Epilepsy is traditionally defined by recurrent seizures arising from abnormal neuronal excitability, yet growing evidence indicates that this view is incomplete. This narrative review examines epilepsy through the framework of neural–glial network instability, an integrative perspective that places neuronal dysfunction within a broader system shaped by glial regulation, calcium dysregulation, neuroinflammatory signaling, and circuit remodeling. The review first reframes epilepsy as a disorder of progressive instability in which failures of excitation–inhibition balance, extracellular homeostasis, inflammatory restraint, and adaptive plasticity shift neural networks from compensated function toward seizure-prone states. It then synthesizes neuronal mechanisms, including excitation–inhibition imbalance, GABAergic dysfunction, and altered intrinsic excitability, together with glial mechanisms involving astrocytic regulation of ionic and neurotransmitter environments, microglial inflammatory and synaptic responses, and oligodendroglial contributions to conduction and network coordination. Calcium dysregulation is considered a cross-cutting mechanism linking excitability, intracellular stress, gliotransmission, inflammation, and long-term remodeling. The review further examines how neuroinflammation and chronic circuit reorganization help convert transient disturbances into persistent epileptic networks. Together, this framework offers a more integrated account of seizure emergence, epileptogenesis, and chronic seizure susceptibility and points toward mechanism-informed therapeutic strategies aimed at restoring durable network stability.
Thymoquinone (TQ), the main bioactive constituent of Nigella sativa, has gained great attention for its neuroprotective properties, especially for Alzheimer’s disease (AD), which is a progressive neurodegenerative disorder with limited therapeutic options. This review provides several experimental evidence on the effects of TQ in AD models. The evidences indicate that TQ reduces the amyloid-β accumulation, reduces the oxidative stress and neuroinflammation, and improves cognitive and behavioral outcomes. Additionally, TQ should be able to promote the neuronal survival and neurogenesis while reducing biological markers that indicate brain damage or neuron loss. Although these findings clearly highlight and show the promising therapeutic potential of the TQ molecule in the AD, it is important to note that further in-depth studies are still needed to fully understand its underlying molecular mechanisms and to determine its clinical relevance in patients.
Aim: To investigate the mechanisms underlying MK-801-induced schizophrenia-like cognitive dysfunction by examining the interplay between brain interstitial fluid (ISF) drainage impairment, myelin structural integrity, and regional neurometabolic disturbances. Methods: Mice received chronic administration of MK-801 (2 mg/kg/day) for two weeks to induce schizophrenia-like phenotypes. Cognitive function and sensorimotor gating were evaluated using the novel object recognition test and pre-pulse inhibition (PPI) assessment. ISF drainage patterns were visualized via fluorescent tracing with Lucifer Yellow. Myelin integrity in the internal capsule was quantified using Luxol Fast Blue (LFB) staining and transmission electron microscopy (TEM). Regional metabolic profiles in the caudate nucleus and thalamus were analyzed using untargeted metabolomics. Results: MK-801 treatment resulted in significant recognition memory impairment and sensorimotor gating deficits. Fluorescent tracing revealed pathological ISF reflux from the caudate nucleus toward the thalamus, which was restricted in control mice. This drainage failure corresponded to severe demyelination and ultrastructural damage in the internal capsule, characterized by increased myelin thickness and a significantly decreased G-ratio. Furthermore, regional metabolomic analysis identified distinct dysregulation of tryptophan metabolism in the caudate nucleus and tyrosine metabolism in the thalamus. Conclusions: Myelin degradation in the internal capsule disrupts the structural barrier required for compartmentalized ISF drainage. The resulting ISF reflux facilitates regional metabolic imbalances, particularly within tryptophan and tyrosine pathways, suggesting that fluidic dynamics failure is a critical contributor to the neurochemical pathology of schizophrenia.
Type 2 diabetes continues to grow in prevalence globally due to contemporary dietary patterns and physical inactivity. Among its multiple complications, neurological injury is a long-known consequence of diabetes, especially in the peripheral nerve as diabetic peripheral neuropathy. However, the adverse effects of diabetes on brain health are also increasingly appreciated, raising patients’ risk of developing cognitive impairment and eventual dementia along with brain structural changes. Thus, despite the highly heritable nature of Alzheimer’s disease, addressing modifiable risk factors, including type 2 diabetes, may help curb dementia development. This review covers epidemiological evidence for the link between diabetes and dementia as well as mechanistic evidence on similar underlying pathophysiological pathways, describing potential links between the two diseases. Given excess dementia risk from diabetes, this review also covers how optimal diabetes control and, ideally, diabetes prevention, may mitigate future dementia burden, concluding with some practical interventions.
The Cambridge Centre for Ageing and Neuroscience (Cam-CAN) started in 2010 to study the effect of healthy adult ageing on cognition and the brain in a population-derived sample. The study design and protocol for Phases 1–3 of Cam-CAN were detailed in 10.1186/s12883-014-0204-1; this paper outlines the design and protocol of Phases 4–5, which enable longitudinal investigation of cognitive and brain ageing over approximately 12 years. More details about the Cam-CAN project can be found here: www.cam-can.org. Phase 4 was an at-home assessment of cognition, demographics and lifestyle, performed approximately 6 years after Phase 1 (baseline assessment), for which all people from Phase 1 were invited. Phase 5 combined repeated online cognitive, demographics and lifestyle assessment, followed by in-lab attendance for MRI and MEG brain scanning, approximately 12 years after Phase 1, for which all people from Phase 2 (baseline brain assessment) were invited. Demographics, lifestyle and cognitive data are therefore now available for three timepoints, and MRI and MEG brain data for two timepoints. The Cam-CAN study offers deep and wide phenotyping of neurocognitive health across the adult lifespan (18–96). These rich data will allow researchers to address questions like: why do some people maintain their cognitive abilities better than others, in terms of their brain structure or function, their lifestyle and/or their genetics? Given the shifting demographics towards old age in most countries, this knowledge will be important to help people function independently for longer, reducing both individual and societal burden.
Major depressive disorder (MDD) is increasingly understood as a multifactorial psychiatric disorder involving interacting neural, immune, metabolic, and microbial processes. Within this framework, the microbiota–gut–brain axis and mitochondrial bioenergetics have emerged as potentially intersecting contributors to depressive symptomatology. Preclinical studies suggest that microbial metabolites—especially short-chain fatty acids (SCFAs)—can influence oxidative phosphorylation, redox balance, neuroinflammation, and synaptic plasticity, whereas inflammatory signals such as lipopolysaccharide may disrupt mitochondrial dynamics. However, the strength of evidence is uneven: mechanistic support is strongest in cell and animal models, whereas human data remain heterogeneous and largely associative. This narrative review critically synthesizes current evidence on microbiota–mitochondria crosstalk in MDD, distinguishing established findings from emerging hypotheses. It also examines recent psychobiotic trials, metabolomic and biomarker studies, and microglia–mitochondria mechanisms, and discusses the translational limitations that currently constrain clinical application. Overall, this axis represents a plausible and clinically relevant framework for hypothesis generation and adjunctive intervention development, but it should not yet be regarded as a fully validated causal pathway or stand-alone therapeutic target in MDD.
Aim: Tissue transglutaminase [transglutaminase 2 (TG2)] is implicated in central neuronal apoptosis and is expressed in the peripheral nervous system; however, its role in sensory neuron survival and neuropathic pain after nerve injury remains poorly defined. This study examined whether TG2 knockout (KO) affects dorsal root ganglion (DRG) neuron survival and pain-related behaviors following sciatic nerve injury. Methods: TG2 KO mice and wild-type (WT) controls underwent complete sciatic nerve transection (axotomy). Pain-related behavior was evaluated using detailed autotomy scoring over 14 days. DRG neuron survival was assessed using unbiased stereological counts. Results: TG2 KO resulted in a distinct, previously unreported “atypical autotomy” pattern, with lesions localized mainly to the midplantar paw region. In contrast, WT mice exhibited typical autotomy directed primarily at the toes. Despite this clear difference in pain phenotype, stereological analysis revealed that TG2 KO did not alter neuronal counts in intact or axotomized DRGs, with both groups showing comparable, significant neuronal loss after injury. Conclusions: These findings indicate that TG2 functions as an important modulator of neuropathic pain but is not required for neuronal survival in the adult DRG following nerve injury.
Flavonoids are a large class of natural polyphenolic substances ubiquitously synthesized in the plant kingdom. When entering the human body, these compounds can exert a wide range of biological activities, including immunomodulatory, antiinflammatory, and anticancer effects. Over the recent years, the mechanisms underlying these actions have become increasingly clear, also indicating the important involvement of G protein-coupled receptors (GPCRs), such as adenosine receptors, in signal transduction networks. In this perspective article, the potential role of flavonoids as adenosine receptor antagonists on the development, progression, and spread of glioblastoma is discussed, blocking the tumor-promoting and immunosuppressive actions of elevated levels of endogenous adenosine. Therefore, flavonoids can be considered as structural leads for developing novel antiglioblastoma agents, applied either alone or as boosters of chemo- or immunotherapy to improve the quality of life and outcome of patients. The importance of these studies is, in turn, emphasized by the current lack of effective treatment strategies for this highly aggressive and fast-growing brain tumor, associated with poor prognosis.
Aim: Male infertility resulting from neurological disorders, oxidative stress, and hormonal imbalance is a growing health concern. This study, therefore, investigated the effects of Aframomum melegueta and Aframomum danielli-supplemented diets on sperm quality and testicular oxidative damage in a scopolamine-induced rat model. Methods: Adult male rats were randomly allocated into seven groups: normal group; scopolamine-induced group; donepezil-treated scopolamine group and four treatment groups receiving 4% or 8% dietary supplementation of Aframomum melegueta or Aframomum danielli, respectively. Sperm motility, count, and morphology were evaluated. In addition, serum testosterone and follicle stimulating hormone levels, testicular oxidative stress markers, inflammatory cytokines, and antioxidant activities were assessed to determine reproductive and biochemical responses. High performance liquid chromatography (HPLC) profiling was also conducted to identify the major phenolic compounds in both seeds. Results: Scopolamine administration impaired sperm quality, decreased hormonal levels, promoted oxidative stress, and altered inflammatory responses. These alterations were, however, reversed by diets supplemented with Aframomum melegueta and Aframomum danielli in a dose-dependent manner. The 8% supplementation produced better outcomes than 4% supplementation and donepezil treatment in most parameters, indicating protective effects on sperm quality and other reproduction-related indices. HPLC profiling revealed bioactive compounds that may collectively account for the observed restorative effects of the seeds. Conclusions: These findings demonstrate that Aframomum melegueta and Aframomum danielli seeds effectively reversed the adverse reproductive alterations caused by scopolamine-induced neurotoxicity. Both species significantly improved sperm quality and testicular function, which may suggest their possible development as plant-based nutraceuticals for protecting male reproductive health in future studies. Their phytochemical abundance further supports their potential as plant-based nutraceuticals.
Cerebral amyloid angiopathy (CAA), characterized by amyloid β deposition in cerebral vasculature, is increasingly recognized as a major contributor to both cognitive decline and lobar intracerebral hemorrhage (ICH) in older adults and often coexists with Alzheimer’s disease (AD). Understanding CAA is a crucial step for improving health outcomes and the development of effective therapies. However, significant gaps remain in our understanding of CAA’s pathophysiology, diagnostic approaches, biomarker development, and clinical management. A comprehensive review is therefore essential to synthesize existing knowledge and highlight key directions for future research. This review goes beyond prior summaries by critically synthesizing recent evidence on diagnostic innovations—including the Boston criteria v2.0 and emerging plasma biomarkers—and addressing pressing clinical dilemmas such as anticoagulation management in patients with coexisting atrial fibrillation and CAA. It also highlights ongoing research into multimodal diagnostic frameworks and precision treatment strategies aimed at bridging current diagnostic and therapeutic gaps. Together, these updates underscore how advancing biomarker validation, individualized risk stratification, and amyloid-targeted approaches may shape future CAA management and prevention.
Parkinson’s disease is typified by Lewy bodies and the selective death of dopaminergic neurons in the substantia nigra. α-Synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and oxidative stress are key components of its pathophysiology. The neuroprotective potential of natural substances with anti-inflammatory and antioxidant qualities has drawn attention in recent years. A naturally occurring isoflavone that is mostly present in red clover and other legumes, biochanin A has shown promise as a treatment option for Parkinson’s disease. Preclinical research has shown that biochanin A uses a variety of methods to provide notable neuroprotective benefits. By activating the Nrf2/ARE pathway, it scavenges reactive oxygen species (ROS), upregulates antioxidant defense enzymes, and inhibits pro-inflammatory mediators by modifying the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling cascade. Additionally, it has been demonstrated that biochanin A preserves neuronal integrity in Parkinson’s disease models by reducing dopaminergic neuronal death, inhibiting microglial activation, and mitigating mitochondrial dysfunction. Its potential as a neurotherapeutic agent is increased by its capacity to pass the blood-brain barrier. To investigate its safety, bioavailability, and effectiveness in people, more translational and clinical research is necessary. Biochanin A’s incorporation with neuroprotective techniques may pave the way for novel supplementary treatments for Parkinson’s disease. Therefore, the current review aims to present a thorough investigation of the molecular basis of biochanin A’s anti-Parkinson properties in Parkinson’s disease, building on the body of existing research that explains these properties.
Neurogenetic disorders remain genetically uncharacterized in many populations, including Libya. We report three Libyan patients from two consanguineous families with pathogenic variants in sodium channel genes. Two adult sisters (Patients 1 & 2) presented with global developmental delay and progressive spastic paraparesis without epilepsy. Whole exome sequencing identified the same heterozygous SCN8A variant (c.142G>A; p.Asp48Asn) in both sisters, classified as a variant of uncertain significance (VUS). Its occurrence in two affected siblings with a consistent phenotype and the absence of other explanatory variants provide supporting evidence for its potential pathogenicity. These cases represent the first documented instances of a suspected SCN8A-related disorder in Libya. A third, unrelated 10-year-old boy (Patient 3) with a phenotype consistent with Dravet syndrome, including refractory seizures and neurodevelopmental regression, was found to harbor a likely pathogenic heterozygous SCN1A variant (c.2113del; p.Glu705Lysfs*10). This report expands the genetic and phenotypic spectrum of neurological disorders in Libya and underscores the critical role of genetic testing, while also highlighting the need for segregation studies to achieve a definitive molecular diagnosis.
Although addiction is a complex and contextually embedded disorder that extends beyond individual pathology and neurobiological dysfunction, prevailing computational and clinical models often reduce addiction to a chronic brain disease. While such frameworks have shaped dominant approaches to treatment and theory, they remain poorly aligned with the lived experience and behavioral phenomena of addiction, ignoring its psychological, social, and systemic dimensions. This paper examines the limitations of various disease and compulsion models both critically and in-depth, highlighting their empirical and conceptual shortcomings. In doing so, it argues for the development of context-sensitive and psychologically grounded computational models, ones capable of capturing the nuanced realities of addiction and informing more effective, personalized interventions.
Primary central nervous system lymphoma is a rare form of extranodal non-Hodgkin lymphoma that is confined to the brain, spinal cord, leptomeninges, or eyes, representing less than one percent of all non-Hodgkin lymphomas and approximately four percent of primary brain tumors. When the disease is truly isolated to the central nervous system, with no evidence of systemic spread, it poses unique diagnostic and therapeutic challenges, particularly in immunocompetent patients. We reviewed nine recently published cases from 2021 to 2024 that described isolated primary central nervous system lymphoma without extracranial involvement. Patients ranged in age from forty-four to eighty-five years, with both immunocompetent and immunosuppressed individuals represented. Presenting symptoms include focal neurological deficits, seizures, progressive confusion, cranial neuropathies, and neurolymphomatosis. Magnetic resonance imaging findings were diverse, including intra-axial masses, leptomeningeal and cranial nerve enhancement, and mass effect. Cerebrospinal fluid analysis was variably positive for lymphoma cells. Histopathological analysis confirmed diffuse large B-cell lymphoma in all cases, although initial biopsies were sometimes inconclusive, underscoring the importance of repeat tissue sampling and expert pathology review. Treatment strategies most often included high-dose methotrexate-based chemotherapy, monoclonal antibody therapy, and radiotherapy, with some patients undergoing surgical decompression or diagnostic craniotomy. Follow-up data revealed variable survival outcomes, with a subset of patients achieving disease-free survival beyond one year. These cases highlight the wide clinical spectrum and diagnostic complexity of isolated primary central nervous system lymphoma and reinforce the need for a high index of suspicion, timely advanced imaging, multidisciplinary discussion, and appropriate tissue diagnosis to guide individualized management.
Neurological disorders constitute a major global health burden with limited effective treatments. Despite advances in molecular neuroscience, critical gaps persist in understanding intercellular communication systems underlying central nervous system homeostasis and neurodegeneration. Extracellular vesicles (EVs), nanoscale to microscale membrane-bound vesicles secreted by virtually all cell types, have emerged as pivotal mediators of intercellular communication in neurological pathologies. This review examines molecular mechanisms governing EV biogenesis, cargo selection, and pathological functions in neurological disorders, emphasizing the emerging role of ubiquitin-like protein 3 (UBL3) as a novel regulator of EV-mediated protein sorting. Neural cell populations produce specialized EV subtypes containing distinct molecular cargo reflecting their physiological states. UBL3, a membrane-anchored post-translational modifier, operates through geranylgeranylation-dependent mechanisms to promote selective protein incorporation into small EVs (sEVs), with knockout studies demonstrating approximately 60% reduction in EV protein content. Proteomic analyses reveal UBL3 interacts with over 1,200 proteins, with ~30% classified as EV cargo proteins. Critically, UBL3-mediated sorting influences disease-associated protein trafficking, including α-synuclein in Parkinson’s disease and mutant huntingtin in Huntington’s disease, suggesting involvement in prion-like spreading mechanisms. EVs’ dual nature as pathological mediators and therapeutic vehicles represents a paradigm shift in neurological medicine. EVs offer advantages as natural drug delivery systems capable of crossing the blood-brain barrier, accessible biomarkers for noninvasive disease monitoring via liquid biopsies (achieving diagnostic accuracies exceeding 0.88 ROC-AUC), and engineered therapeutic platforms for delivering CRISPR-Cas9 systems and neuroprotective factors. However, clinical translation requires addressing challenges, including standardizing isolation protocols, elucidating cell-type-specific cargo sorting mechanisms, and defining optimal administration routes. Understanding UBL3-mediated cargo sorting mechanisms presents promising therapeutic opportunities by selectively modulating pathogenic protein trafficking. EVs, positioned at the intersection of pathogenesis and therapy, represent attractive targets for precision medicine approaches in neurological conditions, with UBL3 emerging as a novel molecular handle for manipulating EV composition and function.
Background: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, with a poor prognosis despite advances in treatment options. T-cell-engager therapies, which have an antibody-based structure connecting immune cells to target cancer cells with high affinity, offer a promising strategy but face four key barriers: antigen heterogeneity, immune escape, the blood-brain barrier (BBB), and the immunosuppressive tumor microenvironment (TME). This systematic review synthesizes preclinical developments in bispecific T-cell engager (BiTE), tri-specific T-cell engager (TriTE), and multi-specific T-cell engagers for GBM over the last 10 years, evaluating their capacity to overcome these barriers. Methods: A systematic search was conducted in OVID Medline, Embase, and ClinicalTrials.gov for pre-clinical and clinical studies. A descriptive analysis without meta-analysis was formulated in which data were grouped thematically by the ability of treatments to overcome GBM-specific barriers. Results: Among the 14 studies meeting inclusion criteria, all studies were preclinical, with 12/14 (85.7%) utilizing an in vivo mouse model. BiTEs were used in 12/14 (85.7%) studies, while 4/14 (28.6%) studies targeted multiple antigens through either TriTEs or multivalent BiTEs. There was a range of antigen targets with the most common being interleukin 13 receptor alpha 2 (IL13Rα2) as well as epidermal growth factor receptor (EGFR) or EGFR variant III (EGFRvIII) in 7/14 (50.0%) studies. Most studies (85.7%) addressed two or more barriers, with 13/14 (92.9%) showing evidence of affecting the TME. Discussion: In the last decade, T-cell engager therapies have evolved in both antigenic targets and delivery vehicles used to overcome the key barriers. An emerging area within T-cell engager therapies is targeting multiple antigens through multi-specific T-cell engager therapies, such as the TriTEs. Studies have explored chimeric antigen receptor T-cells (CAR-Ts) as a potential delivery vehicle for BiTEs. A future clinical trial using multi-specific T-cell engager therapies or a CAR-T-secreting BiTE in adult patients is required to determine the potential clinical utility of T-cell engagers.
Aim: This study investigated the effect of brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on post-stroke outcomes, including quality of life, physical fitness, cognitive function, depression, and overall disability. Methods: The difference between Met carriers and non-Met carriers was analyzed for the entire sample and in pair-matched analysis, using age, sex, time since stroke, and race. Results: We evaluated 89 stroke participants (mean age, 57 ± 10 years; 58% male; 54% White, and 49% Hispanic). Twelve participants (13%) had one copy of the BDNF Val66Met (Val/Met heterozygotes) and none had two copies (Met/Met homozygotes). Comparing Met (n = 12) and non-Met carriers (n = 77), no significant differences were observed in demographics or clinical characteristics, including motor or cognitive outcomes. In pair-matched analysis, a significant difference was observed for the Center for Epidemiological Studies Depression (CES-D) scale, where Met carriers had significantly greater CES-D scores than non-Met carriers (24 ± 16 vs. 9 ± 9, p = 0.011). Regardless of the chosen CES-D cut-off scores (≥ 16 vs. ≥ 20), more cases of depressive symptomatology were observed among those with the BDNF Val66Met polymorphism than those without it (p values < 0.05). Conclusions: The BDNF Val66Met polymorphism may be associated with post-stroke depression but not motor or cognitive recovery.
Guillain-Barré Syndrome (GBS) is a rare cause of acute, flaccid paralysis and affects populations around the world, usually in the setting of recent gastrointestinal infection. The myelin sheaths of affected patients are destroyed, and consequently, the disease can manifest variably with the most common complaints including weakness, disturbances in sensation, and pain. Multiple available pharmacotherapies are employed to address disease progression and promote the reversal of symptoms. However, there is no widely accepted guideline detailing tiers of pain management options, despite pain being a significant primary complaint during the acute phase of the disease. To address this, we searched the GBS literature for publications that specifically discussed patient pain, how the pain was managed by the clinician, and how patients responded to various modalities. We discuss the findings of the literature review we conducted, evaluate the expansive list of existing options for treating pain and how they fared in symptom resolution, and draw conclusions based on our observations of which interventions addressed patient pain effectively and which were less successful. While general management of GBS, including treatment and efforts towards symptom reversal, has been robustly discussed in the literature, our work stresses the lack of research towards pain management in GBS and emphasizes the need to fill the gap in patient care for patients with this disease.
Cyclic vomiting syndrome (CVS) is a rare disorder in which stereotypical periods of intermittent nausea and vomiting last between hours and over a week. The disorder overlaps with migraine, and the current treatment recommendations follow those of migraine management. The current patient had experienced vomiting periods lasting up to a week since the age of two. Prophylactic amitriptyline had led to probably slightly longer intervals between CVS periods, while several medications had proven ineffective. At the age of 17, there was an excellent response to peroral olanzapine, which eventually proved sufficient to abort the vomiting periods in a single dose when taken at the beginning of one. In light of these and previously reported cases, early administration of olanzapine is suggested to treat CVS periods.
