Biomolecular mechanisms of epileptic seizures and epilepsy: a review

Abstract

Epilepsy is a recurring neurological disease caused by the abnormal electrical activity in the brain. This disease has caused about 50 new cases in 100,000 populations every year with the clinical manifestations of awareness loss, bruising, and mobility abnormalities. Due to the lack understanding of the pathophysiology behind the illness, a wide variety of medications are available to treat epilepsy. Epileptogenesis is the process by which a normally functioning brain undergoes alterations leading to the development of epilepsy, involving various factors. This is related to the inflammation which is driven by cytokines like IL-1 and tumor necrosis factor-α (TNF-α) leads to neuronal hyperexcitability. Pro-inflammatory cytokines from activated microglia and astrocytes in epileptic tissue initiate an inflammatory cascade, heightening neuronal excitability and triggering epileptiform activity. The blood-brain barrier (BBB) maintains central nervous system integrity through its tight endothelial connections, but inflammation impact BBB structure and function which leads to immune cell infiltration. The mammalian target of rapamycin (mTOR) pathway's excessive activation influences epileptogenesis, impacting neuronal excitability, and synapse formation, with genetic mutations contributing to epilepsy syndromes and the modulation of autophagy playing a role in seizure onset. The apoptotic pathway contribute to cell death through glutamate receptor-mediated excitotoxicity, involving pro-apoptotic proteins like p53 and mitochondrial dysfunction, leading to the activation of caspases and the disruption of calcium homeostasis. Ionic imbalances within neural networks contribute to the complexity of epileptic seizures, involving alterations in voltage-gated sodium and potassium channels, and the formation of diverse ion channel subtypes. Epileptogenesis triggers molecular changes in hippocampus, including altered neurogenesis and enhanced expression of neurotrophic factors and proteins. Oxidative stress leads to cellular damage, disrupted antioxidant systems, and mitochondrial dysfunction, making it a key player in epileptogenesis and potential neuroprotective interventions. Thalamocortical circuitry disruption is central to absence epilepsy, the normal circuit becomes faulty and results in characteristic brain wave patterns.

Keywords: Epilectic seizures; Epilepsy; Epileptogenesis; Molecular mechanism.

Fig. 1

The role of inflammation in epileptic seizure and epilepsy. A cascade of events unfolds after brain injury that triggers central inflammation and alters normal neuronal connections in the hippocampus. Meanwhile, systemic inflammatory diseases cause inflammation in the peripheral tissues, accelerating the accumulation of inflammatory agents. This dual inflammation, both in the peripheral and central systems, contributes to the weakening of the protective BBB by enhancing the levels of inflammatory agents. This compromised barrier permits the infiltration of immune cells, initiating heightened neuronal activity and further amplifying the production of inflammatory agents. The uncontrolled inflammation in both peripheral and central regions, coupled with the compromised blood-brain barrier, sets the stage for structural changes in synaptic connections within the hippocampus. These processes culminate in the progression of epilepsy. Adapted from Rana and Musto [13]

Fig. 2

The role of mTOR pathway in epileptogenesis. Dysmorphic neurons and balloon cells, which lack dendrites or axons, undergo alterations in neurotransmitter receptor subunit expression and uptake site distribution in conditions like TSC, FCD, and hemimegalencephaly (HME). Notably, changes are prominent in GluR, NMDAR, and mGluR subtypes. The direct causation of these alterations—whether they arise from heightened mTOR signaling, tissue cytoarchitecture changes, or adaptations stemming from recurrent seizures—remains uncertain. The accompanying diagram illustrates various locations where dysregulation of mTORC1 (influenced by both phosphoactivation and phosphoinhibition effects) is implicated in human neurological disorders collectively referred to as “mTORopathies,” which encompass epilepsy. Components such as PTEN, STRADA, TSC1/TSC2, and S6K1 might play roles in this context. Experimental animal models involving these proteins also exhibit compromised seizure susceptibility and/or deficits in social and behavioral functions. Rapamycin and other mTOR inhibitors emerge as primary potential therapeutic agents for modulating mTORC1 signaling. These interventions hold promise for regulating the mTOR pathway, offering prospects for addressing the underlying mechanisms of mTOR-related neurological disorders, including epilepsy [21, 25]. Adapted from Crino [21]

Fig. 3

The mechanism of excitotoxicity. The sustained activation of N-methyl-D aspartate receptors (NMDAR) due to excessively high concentrations of glutamate (Glu) results in a substantial influx of calcium into the cell. This influx, in turn, triggers the activation of lytic enzymes and nitric oxide synthase (NOS). Concurrently, heightened levels of arachidonic acid and mitochondrial impairment foster the generation of reactive oxygen species, initiating a cascade of biomolecular damage. Ultimately, these processes lead to the activation of apoptotic death programs within cells. The impact of energy shortages compounds the degenerative process. Energy deficits prolong membrane depolarization by impairing the energy supply to the sodium/potassium pump (Na/K ATPase). This, in turn, maintains NMDAR in an active state, rendering the cell more susceptible to the typical glutamatergic inputs from the cerebral cortex. Adapted from Lorigados et al [38]

Fig. 4

The mechanism scheme of excitotoxicity induces epilepsy. Adapted from Lorigados et al [38]. ER: endoplasmic Reticulum, ROS: reactive okxidative stress