Neuroinflammation is a hallmark of various neurodegenerative and neuropsychiatric disorders, driven by complex interactions between neurotransmitter receptors and immune signaling pathways. Among these, heteroreceptor complexes—functional assemblies formed by the physical interaction of different G protein-coupled or ionotropic receptor subtypes within the same membrane microdomain—play a crucial role in modulating synaptic activity, neuroimmune responses, and inflammatory cascades. For example, the A2A-D2 receptor complex modulates dopaminergic signaling in the striatum and has been implicated in Parkinson’s disease pathology. These receptor-receptor interactions influence key signaling pathways involving dopamine, serotonin, glutamate, adenosine, and cannabinoid systems, thereby contributing to the pathophysiology of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, schizophrenia, and depression. Dysregulation of heteroreceptor complexes disrupts neuronal homeostasis, exacerbates neuroinflammatory responses, and influences microglial and astrocytic activation. Understanding the molecular mechanisms governing these interactions, including allosteric modulation and biased agonism, offers novel therapeutic avenues for targeting neuroinflammation. Pharmacological strategies, such as selective allosteric modulators, biased agonists, and receptor-specific ligands, aim to restore heteroreceptor function and mitigate neuroinflammatory damage. Emerging clinical trials—such as those evaluating A2A receptor antagonists like istradefylline for Parkinson’s disease and 5-HT2A antagonists for schizophrenia—have shown promising neuroprotective and anti-inflammatory effects, although larger-scale, long-term studies are needed to confirm efficacy. This review highlights the pivotal role of heteroreceptor complexes in neuroinflammation, discusses their therapeutic potential, and underscores the need for further research into their functional dynamics to develop effective interventions for neurodegenerative and neuropsychiatric diseases.

Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.

The diagnosis of attention deficit hyperactivity disorder (ADHD) poses several diagnostic problems, as is widely acknowledged. The name points to two symptoms only, which are unspecific and embedded in many more neuropsychological symptoms. The additional deficits, such as problems with orientation, memory, cognition, emotion, autonomic nervous regulation, and motor dysfunctions, can be more important for patients in their daily lives than attention and hyperactivity. The general term “neurodevelopmental disorder (6A0)” in the International Classification of Diseases (ICD-11) is more appropriate and should be used instead. A further question is, when a dysfunction, such as inattention, becomes a clinical sign. As outlined in the International Classification of Functioning, Disability and Health (ICF), the context and the associated impairment decide on the clinical relevance of dysfunctions. Accordingly, the diagnosis of neurodevelopmental disorders must start with the description of context requirements, then assess capacity restrictions, and finally relate these to neuropsychological deficits. Subdimensions of neurodevelopmental disorders, as listed in ICD-11, are of no additional benefit, as they are comorbid merging syndromes.

Chronic upper limb pain is rather common among people in general and is characterized by a complex diagnosis due to the wide variety of factors that are involved in its development. In terms of treatment, pharmacology and manual therapy have classically been the most used options. However, based on current evidence, recommendations are more inclined to apply multimodal treatments, mainly with exercise therapy and pain education, based on the patient-centered care model. This case report details the evaluation and treatment of a 23-year-old woman with chronic upper limb pain using a multimodal physical therapy with a biobehavioral approach. The intervention lasted 12 weeks with a total of 9 sessions, in which manual therapy, therapeutic exercise, pain neuroscience education, motion representation methods, and sensory retraining were applied. The treatment resulted in a substantial improvement in the patient’s health condition. This case report indicates that a multimodal physical therapy treatment based on a biobehavioral approach may offer benefits in reducing pain symptoms and enhancing somatosensory, motor-functional, and affective-cognitive abilities in patients with chronic upper limb pain, as observed in the described case. Accordingly, this treatment can be a therapeutic option for patients with chronic upper limb pain.

Stroke is the third leading cause of death and disability in industrialized countries. The estimated costs of stroke to the healthcare system are $85 billion in the United States and $40 billion in the European Union. Despite the extensive research over the past decades, only therapies aimed at restoring blood flow to the affected area have been successful. However, the high risk of causing intracranial hemorrhage limits the application of this type of therapy to a small number of patients. Several studies have shown that, in addition to its well-known regulatory function in erythropoiesis, erythropoietin (EPO) is a potent neuroprotective agent against ischemic stroke. However, the use of EPO to treat stroke requires long-term protocols, high doses, and multiple administrations, which may cause thromboembolic complications due to increased hematocrit and blood viscosity, making EPO treatment unsuitable. To mitigate these adverse effects, various EPO analogues with neuroprotective properties but lacking erythropoietic activity have been investigated. This review aims to provide an overview of the protective mechanisms of EPO and its derivatives in the treatment of stroke.

Similar to other psychiatric disorders, drug addiction is linked to changes in neuronal activity within the mesolimbic system, which consists of dopamine (DA) neurons of the ventral tegmental area projecting to the ventral part of the striatum, the nucleus accumbens (NAc). All drugs of abuse indeed artificially increase DA concentration in the NAc, which hijacks the reward system and triggers lasting behavioral alterations, including compulsive drug-seeking and drug-taking behavior despite negative consequences and a high rate of relapse after abstinence. DA chiefly signals through DA receptor (DAR) type 1 (D1R) and type 2 (D2R), which are G protein-coupled receptor (GPCR) that are positively and negatively coupled to adenyl cyclase, respectively. Multiple evidence indicates that the potent modulatory roles of DA on other neurotransmitters and neuromodulator systems implicate the direct physical interactions (i.e., heteromerization) of DAR with other receptors. DAR heteromerization, which is increased in several preclinical models of psychiatric disorders, leads to a reciprocal and fine-tuned modulation of DAR and partner receptors, therefore suggesting that targeting DAR heteromerization may contribute to the development of clinically relevant strategies. Herein, we provide an overview of current methodologies used for detecting receptor heteromers both in heterologous systems and in situ in the brain and discuss their respective advantages and limitations. We also argue that D1R and D2R have been shown to form heteromers with multiple partner receptors in heterologous systems but only few studies were able to a provide proof of their existence in the brain or establish their biological roles. This review will emphasize on studies describing the modulation and functions of DAR heteromerization in the brain in preclinical models of psychiatric disorders, with a particular focus on addiction, a field in which those heteromerization processes have been the most extensively studied.

Neurodegenerative diseases are a complex ensemble of ailments characterized by progressive neuronal deterioration and ultimate loss, resulting in drastic impairments of memory, cognition and other brain functions. These incapacitating conditions are challenging for the public health system worldwide, with unfortunately no real cure and lack of efficient drugs capable of delaying or reversing these diseases. In this context, the endocannabinoid system and exogenous cannabinoids represent an interesting field of research due to numerous studies highlighting the neuroprotective effect of cannabinoids from different sources, i.e., endogenous, phytocannabinoids, and synthetic cannabinoids. This review highlights the multilayered effects of cannabinoids and the endocannabinoid system to block the progression of neurodegeneration and minimize the deleterious effects of insults that affect the brain. We illustrate examples showing that the main effects of cannabinoids modulate different components of the brain response to these insults at the level of three major mechanisms involved in neurodegeneration: neuroinflammation, excitotoxicity, and oxidative stress.

Repeat expansion diseases (REDs) are genetic disorders caused by unusual expansions of DNA sequences within certain genes. They cause several neurodegenerative diseases including Huntington’s disease (HD), myotonic dystrophy (DM), spinal and bulbar muscular atrophy (SBMA), fragile X syndrome (FXS), and others. The pathogenic repeat expansions disrupt normal cellular processes by producing aberrant RNA repeat sequences, leading to toxic protein aggregation, RNA foci, and altered gene expression. Although they belong to the rare disease group, such diseases must be investigated to understand integral mechanisms and prevention. Current methods for alleviating these diseases involve—gene silencing therapies by antisense oligonucleotides (ASOs) and RNA interference (RNAi), CRISPR/Cas9 gene editing, small molecule therapies, etc. ASOs and RNAi reduce toxic protein production genes while CRISPR/Cas9 excise or alter expanded repeats. Small molecule therapies targeting RNA repeat-binding or proteostasis regulation are being developed to alleviate toxic protein accumulation, prevent RNA toxic foci formation, and promote the degradation of misfolded proteins. Additionally, gene replacement and regulatory element modification restore normal gene function. Some researchers tried to modulate toxic protein aggregation using heat shock proteins and chemical chaperones. This is a comprehensive review on the available research on RED treatment and their ongoing challenges, such as efficient delivery of therapies to the central nervous system, minimizing off-target effects in gene editing, sustaining therapeutic efficacy, and addressing toxicity and scalability in large-scale applications.

This review focuses on the current advances in the field of therapeutic targets and treatments for stroke. Stroke is a major health problem worldwide, with significant impacts on morbidity and mortality, and a considerable burden on the medical and socio-economic systems. This review provides a comprehensive overview of the current state of knowledge on acute treatments and therapeutic targets. Current stroke treatments like recanalization therapies focus mainly on restoring blood flow to the brain, reducing cell death, and preventing further damage, but have limitations in terms of efficacy and long-term outcomes. Besides acute treatments (mobile stroke units, telerehabilitation) and acute therapeutic targets, the review focuses on longer-term therapeutic targets, such as neuroprotection and neuroregeneration. Neuroprotective strategies target the mechanisms underlying energy failure, cellular acidosis, mitochondrial dysfunction, endoplasmic reticulum stress, excitotoxicity, calcium channels dysregulation, oxidative stress, neuroinflammation, blood-brain barrier disruption, apoptosis, and ischemia-reperfusion injury. Neuroregenerative approaches include stem cell therapy, gene therapy, growth factors, and rehabilitation techniques that promote the rewiring of neuronal circuits in the brain. Non-pharmacological treatments like neurostimulation and bioengineering are also presented. Additionally, we highlight the challenges and future directions in translating these therapies into clinical practice. Overall, the treatment of ischemic stroke is a complex and multifaceted process that requires a combination of acute measures as well as longer-term strategies to promote brain repair and recovery. The treatment of ischemic stroke has made significant progress in recent years with the development of new treatments and ongoing research to improve outcomes for stroke patients. However, before these therapies can be successfully integrated into routine clinical practise, further research is needed to establish standardised protocols, overcome methodological limitations, and overcome clinical challenges. By further deepening our understanding of the pathophysiology of ischemic stroke and developing innovative treatments, we can improve outcomes and quality of life for stroke survivors.

Insulin-like growth factor-1 (IGF-1) elicits a variety of effects on the regulation of oxidative stress, a topic that remains shrouded in controversy. This intricate regulation plays a pivotal role in the aging process and its associated diseases. Notably, it centers around the challenge posed by endogenous antioxidant defenses, which often struggle to counteract free radicals-induced damage to various neural cell macromolecules. The interplay between IGF-1 and oxidative stress holds significant implications. Both factors are intertwined in the context of degenerative and inflammatory disruptions within the central nervous system (CNS), giving rise to dysfunctions in neurons and glial cells. These dysfunctions encompass detrimental outcomes such as excitotoxicity, neuronal attrition, and axonal impairment, all of which are closely related to behavioral irregularities. However, the complexities of IGF-1’s impact remain a topic of debate. Divergent research findings present IGF-1 as both an antioxidative agent and a catalyst to produce reactive oxygen species (ROS) in various neuropathologies. This diversity of outcomes has contributed to the ongoing controversy in the field. The present theoretical review undertakes a comprehensive vision, shedding light on the role of IGF-1 as a regulator within the mechanistic framework of oxidative stress responses. This regulatory role serves as the basis for the emergence of progressive neurodegenerative and neuroinflammatory conditions. Particularly compelling is the exploration of IGF-1 as a potential target for promising therapeutic interventions in this domain. However, the review also highlights significant limitations, including the considerations to work with this factor and the need for further research to clarify IGF-1’s role. Future perspectives should focus on refining our understanding of IGF-1’s mechanisms and exploring its therapeutic potential in more detail.

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.