Page 59 - Read Online

Victor et al. Neuroimmunol Neuroinflammation 2020;7:234-47 I http://dx.doi.org/10.20517/2347-8659.2020.02 Page 237
[21]
[22]
most common type of epilepsy in adults , but can occur in epilepsy patients without TLE . Sprouting
occurs when granule cell axons in the inner molecular layer (mossy fibers) project into the hilus of the
dentate gyrus and CA3 region of the hippocampal formation, creating their own dendritic field. Mossy
[23]
fibers synapse onto hilar mossy cells, CA3 pyramidal cells, and interneurons to create de novo recurrent
excitatory circuits. Aberrant sprouting in a model of TLE was reported to contribute to excitatory feedback
[24]
loops of normal and ectopic granule cells . Another study described aberrant mossy fibers that drive
[25]
inhibitory basket cells to reduce neuronal excitability . Mossy fiber sprouting is increased through the
activation of several granule cell factors, such as neuromodulin and brain-derived neurotrophic factor
[26]
(BDNF) , and involves the secretion and deposition of molecules of the extracellular matrix that facilitate
aberrant growth [27-29] . The number of granule cells also affects mossy fiber sprouting. Hippocampal
neurogenesis, which leads to the formation of new granule cells, is increased shortly after an epileptic
seizure, but the increase is transient. The development of new granule cells, and their ectopic integration
into neuronal networks contribute to aberrant mossy fiber sprouting that is evident post-seizure.

Reactive gliosis has also been identified as a contributor to epileptogenesis in genetic and chemically-
[30]
induced animal models of epilepsy . Activated astrocytes and microglia exhibit changes that promote
network hyperexcitability [31,32] . Microglia can be activated by cytokines and monocytes circulating in
blood , neurotransmitters released by activated or damaged neurons, or by molecules migrating across
[33]
[31]
the blood brain barrier (BBB) . Disruption of the BBB during status epilepticus (SE) leads to the transport
of plasma proteins and immune cells into the brain. The combined effects on astrocytic functions, ion
concentration changes, entry of infiltrating systemic components, and potential pathogens into the CNS
may lead to neuronal dysfunction, neuroinflammation, and neurodegeneration . The BBB plays a pivotal
[34]
role in diseases associated with neuronal hyperexcitability such as epilepsy, TBI, and post-stroke seizure
activity [35-37] . Microglia-neuron signaling had been shown initially by the release of the neuronal chemokine
fractalkine, which activates the CXC-chemokine receptor 1 (CXCR1) on microglia. Neurogenesis, synaptic
plasticity, and neuronal survival have all been reported to be affected by the CXCR1 signaling pathway .
[31]
Cytokine release of IL-1β and tumor necrosis factor-α (TNF-α) and other signals (such as HMGB1 and
ATP) from activated astrocytes and microglia lead to hyperexcitability in neurons [38,39] . Precise targeting
of reactive astrocytes and microglia for therapeutic intervention during epilepsy and epileptogenesis
may be beneficial due to microglial involvement in the processes of neurogenesis, axonal sprouting, and
neuroinflammation.

Models of epilepsy
The pursuit of AEDs has provided > 30 medications, with many that were developed in the 1980s .
[40]
Although several animal models of epilepsy exist, clinically validated models, ones that are validated
to predict efficacy and tolerability, are limited and currently only consist of three models: the maximal
electroshock (MES) seizure protocol, subcutaneous pentylenetetrazol (scPTZ) acute seizure tests, and
[41]
the kindled rodent model of chronic hyperexcitability . Though not validated, multiple other animal
models have been developed that have contributed to the understanding of the premise of new therapeutic
options . Still, newer drugs continue to have similar adverse events or side effects without exhibiting
[42]
[43]
greater efficacy . Variation in seizure models can result in acute or chronic seizure paradigms, differences
[44]
in severity, or the intervening time until seizures start . Acute models lack persisting changes, like a
decrease in seizure threshold or spontaneous seizures. Chronic seizure models of epilepsy accommodate
[45]
a period during which epileptogenesis takes place and may better represent human epilepsy . Newer
[46]
models, such as the post-SE model, kindling , or genetic models, have become more extensively used due
to their ability to result in spontaneous seizures. The kindling model, where repeated electrical stimulation
leads to enhanced seizure susceptibility, is commonly utilized as it has been associated with seizure induced
plasticity and provides a way to study such plasticity. Combining SRS with convulsive behavior or video-
electroencephalogram (EEG) represents a more accurate epilepsy model, though it is not considered a
clinically validated model for AED discovery.