Neurodegenerative pathways as targets for acquired epilepsy therapy development

Abstract

There is a growing body of clinical and experimental evidence that neurodegenerative diseases and epileptogenesis after an acquired brain insult may share common etiological mechanisms. Acquired epilepsy commonly develops as a comorbid condition in patients with neurodegenerative diseases such as Alzheimer's disease, although it is likely much under diagnosed in practice. Progressive neurodegeneration has also been described after traumatic brain injury, stroke, and other forms of brain insults. Moreover, recent evidence has shown that acquired epilepsy is often a progressive disorder that is associated with the development of drug resistance, cognitive decline, and worsening of other neuropsychiatric comorbidities. Therefore, new pharmacological therapies that target neurobiological pathways that underpin neurodegenerative diseases have potential to have both an anti-epileptogenic and diseasemodifying effect on the seizures in patients with acquired epilepsy, and also mitigate the progressive neurocognitive and neuropsychiatric comorbidities. Here, we review the neurodegenerative pathways that are plausible targets for the development of novel therapies that could prevent the development or modify the progression of acquired epilepsy, and the supporting published experimental and clinical evidence. K E Y W O R D SAMPA, amyloid-β, glutamate, mTOR, neuroinflammation, tau

Revisiting the Impact of Neurodegenerative Proteins in Epilepsy: Focus on Alpha-Synuclein, Beta-Amyloid, and Tau

“…Neuroinflammation and excitotoxicity can result in neuronal loss [21], ultimately leading to changes in the hippocampal networks that account for epileptogenesis [22], further suggesting that the manipulation of neurodegenerative phenomena by inhibition of inflammation and excitotoxicity may limit the disruption of the hippocampal circuitry and the progression of epileptic seizures [23]. Moreover, there is evidence that neurodegenerative diseases and epileptogenesis after an acquired brain insult might share a common underlying mechanism [24].…”

“…It is worth mentioning here that neurodegeneration might not directly lead to epileptogenesis, but neurodegeneration might prompt other processes to initiate epileptogenesis [125,126]. Moreover, the precise association between neurodegeneration and epileptic seizures is not fully understood [24]. However, it could be possible that the neurodegeneration detected in patients and in experimental models with acquired epilepsy is the consequence of an injury or a secondary effect of repeated epileptic seizures [127,128].…”

Behavioral Deficits in Mice with Postnatal Disruption ofNdel1in Forebrain Excitatory Neurons: Implications for Epilepsy and Neuropsychiatric Disorders

“…In the context of epilepsy, Tau hyperphosphorylation was reported in mice with chronic epilepsy ( Alves et al. 2019 ) as well as in brain samples from drug resistant chronic TLE patients (see review, Casillas-Espinosa et al. 2020 ).…”

Neuroelectric Mechanisms of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage

“…The affinity of AMPA receptors for glutamates is relatively low, and the number of glutamate molecules bound to AMPA receptors determines the open probability; in contrast, NMDA receptors have a higher affinity for glutamates and desensitize slower than AMPA receptors, but the slow binding rate puts a considerable limit on the opening probability of NMDA receptors during the short-lived glutamate peak [ 21 ]. This neurotransmitter system not only drives physiological excitatory signal transmission as well as abnormal hyperexcitable circuitry during a seizure but also may initiate neurodegenerative processes by excessive calcium uptake and pushing cells toward apoptotic cell death [ 22 ].…”