Alzheimer’s disease, the main cause of dementia worldwide, is a slowly progressive neurodegenerative disorder. This disease involves a diversity of etiophatogenic processes as it is not only a genetic but also a biological and environmental disease. Owing to that complexity, nowadays there is no efficacious treatment for this disorder. The major Alzheimer’s disease clinical indications include extracellular senile plaques of amyloid-β protein, intracellular hyperphosphorylated τ neurofibrillary tangles, uncommon neuroinflammatory response, oxidative stress, and synaptic and neuronal dysfunction. The evaluation of the neuroprotective potential of new compounds is imperative. As natural products, like phenolic compounds, exhibit several bioactivities, it is urgent to test them and evaluate their inhibition of each clinical indication of Alzheimer’s disease. If phenolic compounds target more than one Alzheimer’s disease pathogenic mechanism (multi-target drug ligands), they will have the potential of becoming a leading Alzheimer’s disease treatment. Thus, this review analyzes, for each Alzheimer’s disease clinical indication, the scaffolds of several phenolic compounds leading to the highest activity with the objective to find phenolic compounds active against all the clinical indications. It was concluded that compounds presenting scaffolds like rugosin E or isocorilagin show potential in combating Alzheimer’s disease.

All living beings, from microorganisms to plants, animals, and humans, require iron as an essential micronutrient for their lives. However, iron overload can constitute a scenario prone to damage to the organism, including oxidative stress, deterioration of cellular and subcellular membranes, and thus leading to cell death. This process involves unrestricted lipid peroxidation caused by the generation of reactive oxygen species (ROS) because of an abrupt increase in free Fe²⁺ in the cytoplasm, all of which leads to subsequent membrane damage and iron-dependent cell death, now known as “ferroptosis”. This process can be induced by convulsive stress, and conversely, inducing seizures, and in both situations under a context of neuroinflammation. In this critical review, we will highlight the most relevant aspects of this recently described mechanism, which has been studied little in epilepsy, its impact on the prognosis of the disease, and its effects on the development of central and/or peripheral comorbidities, including SUDEP (sudden unexpected death in epilepsy).

Ectonucleoside triphosphate diphosphohydrolases (ENTPDases), members of the cluster of differentiation 39 (CD39) family, are key regulators of purinergic signaling through the hydrolysis of tri and diphosphate nucleotides. These enzymes are expressed on the cell surface, extracellular environment, or within intracellular organelles such as the Golgi apparatus. ENTPDases play critical roles in modulating immune responses, inflammation, and neuroinflammation by controlling extracellular nucleotide availability in mammals. Moreover, they contribute to adenosine-mediated signaling in cooperation with 5’-nucleotidases (CD73). Pathogenic microorganisms also express ENTPDases, manipulating host purinergic signaling, suppressing adenosine triphosphate (ATP)-driven inflammation, and promoting immune evasion via increased adenosine production. Pathogenic parasites also express ENTPDases, manipulating host purinergic signaling, suppressing ATP-driven inflammation, and promoting immune evasion via increased adenosine production. Given their involvement in infection and inflammatory diseases, ENTPDases have emerged as promising pharmacological targets. This review comprehensively analyzes the ENTPDases from mammals and pathogenic parasites, emphasizing their role in purinergic signaling and their potential as therapeutic targets. While ENTPDase inhibitors hold promise for modulating inflammation and infection, their clinical translation faces challenges, including selectivity, off-target effects, and systemic alterations in purinergic homeostasis. Addressing these concerns through targeted drug delivery, allosteric modulation, and improved inhibitor specificity is crucial for therapeutic advancements.

The choroid plexus, pivotal for cerebrospinal fluid (CSF) regulation and blood-CSF barrier function, becomes a focal point for primary central nervous system lymphoma (PCNSL). This article delves into a case of this uncommon presentation, highlighting diagnostic challenges, treatment complexities, and post-treatment outcomes. A 30-year-old Lebanese patient with mild headaches and vomiting was initially diagnosed with vasculitis but later confirmed through endoscopic biopsy to have diffuse large B-cell lymphoma of the choroid plexus. Treatment with intravenous methotrexate, intrathecal cytarabine, rituximab, and radiotherapy led to gradual neurological improvement. Treatment strategies, aligned with PCNSL standards, include intravenous methotrexate, intrathecal cytarabine, rituximab, and radiotherapy, leading to gradual neurological improvement post-treatment. Prognostic factors, such as age and specific brain area involvement, guide tailored treatment plans. This report emphasizes the need for a multidisciplinary approach, increased awareness, and ongoing research for optimal outcomes in PCNSL cases involving the choroid plexus.

CD36 is a transmembrane protein that plays a role in various biological processes, including oxidized low-density lipoprotein and fatty acid uptake as well as regulatory control for inflammation signaling. Its robust expression in monocytes and macrophages associated with its ability to translocate fatty acids linked this scavenger receptor to foam cell formation and atherosclerosis. In the context of ischemic stroke, CD36 has been shown to contribute to brain injury and inflammation. Preclinical studies have demonstrated that CD36 expression increases in the brain after stroke and that inhibiting CD36 can reduce infarction size and improve neurological outcomes in animal models. These findings suggest that CD36 may be a potential therapeutic target for ischemic stroke. However, no clinical trials addressing CD36 and acute ischemic stroke are registered in the American or European databases. This review will discuss the relationship between CD36 and ischemic stroke and present some clinical findings in patients with single nucleotide polymorphisms of the CD36 gene.

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.