Candidate drug targets for prevention or modification of epilepsy

Abstract

Epilepsy is a prevalent neurological disorder afflicting nearly 50 million people worldwide. The disorder is characterized clinically by recurrent spontaneous seizures attributed to abnormal synchrony of brain neurons. Despite advances in the treatment of epilepsy, nearly one-third of patients are resistant to current therapies, and the underlying mechanisms whereby a healthy brain becomes epileptic remain unresolved. Therefore, researchers have a major impetus to identify and exploit new drug targets. Here we distinguish between epileptic effectors, or proteins that set the seizure threshold, and epileptogenic mediators, which control the expression or functional state of the effector proteins. Under this framework, we then discuss attempts to regulate the mediators to control epilepsy. Further insights into the complex processes that render the brain susceptible to seizures and the identification of novel mediators of these processes will lead the way to the development of drugs to modify disease outcome and, potentially, to prevent epileptogenesis.

Keywords: anticonvulsant; cytokines; disease modification; epileptogenesis; neuroinflammation; neuroprotection.

Figure 1

Potential epileptogenic mechanisms and epileptic mediators. ① A defective blood-brain barrier (BBB) allows serum albumin to enter the brain. ② Albumin binds to astrocyte transforming growth factor-β (TGF-β) receptors, resulting in downregulation of the potassium channel Kir4.1. ③ Decreased expression of glutamic acid (Glu) transporters, EAAT-1 and -2, occurs in brain tissue after seizures. These events cause neuronal hyperexcitability through loss of K⁺ buffering and Glu trafficking. ④ Seizure-induced inflammation can be propagated by cytokine production by astrocytes and microglia. Elevated levels of inflammatory cytokines as well as brain-derived neurotrophic factor (BDNF) can also sustain neuronal hyperactivity. ⑤ Inhibiting inflammatory pathways with E prostanoid 2 (EP2) antagonists results in reduced cytokine levels, delayed mortality, rescue of BBB dysfunction, and less neuronal injury after status epilepticus. ⑥ Astrocytic adenosine kinase is the main route for degradation of adenosine, a neuron-derived anticonvulsant. Inhibition of adenosine kinase–mediated degradation of adenosine or mammalian target of rapamycin (mTOR) inhibition with rapamycin ⑦ represents two disease-modifying strategies. ⑧ Seizure-induced elevated expression of endothelial P-glycoprotein can limit effective therapy by increasing efflux of drugs out of the brain. Other abbreviations: A1R, adenosine A1 receptor; EAAT, excitatory amino acid transporter; IL-1, interleukin-1; IL-1R, interleukin-1 receptor; TNFα, tumor necrosis factor-α; TrkB, neurotrophic tyrosine kinase receptor, type 2.