Epilepsy is one of the most prevalent neurological disorders, marked by the repeated occurrence of sudden and temporary episodes known as seizures, which can affect motor, sensory, autonomic, and psychological functions. This condition can considerably reduce the quality of life, as it often restricts daily activities, social interactions, and employment opportunities. Approximately 50 new cases of epilepsy are diagnosed per 100,000 people each year. About 75% of these cases begin in childhood, highlighting the increased vulnerability of the developing brain to seizures. Clinical signs of epilepsy may include loss of awareness, abnormal movements, changes in sensation (such as vision, hearing, and taste), mood or cognitive disturbances, bruising, and, in severe cases, the risk of mortality¹.

Due to the incomplete understanding of the underlying mechanisms of the illness, a wide range of medications is available for treating epilepsy. This has led to the development of various pharmaceutical agents to address the condition. Brain areas specialized for learning and memory, particularly the neocortical regions and the hippocampus, are comparatively more prone to seizures. These seizures occur when there is a sudden imbalance between excitation and inhibition in the network of neurons. The process begins when neurons display heightened, coordinated, and sustained activity, increasing neuronal excitability.

Epilepsy can arise from a variety of causes. They are perpetuated through positive reinforcement, where an initial imbalance between neural inhibition and excitation leads to further imbalances. The process by which a normal brain undergoes changes that lead to the development of epilepsy is known as epileptogenesis. This process is influenced by several factors, including oxidative stress, neurochemical changes in the brain due to neurotransmitters and ion channels, fluctuations in ion concentrations, variations in cell surface receptors, and inflammation. Key targets in epileptogenesis include the mammalian target of rapamycin (mTOR), P-glycoprotein (P-gp), and mutations in voltage-gated ion channels, such as hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and Kv7 channels (also known as M-channels), as well as the Na-K-2Cl cotransporter isoform 1 (NKCC1)².

Epileptogenesis is closely associated with high levels of inflammation in both acute and chronic neural tissue. The central nervous system may initiate this inflammatory response, which can damage the blood-brain barrier (BBB). This inflammation can spread from the central nervous system into systemic circulation, and acute neuroinflammation may exacerbate existing chronic neuroinflammation.

Microglia, astrocytes, glial cells, and essential central nervous system components produce pro-inflammatory cytokines in epileptic tissue. During the development of epilepsy, these glial cells regulate inflammatory and immune responses, leading to a rapid inflammatory reaction during seizures triggered by either chemical or electrical stimulation. Within the first 30 minutes of an epileptic seizure, activated astrocytes and microglia release elevated levels of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α. This response initiates an inflammatory cascade that involves neurons and the endothelial cells of the BBB, ultimately activating the acquired immune system. This cascade includes the activation of several factors, such as NF-κB, COX-2, chemokines, and acute-phase proteins. These cytokines can increase susceptibility to epileptic seizure triggers, contributing to elevated levels of IL-1β resulting from seizures. Moreover, the activation of this signaling cascade can aggravate the severity of epileptic seizures³.

A comprehensive understanding of the signaling pathways involved in both the acute and long-term responses to seizures is essential for uncovering the origins of epileptic behaviors. This knowledge can ultimately help identify novel therapeutic targets for curing epilepsy. Our epilepsy pathway poster illustrates the diverse and complex processes associated with this neurological disorder that affects many individuals worldwide.

References

1. Sumadewi, K. T., Harkitasari, S. & Tjandra, D. C. Biomolecular mechanisms of epileptic seizures and epilepsy: a review.  Acta Epileptologica   5, 28 (2023).

2. Staley, K. Molecular mechanisms of epilepsy.  Nat. Neurosci.   18, 367–372 (2015).

3. Wei, F. et al. Ion channel genes and epilepsy: functional alteration, pathogenic potential, and mechanism of epilepsy.  Neurosci. Bull.   33, 455–477 (2017).