Neuropathic pain, defined by the International Association for the Study of Pain as “pain caused by a lesion or disease of the somatosensory system”, has an estimated prevalence of 7–9.2% in the general population and is associated with poorer health-related quality of life than other types of pain. Diagnosis can be improved by the use of diagnostic algorithms, but treatment remains rather unsatisfactory, with only 30–40% of patients achieving an acceptable response. Some authors have suggested that the poor results in the treatment of neuropathic pain may be related to the different mechanisms present in each patient and have tried to correlate them with clinical characteristics in order to evaluate possible targeted treatments. This approach has been used in some studies evaluating the response to specific pharmacotherapies in clusters of patients, with encouraging results but still limited applicability to clinical practice. In this narrative review, we attempt to analyse the literature suggesting possible pathogenetic mechanisms manifested along the nociceptive pathway due to a lesion or disease of the nervous system; aware of the limitations of exploring such a wide field, we look for conditions that could be targeted by the available pharmacological or interventional treatment options. Functional changes may occur in the nociceptive system from the periphery to the cerebral cortex, in particular in the nociceptive terminals, along the first-order neuron and the dorsal root ganglion, at the first synapses, or at supraspinal levels. Clinical assessment is the first step in the study of anatomical and functional changes; the diagnostic hypothesis should be confirmed, if possible, by instrumental studies or diagnostic blocks or procedures to guide an individualised therapeutic algorithm from less to more invasive treatments.

“Functional” gut disorders are clinical conditions frequently encountered in clinical practice, often characterized by abnormalities of the intestinal sensory and motor functions. Although traditionally believed not harboring organic abnormalities, some of these disorders have been demonstrated to have more or less subtle involvement of the enteric nervous system. This involvement has been especially documented for enteric glial cells, even though other elements may be involved. Given the pivotal role of enteric glial cells in gut pathophysiology and their evident abnormalities in some disorders of gut-brain interaction, it may be time to reconsider their role and recognize them as an important pathophysiological factor in these conditions. Thus, due to the prominent neuronal and glial involvement in some clinically severe forms, it is proposed that at least some of the “functional” gut disorders should be reclassified as enteric neuro-gliopathies.

Alzheimer’s disease (AD), the term “dementia”, describes a specific neuropathology together with the development and progression of age-related cognitive and functional loss. Formononetin is naturally occurring isoflavone recognized for its potential health benefits, anti-oxidant, anti-inflammatory, anti-cancer, and anti-apoptotic properties. Neurodegenerative disorders arise from the gradual loss of function and eventual death of nerve cells in the brain or peripheral nervous system. Astragalus membranaceus is a traditional plant with a variety of pharmacological and biochemical properties, including antiviral, anti-hyperglycaemic, and immunomodulatory effects. Moreover, the expression of membrane-bound and soluble receptor for advanced glycation end products (RAGE) is enhanced in the AD brain due to increased levels of soluble and insoluble amyloid-beta (Aβ) peptides. Additionally, in inflammatory circumstances, leukocytes’ firm attachment and transmigration to endothelial cells are regulated by intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1). Formononetin also possesses anti-bacterial, anti-inflammatory, anti-cancer, anti-oxidant, and estrogenic activity. Formononetin has emerged as a promising agent in the modulation of mediators involved in neurodegenerative disease. Formononetin might modulate nuclear factor erythroid 2-related factor 2 (Nrf-2) signaling pathway to potentiate the anti-Alzheimer’s activity. Additionally, formononetin might inhibit the Aβ/RAGE interaction which further inactivates the activity of extracellular signal regulated kinase (ERK), Janus kinase (JNK) signaling pathway that results in the reduction of nuclear translocation of nuclear factor kappa B (NF-κB) and also reduces the cytokines level to ameliorate AD. It might inhibit the ICAM, VCAM, and THP-1 proteins. Therefore, this compound offers potential therapeutic benefits by reducing cytokine levels to ameliorate AD. This review article is designed to explore the mechanistic interplay underlying the anti-Alzheimer’s effect of A. membranaceus, especially formononetin.

Glioma is a highly aggressive brain cancer associated with significant mortality. Despite advances in diagnostic and therapeutic strategies, the prognosis for glioma patients remains poor due to limited diagnostic accuracy and monitoring capabilities. Translocator protein (TSPO) is a mitochondrial protein implicated in various cancers, including glioma, where it plays a significant role in cell survival, proliferation, and chemo-resistance. This review article aimed to comprehensively analyze the role of TSPO in glioma, particularly its potential applications in enhancing diagnostic methods and therapeutic strategies. Molecular imaging techniques have emerged as promising tools for non-invasive diagnosis, disease progression monitoring, and treatment selection of gliomas. A comprehensive literature review was conducted to explore TSPO’s expression patterns, biological functions, and applications in molecular imaging. Studies utilizing positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and other imaging modalities were included. TSPO is overexpressed in glioma cells, particularly in high-grade tumors, correlating with tumor aggressiveness and patient prognosis. TSPO-targeted imaging agents demonstrate high specificity and sensitivity for glioma detection, positioning TSPO as a promising marker for accurate diagnosis and therapeutic monitoring. Future studies should focus on optimizing TSPO imaging protocols, validating their clinical utility, and exploring combined imaging modalities to improve diagnostic precision.

Neuropathic pain (NP) is a significant global health challenge, affecting an estimated 7–10% of the population. Painful diabetic neuropathy (PDN), a severe complication of diabetes, impacts approximately one in every three diabetic patients. With the rising global prevalence of diabetes, PDN is projected to become an increasingly urgent health concern. Current treatments for PDN often provide inadequate pain relief and are associated with adverse side effects, emphasizing the need for safe and effective therapeutic options. This review examines the limitations of existing pharmacological therapies for PDN and presents the sigma-1 receptor (S1R) as a promising therapeutic target. We explore the biological role of S1R, its implication in NP and PDN, its structural biology, and the expanding preclinical and clinical evidence supporting its potential. Furthermore, we present evidence for various S1R antagonists in addressing NP and PDN, with a particular focus on E-52862 and [¹⁸F]FTC-146. These compounds represent first-in-class ligands for therapeutic and diagnostic applications, respectively, marking significant advances in the development of S1R antagonists. This review underscores the potential of S1R antagonism as a strategy for developing more effective treatments for PDN, with the ability to significantly improve patient outcomes.

The SAR-CoV-2 virus has evolved to co-exist with human hosts, albeit at a substantial energetic cost resulting in post-infection neurological manifestations [Neuro-post-acute sequelae of SARS-CoV-2 infection (PASC)] that significantly impact public health and economic productivity on a global scale. One of the main molecular mechanisms responsible for the development of Neuro-PASC, in individuals of all ages, is the formation and inadequate proteolysis/clearance of phase-separated amyloid crystalline aggregates—a hallmark feature of aging-related neurodegenerative disorders. Amyloidogenesis during viral infection and persistence is a natural, inevitable, protective defense response that is exacerbated by SARS-CoV-2. Acting as chemical catalyst, SARS-CoV-2 accelerates hydrophobic collapse and the heterogeneous nucleation of amorphous amyloids into stable β-sheet aggregates. The clearance of amyloid aggregates is most effective during slow wave sleep, when high levels of adenosine triphosphate (ATP)—a biphasic modulator of biomolecular condensates—and melatonin are available to solubilize amyloid aggregates for removal. The dysregulation of mitochondrial dynamics by SARS-CoV-2, in particular fusion and fission homeostasis, impairs the proper formation of distinct mitochondrial subpopulations that can remedy challenges created by the diversion of substrates away from oxidative phosphorylation towards glycolysis to support viral replication and maintenance. The subsequent reduction of ATP and inhibition of melatonin synthesis during slow wave sleep results in incomplete brain clearance of amyloid aggregates, leading to the development of neurological manifestations commonly associated with age-related neurodegenerative disorders. Exogenous melatonin not only prevents mitochondrial dysfunction but also elevates ATP production, effectively augmenting the solubilizing effect of the adenosine moiety to ensure the timely, optimal disaggregation and clearance of pathogenic amyloid aggregates in the prevention and attenuation of Neuro-PASC.

Purinergic signaling, mediated by ATP and adenosine receptors, plays a crucial role in cellular communication and homeostasis within the central nervous system (CNS), particularly by regulating synaptic activity, glial cell functions, and neuroplasticity. Glial cells, including astrocytes and microglia, contribute to both short-term processes, such as neurotransmission and neuroinflammation, and long-term functions, including synaptic remodeling, tissue repair, and behavioral adaptation. Dysregulation of purinergic signaling in these cells has been implicated in the pathogenesis of various neurodegenerative and neuropsychiatric disorders. This article explores the evolving concept of the synapse, highlighting the active role of glial cells in synaptic modulation and emphasizing the significance of purinergic signaling in synaptic function and responses to conditions such as injury and neurotoxicity. Specifically, it examines the roles of ATP and adenosine receptors—such as P2X4, P2X7, P2Y1, and P2Y12—in mediating key astrocytic and microglial functions, including neuroinflammation, phagocytosis, synaptic plasticity, and neuronal damage. Furthermore, the article discusses the involvement of purinergic receptors in neurological disorders such as epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, ischemic stroke, Rett syndrome, and autism spectrum disorder, as well as potential therapeutic strategies targeting these receptors to mitigate inflammation, promote tissue repair, and improve clinical outcomes.

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects millions of people worldwide. It presents a significant challenge in terms of accurate diagnosis, disease progression monitoring, and the development of effective treatments. This article addresses the role of neuroimaging as an advancing tool for diagnosis, monitoring progression, and treatment of AD. A comprehensive review of existing literature on the use of neuroimaging in AD was conducted using various databases. The different imaging techniques, such as magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET), were examined in terms of their ability to detect amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), the hallmark pathological features of AD. Neuroimaging enables the visualization of Alzheimer-related biomarkers, such as Aβ plaques, tau protein tangles, neuro-inflammation, and synaptic dysfunction, providing valuable insights into disease pathophysiology and progression. These imaging techniques assist in the early detection of AD, distinguishing it from other conditions and evaluating the effectiveness of treatments. This has the potential to significantly transform the way AD is managed clinically. By providing insights into the molecular changes that occur in the brain during the course of the disease, neuroimaging can facilitate early diagnosis, monitor disease progression, and inform treatment decisions. Furthermore, neuroimaging holds great potential for accelerating drug development by allowing researchers to assess the efficacy of novel therapies in real time. Overall, the integration of neuroimaging into the clinical management of AD has the potential to revolutionize the way we approach diagnosis, treatment, and research in AD.

The use of neurostimulation devices for the treatment of Alzheimer’s disease (AD) is a growing field. In this review, we examine the mechanism of action and therapeutic indications of these neurostimulation devices in the AD process. Rapid advancements in neurostimulation technologies are providing non-pharmacological relief to patients affected by AD pathology. Neurostimulation therapies include electrical stimulation that targets the circuitry-level connection in important brain areas such as the hippocampus to induce therapeutic neuromodulation of dysfunctional neural circuitry and electromagnetic field (EMF) stimulation that targets anti-amyloid molecular pathways to promote the degradation of beta-amyloid (Aβ). These devices target specific or diffuse cortical and subcortical brain areas to modulate neuronal activity at the electrophysiological or molecular pathway level, providing therapeutic effects for AD. This review attempts to determine the most effective and safe neurostimulation device for AD and provides an overview of potential and current clinical indications. Several EMF devices have shown a beneficial or harmful effect in cell cultures and animal models but not in AD human studies. These contradictory results may be related to the stimulation parameters of these devices, such as frequency, penetration depth, power deposition measured by specific absorption rate, time of exposure, type of cell, and tissue dielectric properties. Based on this, determining the optimal stimulation parameters for EMF devices in AD and understanding their mechanism of action is essential to promote their clinical application, our review suggests that repeated EMF stimulation (REMFS) is the most appropriate device for human AD treatments. Before its clinical application, it is necessary to consider the complicated and interconnected genetic and epigenetic effects of REMFS-biological system interaction. This will move forward the urgently needed therapy of EMF in human AD.

Neurodegenerative disorders, including Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis, are among the most significant health concerns worldwide, characterized by neuronal dysfunction, oxidative stress, neuroinflammation, and protein misfolding. Epigallocatechin gallate, a green tea polyphenol, has been reported to possess multifaceted neuroprotective properties. It reduces oxidative stress through free radical scavenging, activation of antioxidant enzymes, and stabilization of mitochondrial function. It also inhibits neuroinflammation through modulation of key signaling pathways. It suppresses amyloid-beta aggregation in Alzheimer’s and alpha-synuclein fibrillation in Parkinson’s, thus attenuating toxic protein accumulation. Its activity in the induction of autophagy and promotion of synaptic plasticity supports neuronal survival and function. However, low bioavailability and metabolic instability hinder its translation into the clinic. Strategies including nanoparticle encapsulation, structural modifications, and combination therapies are being explored to overcome these challenges. Future research could establish epigallocatechin gallate as a viable candidate for managing neurodegenerative disorders.

Intracellular amyloid β oligomers (AβOs) have been linked to Alzheimer’s disease (AD) pathogenesis and to the neuronal damage in this neurodegenerative disease. Calmodulin, which binds AβO with very high affinity, plays a pivotal role in Aβ-induced neurotoxicity and has been used as a model template protein for the design of AβO-antagonist peptides. The hydrophobic amino acid residues of the COOH-terminus domain of Aβ play a leading role in its interaction with the intracellular proteins that bind AβO with high affinity. This review focuses on Aβ-antagonist hydrophobic peptides that bind to the COOH-terminus of Aβ and their endogenous production in the brain, highlighting the role of the proteasome as a major source of this type of peptides. It is emphasized that the level of these hydrophobic endogenous neuropeptides undergoes significant changes in the brain of AD patients relative to age-matched healthy individuals. It is concluded that these neuropeptides may become helpful biomarkers for the evaluation of the risk of the onset of sporadic AD and/or for the prognosis of AD. In addition, Aβ-antagonist hydrophobic peptides that bind to the COOH-terminus of Aβ seem a priori good candidates for the development of novel AD therapies, which could be used in combination with other drug-based therapies. Future perspectives and limitations for their use in the clinical management of AD are briefly discussed.

Intracranial artery dolichoectasia (IADE) is a vascular anomaly characterized by dilation and/or tortuosity of one or more intracranial arteries. While many cases are incidental findings on imaging, the associated ischemic neurological complications of IADE can be severe and must be promptly recognized. This study aims to increase awareness among general practitioners and neurologists regarding this rare and potentially life-threatening condition. We utilized reputable databases for this scoping review, including PubMed, Scopus, and Google Scholar, from database inception through September 2024, using a combination of terms such as “Dolichoectasia of Basilar Artery”, “Intracranial Dolichoectasia”, and “Ischemic Stroke”. Our scoping review revealed that IADE is a challenging and often underdiagnosed condition, with an estimated prevalence of less than 1% in the general population. Hypertension, atherosclerosis, and advanced age are well-documented risk factors. To minimize the risk of misdiagnosis, we briefly elucidated the pathophysiology of IADE, correlating it with clinical and radiological features. We discuss the diagnostic criteria for IADE based on radiological imaging, addressing the advantages and limitations of different techniques. Finally, we highlight the unmet clinical needs related to IADE management, which may involve pharmacological and surgical therapies tailored to individual cases, with careful consideration of safety and efficacy.

Epilepsy, a complex and widespread neurological disorder, has evolved in its understanding from ancient misconceptions to modern scientific advancements. This special issue highlights pivotal research and reviews on the mechanisms underlying epilepsy, innovative treatment strategies, and the psychosocial dimensions of living with this condition. Together, these contributions reflect the growing interdisciplinarity and depth in epilepsy research.

Depression is characterized by affective symptoms and neuropsychological deficits. After treatment, affective symptoms frequently remit, but cognitive alterations may remain affecting the lives of people and having an impact on health, economy, and societies. The present work describes the methods, procedures, and equipment for a randomized three-arm controlled experiment designed to measure the effects of exergames on executive functions (EFs) under depression. EFs are complex cognitive functions that are essential for organizing information, planning an action, reasoning, decision-making, and problem-solving. Literature shows that EFs are compromised in depression, affecting daily-life activities and other cognitive domains. To conduct the experiment, depressed middle-aged adults will be randomly distributed into three experimental groups: an intervention group training with exergames, an active control group training only with cognitive video games, and a passive control group or wait-list. EFs are evaluated at three different time points: pre-post intervention, and three months follow-up, using the Wisconsin Card Sorting Test (WCST). Researchers will collect cognitive-behavioral and neural information [event-related potentials (ERPs)]. Results will be explored by performing analysis of variance to compare the outcomes of the diverse groups at the three different time points, understanding the benefits of exergames in terms of EFs under depression. The study of simultaneous multidomain interventions in depression holds promise for the development of novel approaches, to implementing psychological and neuropsychological health [this experiment is part of a registered clinical trial entitled “MUDgame” (ClinicalTrials.gov identifier NCT06536530). Registered on August 2024, https://clinicaltrials.gov/study/NCT06536530].