Novel Targets for Developing Antiseizure and, Potentially, Antiepileptogenic Drugs

Abstract

Epilepsy is a devastating neurological disorder affecting nearly 65 million people worldwide. The etiology of epilepsy is heterogeneous in nature and a variety of factors-such as infection, stroke, traumatic brain injury, brain tumors, cerebral ischemia, and importantly, mutations in genes that are crucial for the development, migration, and function of neurons and glia-may cause seizures and lead to the development of epilepsy. Over 25 drugs are clinically available for the symptomatic treatment of the seizures that are the defining criteria of epilepsy. However, most of these drugs tend to optimize the balance between excitatory and inhibitory neurotransmission by modulating the functions of ion channels, receptors, enzymes, and transporters expressed by neurons (1). Importantly, around one-third of epilepsy patients are still pharmacoresistant, and many patients who respond to antiseizure drugs (ASDs) often present with significant adverse effects (2). In addition, people with epilepsy also suffer from co-morbidities such as anxiety, depression, and cognitive impairment. Many ASDs either do not address or, in some instances, aggravate these co-morbidities. Therefore, future ASD development efforts should 1) include novel mechanisms of action for ASDs, 2) evaluate potential therapeutic targets for disease modification, and 3) identify potential therapeutic interventions for the prevention of epilepsy. There are several promising targets for developing novel drugs that might prevent or impede epileptogenesis. Some of these novel targets are discussed in this brief review. Transforming Growth Factor β (TGFβ)Sustained damage to the blood brain barrier (BBB) is associated with increased incidence of seizures (3). Animal studies show that the activation of the TGFβ signaling pathway, mainly in astrocytes by albumin extravasated into brain parenchyma following BBB injury, disrupts regulatory functions of astrocytes and causes hyperexcitability in cortical and limbic structures (4). Direct activation of the TGFβ signaling pathway by TGFβ1 also causes epileptiform activity in rats, whereas TGFβ receptor blockers ameliorate TGFβ1-or albumin-induced epileptiform activity (5). Mice overexpressing TGFβ1 specifically in astrocytes develop seizures (6). It was recently found that losartan, which inhibits TGFβ1 signaling, decreased the number of rats developing albumin-induced chronic spontaneous seizures and inhibited epileptogenesis in this vascular injury-induced model of epilepsy (7). It is evident from these animal studies that inhibition of the TGFβ signaling pathway might be an effective strategy to inhibit seizures and epilepto-

Suppressing pro-inflammatory prostaglandin signaling attenuates excitotoxicity-associated neuronal inflammation and injury

“…6). We chose the expression of IL-1β, IL-6 and TNF-α as a surrogate for neuroinflammation because these three prototypical inflammatory cytokines are the most widely studied cytokines in animal seizure models and human epilepsy patients, owing to their contributions to inflammation within the brain and epileptogenesis (Wilcox and Vezzani, 2014;Vezzani and Viviani, 2015;Patel et al, 2017). Though an increase in the mRNA levels of cytokines does not necessarily always lead to an increase in their protein levels, these positive correlations insinuate that the neuroprotection from inhibiting EP2 receptor activation is strongly associated with the anti-inflammatory action of the antagonist.…”

How to Find Candidate Drug-targets for Antiepileptogenic Therapy?

“…These findings provide us a number of interesting sites for antiepileptogenic drugs (AEGDs). AEGDs have been evidenced as roles of postponing or completely blocking the development of epilepsy in experimental models [ 21 , 22 ]. The present review will focus on the current understanding of the proposed preventive strategy for epilepsy, so as to address some potential candidate drug-targets for lowering or inhibiting the development of epilepsy.…”

Proceedings of the Epilepsy Foundation's 2017 Cannabinoids in Epilepsy Therapy Workshop

“…A possible explanation of this difference is that the therapeutic response of CBD could be due to its action at distinct targets depending on the model. This work further emphasizes the need for a better understanding of CBD’s effects on its several molecular target candidates in each epileptic conditions, as well as if and how its therapeutic effect is affected when used in combination with additional ASDs and other drug therapies, as recently reviewed [33].…”