Dl-3n-butylphthalide reduces epileptiform activity through GluA2-lacking calcium-permeable AMPARs in epilepsy models.

Qin Yang,Fang-Shuo Zheng,Yi-Da Hu,Xue-Feng Wang

doi:10.18632/oncotarget.21529

Qin Yang, Fang-Shuo Zheng + Show 2 more

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https://doi.org/10.18632/oncotarget.21529

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Abstract

Epilepsy is the most prevalent chronic neurological disorder, and its pathological mechanism indicates that an imbalance between excitatory and inhibitory neurotransmission leads to neuronal hyperexcitability. Previous studies have suggested that dl-3n-butylphthalide (NBP) regulates the excitatory neurotransmitter glutamate in the brains of epileptic mice, however, the mechanisms are unknown. We investigated behavioral and electrophysiological factors in rats using NBP. In an in vivo pentylenetetrazole (PTZ)-induced epileptic seizure animal model, NBP decreased the generalized tonic-clonic seizure (GTCS) severity. In an acute hippocampal slice 4-aminopyridine (4-AP) epilepsy model in vitro, NBP decreased the epileptiform activity and miniature excitatory postsynaptic current (mEPSC) amplitude; there was no change in the miniature inhibitory postsynaptic current (mIPSC) amplitude or frequency. This effect suggested changes in excitatory synaptic transmission, which was altered through postsynaptic GluA2-lacking calcium-permeable AMPA receptors (CP-AMPARs). These findings showed that NBP suppressed epileptiform activity in these epilepsy models and provided the first detailed electrophysiological analysis of the impact of NBP in epilepsy models, which may be employed in future experimental or clinical therapies for patients with epilepsy.

Highlights

The carbonyl compound 3n-butylphthalide is one of the chemical constituents of celery essential oil, along with sedanolide, which is obtained from celery leaves and stalks and is primarily responsible for the aroma and taste of celery [1]
In an acute hippocampal slice 4-aminopyridine (4-AP) epilepsy model in vitro, NBP decreased the epileptiform activity and miniature excitatory postsynaptic current amplitude; there was no change in the miniature inhibitory postsynaptic current amplitude or frequency
Using a pentylenetetrazole (PTZ)-induced epileptic seizure animal model in vivo and electrophysiological techniques in in vitro 4-aminopyridine (4-AP; 100 μM) acute hippocampal slice epilepsy models, we revealed that NBP decreased neuronal hyperexcitability through postsynaptic GluA2-lacking calcium-permeable AMPA receptors (CP-AMPARs)

Summary

Introduction

The carbonyl compound 3n-butylphthalide (butylphthalide) is one of the chemical constituents of celery essential oil, along with sedanolide, which is obtained from celery leaves and stalks and is primarily responsible for the aroma and taste of celery [1]. Previous studies have suggested that 3n-butylphthalide may be useful for the effective treatment of hypertension [2, 3] and cerebral ischemia, the alleviation of oxidative stress caused by chronic cerebral ischemia, the improvement of cholinergic function, and the inhibition of amyloid beta accumulation, thereby improving cerebral neuronal injury and cognitive deficits and significantly inhibiting platelet aggregation [4,5,6]. This compound possesses antithrombotic and anti-inflammatory effects and reduces neural apoptosis [7, 8]. Using a pentylenetetrazole (PTZ)-induced epileptic seizure animal model in vivo and electrophysiological techniques in in vitro 4-aminopyridine (4-AP; 100 μM) acute hippocampal slice epilepsy models, we revealed that NBP decreased neuronal hyperexcitability through postsynaptic GluA2-lacking calcium-permeable AMPA receptors (CP-AMPARs)

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