Abstract
Epilepsy and spreading depolarization (SD) are both episodic brain disorders and often exist together in the same individual. In CA1 pyramidal neurons of mouse hippocampal slices, induction of SD evoked epileptiform activities, including the ictal-like bursts, which occurred during the repolarizing phase of SD, and the subsequent generation of paroxysmal depolarization shifts (PDSs), which are characterized by mild depolarization plateau with overriding spikes. The duration of the ictal-like activity was correlated with both the recovery time and the depolarization potential of SD, whereas the parameters of PDSs were not significantly correlated with the parameters of SD. Moreover, we systematically evaluated the effects of multiple anti-epileptic drugs (AEDs) on SD-induced epileptiform activity. Among the drugs that are known to inhibit voltage-gated sodium channels, carbamazepine, phenytoin, valproate, lamotrigine, and zonisamide reduced the frequency of PDSs and the overriding firing bursts in 20–25 min after the induction of SD. The GABA uptake inhibitor tiagabine exhibited moderate effects and partially limited the incidence of PDSs after SD. AEDs including gabapentin, levetiracetam, ethosuximide, felbamate, and vigabatrin, had no significant effect on SD-induced epileptic activity. Taken together, these results demonstrate the effects of AEDs on SD and the related epileptiform activity at the cellular level.
Highlights
Spreading depolarization (SD, called spreading depression) is a pathophysiological phenomenon that occurs under many neurological conditions, such as traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage, intracerebral hemorrhage, and malignant cerebral infarction[1,2]
Previous studies have shown that spreading depolarization (SD) could evoke long-lasting epileptiform activity in partially disinhibited slices, that is, using 1.25 μM bicuculline to partially block GABAA receptors[8]
After the membrane potentials recovered to baseline, another form of epileptiform activity that was characterized by paroxysmal depolarization shifts (PDSs) developed from a pattern of broadened action potentials (Fig. 1A3)
Summary
Spreading depolarization (SD, called spreading depression) is a pathophysiological phenomenon that occurs under many neurological conditions, such as traumatic brain injury (TBI), aneurysmal subarachnoid hemorrhage (aSAH), intracerebral hemorrhage, and malignant cerebral infarction[1,2]. SD is characterized by profound depolarization of neurons and glia, which is accompanied by massive ion exchange across plasma membranes of the affected cells[3,4] These electrical and ionic changes cause a disturbance in cell metabolism and might lead to cell death in metabolically compromised brain tissue[5]. After the membrane potential recovers from the depolarization resulting from the SD, the neuronal activity transforms into epileptic discharge patterns that are characterized by paroxysmal depolarization shifts (PDSs)[8]. AEDs are effective by different mechanisms of action, including modulation of voltage-gated Na+ channels (VGSCs) and/or voltage-gated Ca2+ channels (VGCCs), enhancement of inhibitory synaptic transmission, or inhibition of excitatory neurotransmission[12,13]. Activation of VGSCs is crucial for the generation of high-frequency repetitive discharges and PDSs, which are responsible for the generation of the ictal and interictal states of the seizure[14]. The effects of a range of existing AEDs, including carbamazepine, phenytoin, valproate, lamotrigine, zonisamide, felbamate, gabapentin, levetiracetam, ethosuximide, tiagabine and vigabatrin, were tested on the PDSs following SD induction in hippocampal CA1 pyramidal neurons of mouse brain slices
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