurogenesis, impacting post-stroke outcomes. The subventricular zone (SVZ) of striatum and sub granular zone (SGZ) in hippocampus play pivotal roles in adult neurogenesis, with distinct characteristics and functions. SVZ neurogenesis involves neuroblast progenitors migrating to the olfactory bulb, while SGZ facilitates granule cell generation for hippocampal function. Understanding the intricate processes of neuroinflammation, neurogenesis, and angiogenesis is crucial for developing effective stroke therapeutics. Promising avenues include drug therapy, selective serotonin reuptake inhibitors, antibody therapy, angiogenesis stimulation, growth factor therapy, hormone therapy, miRNAs, extracellular vesicles, and neuroprotective agents. Stem cell therapy, exploring various cell types, holds potential for neuronal replacement and recovery. In conclusion, deciphering the roles of SVZ and SGZ in neurogenesis, unraveling the complexity of neuroinflammation’s impact on repair, and exploring diverse therapeutic approaches highlight the need for comprehensive investigations to enhance stroke outcomes. The multifaceted landscape of stroke therapeutics presents challenges, but ongoing research offers promising avenues for bridging the gap between preclinical findings and clinical treatments.

It is widely known that each tissue has unique mechanisms to respond to injury and maintain homeostasis effectively. Although peripheral nerves have limited regeneration capacity, they conduct a complicated regeneration process by orchestrating multiple cell complexes after injury. In addition to drawing attention to anterograde and retrograde transportation, the absence of a cell body in the damaged area also points to the significance of immune and glial cells in the environment. Cellular reorganization following injury in the dorsal root ganglion, which takes place in the cell bodies of sensory peripheral nerve fibers, has attracted much attention. Growing research has been focused on investigating the molecular and cellular interactions occurring in sensory neurons and glial cells within the dorsal root ganglia after injury. It is clearly becoming that the sensory neurons and glial cells in the dorsal root ganglion are derived from the same embryological origins. Therefore, this information attracts attention to the potential of these two cells to differentiate into each other in case of injury. The focus of these studies is to illuminate the genes and pathways responsible for an increase in the plasticity of the neurogenic cell line following nerve injury. This review explores and discusses the underlying mechanisms responsible for maintaining homeostasis in the dorsal root ganglion and regeneration of peripheral nerves and how neuronal plasticity functions in the regeneration of the injury.

Degeneration and dysfunction of neurons in the brain are hallmarks of neurodegenerative diseases. Over the past decades, significant efforts have been devoted to the development and validation of biomarkers for neurodegenerative diseases. The range and diversity of biomarkers for central nervous system (CNS) diseases has continued to expand, encompassing biofluid-based sources such as blood or cerebrospinal fluid (CSF), nucleic acids, tissues, and imaging. While imaging and tissue biopsy-based markers are continually being identified and their applications expanding, they do have limitations compared with RNA and protein biomarkers. This review comprehensively summarizes various biomarkers, including microRNA (miRNA), long noncoding RNA (lncRNA), circulating miRNA (cimiRNA), and proteins, in the context of CNS disorders. In addition, the review emphasizes the existing limitations and challenges associated with the use of biomarkers in both clinical practice and research on neurodegenerative diseases. In conclusion, this review provides an insightful overview of the identified biomarkers for neurodegenerative diseases, underscoring the crucial role of biomarker research in combating these debilitating conditions. The article also highlights future challenges related to the implementation of novel biomarkers in clinical practice and trials, thereby contributing to the ongoing efforts to advance the understanding and management of neurodegenerative diseases.

Behavioural environment and behavioural responses of an individual are known to affect multiple aspects of physiology including neuroendocrine and growth factor signalling, angiogenesis, stem cell dynamics, tissue homeostasis, and maintenance. Despite substantial evidence, the role of behaviour-physiology interface in human health and disease remains underappreciated. The hypothesis proposed here suggests that deficiencies of certain behaviours that have evolved to become essential or “vitactions” can potentially trigger multiple health problems. Altered growth factor expression because of vitaction deficiencies affects angiogenesis and vascular function, neuronal maintenance, transport of glucose and other nutrients to the brain, mitochondrial function, oxidative stress, inflammation, and protein aggregation dynamics all implicated in Alzheimer’s disease (AD). Exercise is already known to be effective in prevention of AD. The hypothesis suggests that it is the behavioural component of exercise over mechanical activity and calorie burning that has crucial effects on brain health through multiple signalling pathways. Similar to vitamin deficiencies, where supplying the deficient vitamin is the only effective solution, for vitaction deficiencies supplying the deficient behavioural stimuli through behaviourally enriched exercise can be the most effective remedy.

Short-chain fatty acids (SCFAs) play a key role regulating immune and metabolic homeostasis. Consequently, dysregulation in SCFA levels is involved in the pathogenesis of autoimmune, inflammatory, metabolic, and neurodegenerative disorders. These metabolites are generated by gut microbiota, and their production is influenced mainly by diet. Here, an overview is provided of how SCFA production is associated with diet and with neurological disorders. The mechanisms by which SCFAs exert beneficial effects are analysed, along with how their production may be boosted by diet and how the use of specific dietary interventions might improve the outcome of neurological diseases.