Jul 2026· International Journal of Molecular Sciences· Vol 27· 0 citations· 925 references
Medicine
TL;DR
This work proposes a threshold management framework for DRE, built on a revised reservoir model, and translates it into three structural priorities: mechanistic phenotyping to stratify patients by pathophysiological domain, dual-mechanism drug development, and trial designs suited to multicomponent, context-dependent interventions.
Abstract
Epilepsy is a multifactorial disorder, yet routine management still focuses on neuronal excitation and insufficient inhibition, with antiseizure medications (ASMs) as the primary therapeutic strategy. This approach fails in roughly one-third of patients who develop drug-resistant epilepsy (DRE). Converging evidence links DRE with neuroinflammation, oxidative stress (OS), and mitochondrial dysfunction—an interconnected distal pathophysiological triad that progressively lowers seizure thresholds yet remains peripheral to clinical epilepsy management. We map this triad mechanistically and show that ASMs modulate it beyond their anticonvulsant activity, while triad-targeting pharmacological, dietary, and botanical interventions independently reduce seizure susceptibility. Common precipitants are reinterpreted as acute activators of the distal triad, linking precipitant identification and patient agency to threshold elevation. Integrating these elements, we propose a threshold management framework for DRE, built on a revised reservoir model, and translate it into three structural priorities: mechanistic phenotyping to stratify patients by pathophysiological domain, dual-mechanism drug development, and trial designs suited to multicomponent, context-dependent interventions. Together, these proposals reframe epilepsy management from sequential pharmacological trials toward coordinated optimization of the full seizure threshold landscape.
Epilepsy is increasingly recognized as a multiscale network disorder rather than solely a condition of neuronal hyperexcitability, and the coordinated use of complementary human-relevant platforms may help incorporate multiscale mechanistic insights into therapeutic development and evaluation, narrow persistent translational gaps, and support more predictive and mechanism-informed treatment strategies.
Wonseok Chang, Amy Seomin Kwak, Seung-Ho Han et al.· Pharmaceutics· 0 citations
Depression is a common comorbidity in patients with epilepsy, significantly impacting their quality of life. However, the precise mechanisms underlying depression in epilepsy remain unclear. This review synthesizes the latest research on the pathogenesis of depression in epilepsy, focusing on abnormalities in monoamine neurotransmitters, neuroinflammation, HypothalamicPituitary-Adrenal (HPA) axis dysfunction, neurotrophic factors, mitochondrial dysfunction, and oxidative stress. The article explores the dual roles of antidepressants and antiepileptic drugs (AEDs) in the treatment of depression in epilepsy, highlighting drugs that may exacerbate either depression or seizure activity. The need for more nuanced treatment strategies, including the careful selection of antidepressants and AEDs, is emphasized. Additionally, non-drug interventions, such as Cognitive-Behavioral Therapy (CBT), neuromodulation techniques, and dietary modifications (anti-inflammatory and antioxidant foods), are reviewed as vital adjuncts to pharmacological treatments. This article aims to guide clinicians in choosing optimal treatment strategies and underscores the importance of timely depression screening, long-term management, and personalized therapy for patients with epilepsy and comorbid depression.
Qingyang Zhan, Fanyi Kong, Yi-jie Liu et al.· Current Neuropharmacology· 0 citations
ABSTRACT Background Neurological disorders are a major global health challenge in the current era, and they need new therapeutic treatments. Aims This review evaluates the neurobiological activity of Paeonol (PNL) focusing on its antioxidant, anti‐inflammatory, and cognitive enhancing effects in various neurodegenerative disorders. Methods A literature search (up to March 2025) was conducted via PubMed, ScienceDirect, Scopus, and other databases using MeSH terms related to PNL's pharmacology and neuroprotection. Inclusion criteria encompassed preclinical studies (in vitro and in vivo) and clinical trials, while exclusion criteria eliminated non‐English papers and non‐neurodegenerative research. Results PNL, a bioactive phenolic compound from Paeonia suffruticosa, has shown antioxidative, anti‐inflammatory, and neuroprotective effects. PNL reduces oxidative stress by boosting the activity of superoxide dismutase (SOD) and glutathione (GSH) while decreasing reactive oxygen species (ROS) and lipid peroxidation. It also reduces neuroinflammation by inhibiting key pathways such as nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), toll‐like receptor 4 (TLR4), and mitogen‐activated protein kinase (MAPK), and it affects apoptosis‐related proteins like B‐cell lymphoma 2 (Bcl‐2) and Bcl‐2‐associated X protein (Bax). In Alzheimer's disease (AD) models, PNL reduces amyloid‐β plaques and some pro‐inflammatory cytokines like interleukin‐1 beta (IL‐1β) and tumor necrosis factor‐alpha (TNF‐α), improving cognitive function. For ischemic stroke, it reduces infarction volume and microglial activation by targeting TLR2/4 and NF‐κB. PNL has anticonvulsant effects in epilepsy and protects dopaminergic neurons in Parkinson's disease (PD). It also demonstrates anxiolytic and antidepressant properties by modulating Brain‐Derived Neurotrophic Factor (BDNF), Nerve Growth Factor (NGF), and oxidative stress markers. PNL is quickly absorbed with moderate bioavailability and low blood–brain barrier permeability. It effectively treats unstable angina but is less effective for osteoarthritis pain. Though safe at therapeutic doses, high concentrations can be cytotoxic. Conclusion Further clinical research is needed to confirm its neurotherapeutic potential.
Md. Sakib Al Hasan, Naznin Shahria, Yasin Emon et al.· Immunity, Inflammation and D...· 0 citations
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and irreversible neuronal loss. Despite extensive research, currently approved pharmacological therapies offer only symptomatic relief and fail to halt disease progression. Increasing evidence identifies chronic neuroinflammation, particularly microglia-driven inflammatory signaling, as a central contributor to AD pathology. Among inflammatory regulators, the purinergic P2X7 receptor and downstream NLRP3 inflammasome axis play a pivotal role in sustaining neuroinflammatory cascades, oxidative stress, and neuronal damage. Consequently, this signaling axis has emerged as a promising therapeutic target. Herbal medicines, with their intrinsic multi-target pharmacology and favorable safety profiles, offer an alternative strategy for addressing the multifactorial nature of AD. Cuscuta reflexa Roxb. (Amarbel), a parasitic medicinal plant widely used in traditional systems of medicine, is rich in flavonoids, phenolic acids, glycosides, alkaloids, and lignans with documented anti-inflammatory, antioxidant, and neuroprotective properties. This review critically examines the neurotherapeutic potential of Cuscuta reflexa as a multi-target modulator of the P2X7–NLRP3 inflammasome axis in Alzheimer’s disease. We integrate evidence from AD pathophysiology, purinergic signaling, phytochemistry, and experimental pharmacology to propose a mechanistic framework through which Cuscuta reflexa may attenuate chronic neuroinflammation, preserve synaptic integrity, and support neuronal survival. Finally, translational challenges, formulation strategies, and future research directions are discussed to support the development of Cuscuta reflexa-based interventions for neurodegenerative disorders.
Komal Bhiduri, Abhinash Saini, D. Dhull et al.· Journal of Dynamics and Cont...· 0 citations
Epilepsy is a heterogeneous neurological disorder affecting more than 70 million people worldwide, posing significant challenges for clinicians due to its complex etiology, diverse manifestations, variable treatment responses, and the inability to predict seizures or disease onset reliably. Despite advances in antiseizure medications, approximately 30% of patients remain treatment-resistant, highlighting the urgent need for therapies with antiepileptogenic or disease-modifying effects. To optimize and individualize strategies to predict and treat seizures and epilepsy, efforts to identify biomarkers of epilepsy risk, epileptogenesis, seizures, and therapy response are ongoing. This article reports key presentations and discussions from the 2023 Workshop on Neurobiology of Epilepsy (WONOEP XVII) in Kilkea, Ireland on novel epilepsy biomarkers and treatment strategies beyond the synapse and does not constitute a comprehensive review of biomarkers or treatment strategies. Much of the focus in epilepsy research has centered on identifying primarily neuronal processes or components. The 2023 WONOEP presentations discussed advances in plasma biomarkers for posttraumatic seizures and outcomes, perivascular spaces in posttraumatic epilepsy and poststroke epilepsy, imaging biomarkers of astrogliosis, and plasma microRNA biomarkers of intellectual disability and autism in tuberous sclerosis complex. Furthermore, research on immuno- and anti-inflammatory therapies and blood-brain barrier in drug-resistant focal epilepsies and infantile epileptic spasms syndrome was presented, as well as on the effects of antiseizure and cardioprotective medications on cardiac injury in temporal lobe epilepsy. The review also emphasizes the need for further interdisciplinary collaboration to accelerate the translation of these findings into clinical practice, ultimately improving outcomes and quality of life for people with epilepsy.
Mirte Scheper, Zining Liu, A. Galanopoulou et al.· Epilepsia· 0 citations
Sudden Unexpected Death in Epilepsy (SUDEP) represents a leading cause of epilepsy-related mortality, reflecting a severe disruption of systemic physiology that remains challenging to address using standard clinical protocols. Although generalized tonic–clonic seizures (GTCS) and pharmacoresistance are established risk indicators, current clinical risk stratification frequently lacks the predictive granularity required to anticipate individual cardiorespiratory collapse. This review provides a comprehensive synthesis of the SUDEP pathophysiological framework, aiming to bridge the gap between retrospective clinical observation and proactive precision medicine. We delineate a translational framework focused on the intrinsic biological susceptibility of the neuro-cardiac axis, particularly the genetic “dual pathology” of channelopathies and structural cardiac remodeling. Furthermore, we evaluate the transition from reactive risk identification toward multimodal “digital phenotyping” leveraging artificial intelligence. Finally, we assess the developmental trajectory of “secondary prevention” strategies, such as automated neurostimulation, designed to interrupt the terminal cascade. By integrating genomic vulnerability with emerging preventative technologies, this review outlines a multidisciplinary approach to transforming SUDEP into a more predictable and preventable clinical entity.
Chenxi Xu, Yi-Yuan Wang, Su-Ping Nie et al.· Frontiers in Neurology· 0 citations