Jun 2026· International Journal of Molecular Sciences· Vol 27, pp. 5857· 0 citations· 119 references
Medicine
TL;DR
The role of the main inflammatory targets (Inflammasome/NLRP3, NF-κB, MAPK, mTOR, COX-2/PGE2, and TLR4/HMGB1) to epilepsy is related and natural products acting through these pathways in the treatment of epileptic seizures are investigated.
Abstract
Epilepsy is a chronic neurological disorder prevalent worldwide, characterized by recurrent episodes of epileptic seizures. The primary current treatment approach is pharmacological, aimed at reducing the intensity and frequency of seizures, though it does not provide a cure. Neuroinflammation plays a central role in epilepsy by activating glial cells and stimulating the release of inflammatory mediators, further disrupting the balance between excitation and inhibition, thereby promoting the onset and recurrence of seizures. Furthermore, persistent inflammatory processes induce synaptic remodeling and the formation of dysfunctional neural circuits, establishing a pathological cycle in which inflammation and epileptic activity feed into each other. In this regard, natural products represent an important avenue for the discovery of new treatments. Thus, this review aimed to relate the role of the main inflammatory targets (Inflammasome/NLRP3, NF-κB, MAPK, mTOR, COX-2/PGE2, and TLR4/HMGB1) to epilepsy and to investigate in the literature natural products acting through these pathways in the treatment of epileptic seizures. Consequently, inflammatory pathways have emerged as critical targets in epilepsy, highlighting the importance of strategies capable of modulating neuroinflammatory processes. In this context, natural products stand out as promising therapeutic alternatives, given their multitarget mechanisms of action, potential to attenuate neuroinflammation and neuronal hyperexcitability.
Epilptogenesis is a long-term process that involves the transformation of a healthy brain into a seizure-producing brain. Since approximately 30% of epilepsy patients suffer from drug-resistant seizures, the concept of inhibiting the epileptogenesis process and thus preventing seizures has emerged. The search for effective methods of inhibiting epileptogenesis is possible thanks to animal models, which include kindled seizures; models based on the induction of status epilepticus resulting in subsequent spontaneous recurrent seizures, or brain trauma; and genetic models. Blood–brain barrier dysfunction, inflammatory processes in the brain, and oxidative stress appear to play a major role in epileptogenesis. This prompted testing of a number of anti-inflammatory agents and antioxidants in the epileptogenic process. One noteworthy finding was that losartan (an antihypertensive drug), as a TGF-β antagonist, proved effective in inhibiting epileptogenesis due to blood–brain barrier damage. Due to the many mechanisms involved in the process of epileptogenesis, it seems that the use of a combination of drugs will be an effective method of inhibiting it. The most promising combination includes levetiracetam (a second-generation antiseizure drug), atorvastatin, and ceftriaxone (a beta-lactam antibiotic), which effectively inhibits spontaneous seizures in animals experiencing status epilepticus. Any clinical trials on the inhibition of epileptogenesis must take into account the fact that a small percentage of patients develop epileptic seizures after stroke or brain injury. Recently suggested markers predicting a high probability of epileptic seizures after brain damage may facilitate appropriate patient selection for studies on inhibition of epileptogenesis.
K. Łukawski, Stanisław J Czuczwar, Barbara Miziak· Current Issues in Molecular...· 0 citations
Neurodegenerative diseases are a heterogeneous group of chronic and progressive disorders, which are characterized by selective neuronal destruction, synaptic malfunction and progressive cognitive and locomotor dysfunction. The major ones are Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis which are a formidable and growing global health and socio-economic burden mainly due to demographic aging. Even despite the advances in the symptomatic treatment, predominantly through the cholinergic, dopaminergic, glutamatergic, and GABAergic system, the current treatment regimens are not able to stop the underlying neurodegenerative events or reverse them. There is mounting evidence that convergent pathogenic mechanisms, such as protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, impaired autophagy-lysosomal pathways, synaptic dysfunction, and chronic neuroinflammation, are convergent mechanisms. These convergent molecular and cellular cascades provide a strong rationale behind the identification of new neuropharmacological targets, which include: kinases, phosphatases, epigenetic regulators, neurotrophic signalling pathways and neuroimmune mediators. Advances in the biomarker discovery, genomics and systems biology have further enabled the use of precision based therapeutic stratification and early-intervention approaches. Genetic, nanotechnology, and RNA-based therapeutics as well as biologics are reconfiguring translational models in neurodegeneration. A mechanism-based, multi-target, precision neuropharmacological approach, as a group, has significant potential in achieving long-term neuroprotection, improved clinical and disease modification in neurodegenerative diseases.
Neuroinflammation is increasingly recognized as a pivotal mechanism linking immune dysregulation with the onset, progression, and treatment resistance of major psychiatric disorders. Once considered distinct from classical neurodegenerative diseases, psychiatric conditions such as Major Depressive Disorder (MDD), schizophrenia, bipolar disorder, and anxiety disorders are now known to involve chronic, low-grade inflammation within the Central Nervous System (CNS). Persistent activation of microglia and astrocytes, together with disruption of Blood-Brain Barrier (BBB) integrity, initiates neurotoxic cascades that alter the balance between pro-inflammatory and anti-inflammatory cytokines. These alterations impair neurotransmission, reduce neuroplasticity, increase oxidative stress, and ultimately contribute to neuronal dysfunction. Several molecular pathways, including Nuclear Factor Kappa B (NF-κB), the NLRP3 inflammasome, and the kynurenine pathway (KP), play central roles in mediating these inflammatory responses. Activation of the KP diverts tryptophan metabolism away from serotonin synthesis toward the production of neuroactive metabolites such as quinolinic acid, thereby promoting excitotoxicity and neurodegeneration. Elevated circulating inflammatory biomarkers, including C-Reactive Protein (CRP), interleukin-6 (IL-6), and Tumor Necrosis Factor- alpha (TNF-α), have been consistently associated with increased disease severity and poor response to conventional monoaminergic therapies. Consequently, pharmacological modulation of neuroinflammation has emerged as a promising therapeutic strategy. Current and emerging approaches include cyclooxygenase-2 (COX-2) inhibitors, cytokine-targeted therapies, modulators of microglial activation, antioxidant agents such as N-acetylcysteine and omega-3 fatty acids, as well as novel therapeutics targeting the NLRP3 inflammasome, P2X7 receptors, and microglial polarization. Furthermore, integrating inflammatory biomarker profiling with advanced neuroimaging techniques, including Translocator Protein Positron Emission Tomography (TSPO-PET), may facilitate patient stratification and enable precision psychiatry. A comprehensive understanding of neuroinflammatory mechanisms may therefore provide new opportunities for developing targeted therapeutic interventions and improving clinical outcomes in psychiatric disorders.
P. Karwa, Vaibhav Parekar, Sarthak Buttepatil et al.· Current pharmaceutical desig...· 0 citations
Depression, a prevalent mental health disorder, has attracted increasing attention owing to its association with neuroinflammation. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a crucial role in maintaining cellular and tissue homeostasis by regulating inflammatory responses and cell death signalling pathways, both of which are closely linked to various physiological and pathological processes. Accordingly, RIPK1 functions as an upstream kinase that modulates inflammation and cell death. Tumour necrosis factor-α (TNF-α), a key pro-inflammatory cytokine implicated in the pathogenesis of various human diseases, acts as a principal upstream activator of RIPK1. Accumulating evidence further indicates that RIPK1 may contribute to a detrimental neuroinflammatory environment in mental disorders such as depression. However, its specific regulatory role and underlying mechanisms in depression remain incompletely understood. This review first summarises current advances in understanding the molecular structure and biological functions of RIPK1, with particular emphasis on multiple cellular pathways associated with depression. Subsequently, it discusses the mechanisms by which RIPK1 participates in the pathological process of depression, including its role in neuroinflammation and synaptic plasticity. Finally, we outline the effects of RIPK1 inhibitors in animal models, which have been shown to prevent neuronal cell death and reduce neuroinflammation. Collectively, these findings suggest that targeting RIPK1 may represent a promising therapeutic strategy with potential for clinical translation, highlighting its value as a potential therapeutic target in depression. However, further work is still needed to bridge the gap between preclinical mechanisms related to the RIPK1 inflammatory pathway and their actual clinical efficacy.
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.
Alexander Trofimov, Ksenia Shcherbakova, Alexander Schwarz et al.· International Journal of Mol...· 0 citations
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