2.1 Inflammation
The process of inflammation involves a cascade of inflammatory mediators from tissues and cells present in the bloodstream, and in some situations can have several pathological consequences leading to cellular impairment or loss in tissues [11]. Studies show that inflammation plays an important role during the epileptogenic process, causing a reduction in seizure threshold, neurodegeneration, neurogenesis, synaptic plasticity, and dysregulation of blood–brain barrier (BBB) permeability [12].
Inflammation in the brain, also known as neuroinflammation, is common after traumatic brain injuries (TBI), infections in the central nervous system (CNS), cerebral vascular accident (CVA), and status epilepticus (SE) in humans and animals, having a dual function after injury, manifested through the action of different cell types by generating an immune/inflammatory response in specific CNS cells and BBB component cells [13].
According to [13], one of these common manifestations is the rapid activation of microglia, releasing several inflammatory molecules, including HMGB1, adenosine triphosphate (ATP), S100β (damage-associated molecular patterns); various cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor—α (TNF-α), interleukin-6 (IL-6); various chemokines and related effector pathways cyclooxygenase-2 (COX-2) / prostaglandin-2 (PGE2), and; complement factors, as pictured below (Fig. 1).
In addition to the release of these inflammatory molecules, after the activation of microglia, the production of inflammatory mediators and reactive oxygen species (ROS) will occur, contributing to tissue injury and neurotoxicity from mechanisms associated with cognitive impairments, such as oxidative stress and synapse remodeling. The increase of this oxidative stress in inflammation associated with mitochondrial dysfunction may affect cognitive function through hippocampal neurogenesis [14].
Similarly, a study shows that the induction of a seizure may cause a rapid activation of glial cells in the surrounding parenchyma, which accounts for the production and release of inflammatory molecules. These experimental models using models of SE suggest that the inflammatory response exhibits a distinct profile soon after induction, characterized by early activation of both astrocytes and microglia followed by BBB damage and neuronal activation [5].
For example, astrocytes promote tissue repair in the CNS by releasing insulin-like growth factors but are also involved in perpetuating inflammation by an overproduction of cytokines such as IL-6, as well as modulating BBB and neuronal function, producing excitability and seizures [5]. Furthermore, the mechanisms by which pro-inflammatory molecules can establish chronic neuronal network hyperexcitability involve rapid, non-transcriptional effects on glutamate and gamma-aminobutyric acid (GABA) receptors and transcriptional activation of genes involved in synaptic plasticity [15].
More and more studies evidence that inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and TNF-α, are related to the molecular mechanisms underlying learning, as well as memory consolidation, that is, studies suggest that the release of TNF-α and IL-1β induces synaptic pruning, leading to impaired neuroplasticity and various changes in the brain that may negatively impact cognition; IL-1 may affect neurogenesis and long-term potentiation (LTP); IL-6 may affect synaptic plasticity and neurogenesis; TNF-α may also affect LTP and synaptic scaling [14].
However, there is a need to better understand the difference between pathological responses, repair, and recovery, and to assess in detail the potential similarities between brain injuries, to produce drugs with broad therapeutic potential. As the term "inflammation" is very broad and may have some beneficial pathways after injury, a targeted intervention could succeed when global suppression has failed [13].
According to [16], studies suggest that the fundamental components of epileptogenesis after brain injury are inflammation and BBB breakdown: The positive regulation of inflammatory mediators leads to central and peripheral inflammation which disrupts BBB, thus facilitating the infiltration of leukocytes, generating neuronal hyperexcitability and further increasing the inflammatory mediators, leading to the emergence of morphological synaptic changes in the hippocampus and, as a consequence, the development of epilepsy.
2.2 Neurogenesis, neural reorganization, and aberrant sprouting
A series of epileptogenic changes occur in the hippocampus after an initial lesion, such as SE. These changes lead to hyperexcitability in the dentate gyrus (DG), as well as in the subfield CA1, which eventually evolves to a chronic epileptic state, typified by spontaneous recurrent motor seizures. After SE, DG neurogenesis is characterized by dramatic decreases in the production of new neurons and aberrant migration of newborn neurons to the dentate hilum and the molecular layer [17].
These changes can also lead to brain reorganization, which enlists neural networks previously not involved, or less involved, in a particular task, to compensate for directly injured or disconnected areas [18]. The usual reorganizations found in patients and animal models of SE epilepsy are cell loss, particularly of GABA interneurons, reactive synaptogenesis, and axonal budding of glutamatergic neurons [13]. Studies on molecular and organizational changes that occur after trauma reported that in animal models of neocortical trauma, hippocampal trauma, and human epileptogenic temporal lobes, neuronal circuits reorganize in response to injury and may become hyperexcitable. In the neocortical isolation (cortical recessionalization) model of post-traumatic epilepsy (PTE), pyramidal neurons from axotomized layer V sprouted new collateral axons over several weeks. This reactive emergence is associated with recurrent excitatory connectivity and in vitro epileptiform activity, which propagates throughout the cortical circuitry. Epileptiform activity and seizures in vivo were also developed after a latency in this model of PTE [19].
According to [20], little is known about the underlying pathological mechanisms in patients affected by post-ischemic epileptogenesis, resulting in the development of chronic seizures. However, the author highlights the hypothesis that persistent neuroinflammation and glial scar formation cause aberrant neuronal firing. According to [21], the glial scar works as a physical and chemical barrier against the regeneration of neurons and works as a dense isolation, creating an inhibitory environment that consequently limits optimal neural function and leads to deficits in the human body. However, the glial scar in neurological damage is responsible for the activation of resident astrocytes that surround the lesion nucleus, isolating intact neurons.
Studies indicate that morphological and functional changes also arise in the remaining neural tissue when no seizure is expressed in the latent period. Researchers believe that this period may provide a therapeutic window to modify the disease progression [22]. Studies have also suggested that aberrant sprouting of mossy fibers is a major cause of temporal lobe epilepsy (TLE). Although there is no consensus on this question, there is evidence to believe that it contributes to the frequency and intensity of spontaneous recurrent seizures (SRS) in TLE [7].
Although the manifestation of TLE in humans after SE can take months, years, or even decades, it is noticeable that multiple epileptogenic and neurogenic alterations contribute to the progression of SE-induced injuries into chronic epilepsy typified by SRS, impairments in learning, memory, and mood [7].
A study suggests that the alteration of adult neurogenesis is influenced by several factors, such as the severity of the initial epileptogenic insult, the age of the brain, and the stage of epileptogenesis. In addition, neurogenesis is expected to play a crucial role in epileptogenesis through various aspects such as proliferation, survival, migration and integration after brain injury; however, functional implications of neurogenesis have not yet been fully elucidated [23].
2.3 Neural plasticity
One of the multiple attributes of the CNS is its ability to restructure itself in response to physiological and pathological stimuli, through a process known as neuroplasticity, which is determined by cellular and molecular mechanisms that modify the structure, density, and functionality of synaptic connections. For example, after neuronal damage, various neuroplastic changes predispose the brain to develop spontaneous recurrent seizures, in the process of epileptogenesis [24].
According to [25], there are two widely recognized categories of activity-dependent plasticity, known as synaptic and non-synaptic. According to studies, synaptic plasticity, also called Hebbian plasticity, is related to the strength of synapses between neurons, while non-synaptic plasticity is involved in modifying neuronal excitability in the dendrites, axon, and soma of a single neuron.
Furthermore, synaptic plasticity is essential for normal brain functioning, such as in our ability to learn and to modify our behavior. However, long-term changes in synaptic efficacy are involved in network-dependent activities and can produce either facilitation or depression, depending on the parameters of repetition and stimulus. Long-term potentiation (LTP) of glutamatergic synapses, in neurons of the hippocampus, produce the strengthening of synaptic efficacy and can be induced by high-frequency stimulation or by coincidence, between the pre-and postsynaptic mechanism [26].
The long-term plasticity of glutamatergic and GABAergic transmission occurs in a combined manner, precisely adjusting the inhibitory–excitatory (I/E) balance [26]. The primary excitatory neurotransmitter in the mammalian CNS, known as glutamate (Glu), plays a critical role in the excitation/inhibition balance in the brain [27]. Its effects depend on the activation of several types of specific plasma membrane receptors (GluR), three of which are of the ionotropic type (iGluR), that are nominated by selective agonists and act as ligand-dependent sodium/calcium channels N-methyl D-Aspartate (NMDA); alpha-amino-3-hydroxy-5 methylI-isoxazolepropionate (AMPA); kainate and eight are of the metabotropic type metabotropic glutamate receptor (mGluR), which are G-protein dependent [24].
Diversely, the GABAergic neurotransmitter interacts with two types of receptors: an ionotropic, or gamma-aminobutyric acid ionotropic receptor family A (GABA-A), acting as a ligand-controlled chloride channel, and a metabotropic, or gamma-aminobutyric acid ionotropic receptor family B (GABA-B), which is G-protein dependent. Neuroplastic changes can affect neuron signalings mediated by these neurotransmitters, such as their transport, synthesis, or degradation, and consequently, decreased neuronal inhibition and enhanced excitation, resulting in a brain more susceptible to seizures and epileptogenesis [24].