Current Neuropharmacology - Online First

Multiple Sclerosis (MS), the most common demyelinating disease of the Central Nervous System (CNS), is characterized in its pathogenesis by an interplay of mechanisms pertaining to aberrant immune response, acute and chronic inflammation, glial housekeeping, and neuron survival, ultimately resulting in demyelination, synaptic dysfunction, and neuroaxonal loss. Experimental models as well as epidemiological observations support the hypothesis of a role of diet in the disease onset, activity, and progression. It has been suggested that Western-type diets might be detrimental, while on the other hand, certain dietary regimens, like Mediterranean, low-fat, ketogenic, or intermittent fasting, might lead to disease amelioration, possibly through differential regulatory effects upon inflammation, immunity, and regenerative processes of neurons and glia. Under this perspective, immunometabolites, small intermediates including among the others citrate, itaconate, lactate, glutamate, glutamine, alfa-ketoglutarate, 2-hydroxyglutarate, fumarate, ceramides, whose turn-over reflects metabolic reprogramming of immune cells, might be viewed as significant regulators of cellular responses against either local or systemic noxious stimuli, both in the periphery and in the CNS. The present narrative review aims at summarizing current experimental and clinical evidence regarding the role of immunometabolites in shaping MS pathology, to address whether they could be relevant either as disease markers or therapeutic targets, and whether they might be differentially influenced by dietary approaches, especially by Mediterranean Pattern Diets (MPD).

Neurological disorders are marked by neurodegeneration, leading to impaired cognition, psychosis, and mood alterations. These symptoms are typically associated with functional changes in both emotional and cognitive processes, which are often correlated with anatomical variations in the brain. Hence, brain structural magnetic resonance imaging (MRI) data have become a critical focus in research, particularly for predictive modeling. The involvement of large MRI data consortia, such as the Alzheimer's Disease Neuroimaging Initiative (ADNI), has facilitated numerous MRI-based classification studies utilizing advanced artificial intelligence models. Among these, convolutional neural networks (CNNs) and non-convolutional artificial neural networks (NC-ANNs) have been prominently employed for brain image processing tasks. These deep learning models have shown significant promise in enhancing the predictive performance for the diagnosis of neurological disorders, with a particular emphasis on Alzheimer's disease (AD). This review aimed to provide a comprehensive summary of these deep learning studies, critically evaluating their methodologies and outcomes. By categorizing the studies into various sub-fields, we aimed to highlight the strengths and limitations of using MRI-based deep learning approaches for diagnosing brain disorders. Furthermore, we discussed the potential implications of these advancements in clinical practice, considering the challenges and future directions for improving diagnostic accuracy and patient outcomes. Through this detailed analysis, we seek to contribute to the ongoing efforts in harnessing AI for better understanding and management of AD.

Ischemic stroke, triggered by the interruption of cerebral blood flow, initiates a complex inflammatory process involving both brain-resident and peripheral immune cells. Microglia, the primary brain-resident immune cells of high heterogeneity, regulate central nervous system inflammation upon activation. Activated microglia are commonly classified into two predominant phenotypes (pro-inflammatory M1 and anti-inflammatory M2), which exert dual effects through the secretion of distinct cytokine profiles. Peripheral immune cells, including monocytes, macrophages, and neutrophils, contribute to stroke pathogenesis and progression via diverse inflammatory mechanisms. Multiple microRNAs regulate the inflammatory dynamics of ischemic stroke across all phases by modulating both brain-resident and peripheral immune cells. MicroRNAs play a pivotal role in the activation and polarization of microglia, as well as cytokine release. Furthermore, microRNAs modulate the activation and extravasation processes of peripheral leukocytes by enhancing or attenuating signaling pathways. These mechanisms suggest that microRNA alterations could be biomarkers for predicting, diagnosing, and prognosticating ischemic stroke. Additionally, microRNA modulation offers potential as a therapeutic strategy for the treatment of ischemic stroke.

Perinatal depression, a prevalent mood disorder complicating pregnancy and childbirth, poses significant threats to maternal health and neonatal development. While psychotherapy and antidepressants constitute current standard treatments, their clinical application faces substantial limitations during pregnancy and lactation, including safety concerns, treatment resistance, and poor adherence rates. These therapeutic constraints have spurred growing interest in novel gut-brain axis (GBA)-targeted interventions. Emerging evidence suggests that the gut microbiota communicates with the brain through a complex network of neural, immune, and endocrine pathways, playing a critical role in regulating mood, behavior, and cognitive functions. Interventions such as probiotics and fecal microbiota transplantation (FMT) are increasingly explored for their potential to restore microbial balance and alleviate depressive symptoms. This review aims to systematically examine the role of the GBA in the context of perinatal depression, offering novel insights to inform clinical treatment strategies. Furthermore, it evaluates the promise and limitations of microbiota-targeted interventions while discussing future directions for personalized microbiome therapeutics.

Neuroinflammation has emerged as a critical pathological process that significantly contributes to the development and progression of a wide range of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Recent advances in neuroscience have underscored the pivotal role of neuroinflammation not only in exacerbating these diseases but also in accelerating neuronal degeneration. The growing prevalence of these conditions worldwide, coupled with the limited efficacy of current therapeutic approaches, highlights the urgent need for new therapeutic strategies. Given the central role of neuroinflammation in disease progression, targeting the neuroinflammatory process offers a compelling opportunity for effective intervention. Membrane proteins are key regulators in cellular signal transduction and intercellular communication, and their dysregulation may trigger and sustain neuroinflammatory responses. Consequently, modulators of membrane proteins have emerged as promising candidates for managing neuroinflammation. Current research indicates that natural products and small-molecule compounds can modulate membrane protein activity, effectively mitigating excessive inflammatory responses and exhibiting potent anti-neuroinflammatory effects. This review systematically examines the classification and functional roles of membrane proteins in neuroinflammation, with a particular focus on the therapeutic potential of channel proteins, transporter proteins, and receptor proteins across various neurological conditions. The identification and development of membrane protein modulators present an innovative and urgent avenue for advancing anti-neuroinflammatory therapies, offering potential breakthroughs in treating these prevalent and debilitating diseases.

Bipolar disorder is a severe, recurrent affective disorder that imposes significant pain and burden on both the patients themselves and the social economy. Recent studies have indicated the involvement of intestinal flora in emotional regulation, as well as its close association with the occurrence and progression of diseases such as bipolar disorder. Therefore, conducting comprehensive research on the impact of intestinal microflora and the “gut-brain axis” on bipolar disorder becomes imperative, offering novel insights into its etiology, diagnosis, and treatment options. Consequently, this article provides an overview of the role and potential mechanisms underlying intestinal microbiota in bipolar disorder.

Compared to schizophrenia in adults, Early Onset Schizophrenia (EOS) features diagnostic, clinical, and therapeutic peculiarities that are the subject of ongoing discussion among psychiatrists and neuropsychiatrists. This article presents the outcomes of a meeting and a series of virtual roundtable discussions among specialists who validated practical recommendations for the diagnosis and management of EOS in light of recent literature. The identification of risk factors and prodromal symptoms, as well as the differentiation of EOS from other psychiatric conditions, is crucial for early detection. Timely identification enables the implementation of appropriate psycho-behavioural and pharmacological interventions and supports close monitoring of the developmental trajectories associated with EOS. The collaboration between the different professionals who deal with EOS patients and a therapeutic approach that allows a normal cognitive, sexual, and psychophysical development makes it possible to ensure the therapeutic alliance necessary for the optimal management of the disease over time. In a scenario that is complicated by negative prognostic factors, such as the late recognition of the disease, comorbid and latent psychiatric conditions, the increasingly widespread use of substances among adolescents, and a poor therapeutic adherence often due to antipsychotics side effects, a growing body of literature emphasizes the advantages of lurasidone in the treatment of EOS. Compared to other pharmacological agents commonly used in schizophrenia, lurasidone has been shown to intervene comprehensively and effectively against the positive and negative symptoms of EOS, with manageable side effects and the preservation of a good QoL.

Although medicinal chemistry is constantly looking for new therapeutic approaches against pathological conditions affecting the central nervous system (CNS), such as neurodegeneration and cancer, this quest has not been fully successful yet. The lack of understanding of all the complex mechanisms underlying these conditions makes the identification of new effective drugs challenging. A wide variety of pathophysiological events are regulated at both nuclear and cytoplasmic levels, and in this context, targeting the shuttle system composed of the karyopherin superfamily and their cargoes may provide an alternative strategy. Molecular recognition is highly specific and strictly related to the presence of special “tag” regions, known as nuclear localization signals, that are localized in the amino acid sequences of cargoes. Importantly, their trafficking is involved in various pathophysiological processes, including CNS diseases. Curiously, although this system has been studied intensively, much remains to be discovered to date. Throughout the years, drug discovery allowed the identification of small molecules and peptides able to target karyopherin-cargo complexes to provide new potential pharmacological treatments. Indeed, the first examples of drug candidates targeting this mechanism that reached clinical trials are appearing in the literature. With this mini-review, this study aims at presenting an updated overview on the most recent reports investigating the use of the karyopherin shuttle system as a new therapeutic target especially for CNS-related diseases.