Abstract
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are the predominant mediators of glutamate-induced excitatory neurotransmission. It is widely accepted that AMPA receptors are critical for the generation and spread of epileptic seizure activity. Dysfunction of AMPA receptors as a causal factor in patients with intractable epilepsy results in neurotransmission failure. Brain-specific serine/threonine-protein kinase 1 (SAD-B), a serine-threonine kinase specifically expressed in the brain, has been shown to regulate AMPA receptor-mediated neurotransmission through a presynaptic mechanism. In cultured rat hippocampal neurons, the overexpression of SAD-B significantly increases the frequency of miniature excitatory postsynaptic currents (mEPSCs). Here, we showed that SAD-B downregulation exerted antiepileptic activity by regulating AMPA receptors in patients with temporal lobe epilepsy (TLE) and in the pentylenetetrazol (PTZ)-induced epileptic model. We first used immunoblotting and immunohistochemistry analysis to demonstrate that SAD-B expression was increased in the epileptic rat brain. Subsequently, to explore the function of SAD-B in epilepsy, we used siRNA to knock down SAD-B protein and observed behavior after PTZ-induced seizures. We found that SAD-B downregulation attenuated seizure severity and susceptibility in the PTZ-induced epileptic model. Furthermore, we showed that the antiepileptic effect of SAD-B downregulation on PTZ-induced seizure was abolished by CNQX (an AMPA receptor inhibitor), suggesting that SAD-B modulated epileptic seizure by regulating AMPA receptors in the brain. Taken together, these findings suggest that SAD-B may be a potential and novel therapeutic target to limit epileptic seizures.
Highlights
Epilepsy is a common chronic neurological disease characterized by recurrent spontaneous seizures
We found that the effect of SAD-B downregulation on PTZ-induced seizure was abolished by CNQX [9], suggesting that the antiepileptic effect of SAD-B downregulation on PTZ-induced seizure was mediated by Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors
SAD-B expression was increased in the epileptic brain To examine whether SAD-B is involved in epileptic seizure, we examined SAD-B expression in the patients with Temporal lobe epilepsy (TLE)
Summary
Epilepsy is a common chronic neurological disease characterized by recurrent spontaneous seizures. It is refractory to current therapies in approximately 30% of patients and is associated with pathologic cortical excitability [1]. Temporal lobe epilepsy (TLE), the most prevalent form of refractory epilepsy, representing more than 40% of cases, is intractable [2] and results in serious cognitive impairment, sudden unexpected death in epilepsy (SUDEP), vascular disease, pneumonia, etc. In terms of the pathogenesis of epilepsy, it is widely accepted that an imbalance in neuronal excitation and inhibition results in neurotransmission failure as a causal factor in patients with TLE. A-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, located at the postsynaptic membrane of excitatory synapses, are the predominant mediators of glutamate-induced excitatory neurotransmission in the neural system [4]. Dysfunction of AMPA receptors as one of the most important factors in patients with epilepsy has been extensively reviewed [5]. There has been considerable interest in developing therapeutic strategies aimed at AMPA receptors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
