Biomarkers of Epileptogenesis: The Focus on Glia and Cognitive Dysfunctions

Abstract

The need to find measures that reliably predict the onset of epilepsy after injurious events or how the patient will respond to anti-seizure drugs led to intensive pre-clinical and clinical research to discover non-invasive biomarkers that could increase the sensitivity of existing clinical indicators. The use of experimental models of epileptogenesis and of drug-resistance is instrumental to select the most promising approaches to explore such biomarkers in the pre-clinical setting for further clinical validation. The approaches most frequently used to find clinically useful biomarkers of epileptogenesis include molecular brain imaging, EEG signal analysis and the measure of soluble molecules in biofluids which may reflect brain intrinsic events involved in epilepsy development. Among those, we focused our attention on proton magnetic resonance imaging (H-MRS)-based analysis of astrocytic activation, and related blood biomarkers, since this cell population appears to be pivotally involved in various epileptogenesis processes triggered by differing insults. Moreover, we also investigated behavioral biomarkers by focusing on cognitive dysfunctions since this deficit represents a typical co-morbidity in epilepsy which may manifest even before the onset of spontaneous seizures. In this review article, we will report our recently published evidence supporting the utility of measuring astrocyte activation, the soluble molecules they release, and the associated cognitive deficits during epileptogenesis for early stratification of animals developing epilepsy. We will discuss the potential clinical translation of our findings for enriching the patient population in preventive clinical trials designed to study anti-epileptogenic treatments.

Follow-Up of Peripheral IL-1β and IL-6 and Relation with Apoptotic Death in Drug-Resistant Temporal Lobe Epilepsy Patients Submitted to Surgery

“…The study of different models of epilepsy developed to evaluate the inflammatory response has shown that, in rodents, with convulsive activity occurs the following molecular cascade: a rapid increase in the proinflammatory cytokines (IL-1β, IL-6, and TNF-α), the activation of the signaling pathway of Toll-like receptors (TLRs), the production of chemokines, activation of the complement system, and increased expression of adhesion molecules [ 23 , 25 , 36 , 37 , 38 , 39 ].…”

Bcl‐2/Bax ratio increase does not prevent apoptosis of glia and granular neurons in patients with temporal lobe epilepsy

“…It is possible that continuous central nervous system cells activation, especially glia, can lead to apoptosis in TLE hippocampi by overexpression of pro‐inflammatory cytokines and chemokines, which induce DNA and mitochondrial damage, and by direct upregulation of apoptotic proteins of the Bcl‐2 family …”

An open repository for single-cell reconstructions of the brain forest

“…For instance, glia (astrocytes, oligodendrocytes, microglia, and other types), once considered the ‘dark-matter’ of the nervous system or the ‘forgotten’ brain cells, are now recognized to contribute crucially to fundamental physiological processes, such as neural development 27 , signal processing 28 , and synaptic plasticity 29 . Furthermore, glial cells are involved in major neuropathologies, including Alzheimer’s 30 and Parkinson’s 31 diseases, stroke 32 and epilepsy 33 , as well as traumatic brain 34 and spinal cord injuries 35 . Specifically, glia morphology represents one of the most useful biomarkers of brain function and dysfunction, as exemplified by enlargement of activated microglia upon rising neuronal death 36 , loss of myelination related to retraction of oligodendrocytes 37 , and altered astrocyte architecture in response to pharmacological treatment 38 and neurotoxicity 39 .…”