Abstract
Epilepsy is a serious brain disorder with diverse seizure types and epileptic syndromes. AMPA receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzoquinoxaline-2,3-dione (NBQX) attenuates spontaneous recurrent seizures in rats. However, the anti-epileptic effect of NBQX in chronic epilepsy model is poorly understood. Perineuronal nets (PNNs), specialized extracellular matrix structures, surround parvalbumin-positive inhibitory interneurons, and play a critical role in neuronal cell development and synaptic plasticity. Here, we focused on the potential involvement of PNNs in the treatment of epilepsy by NBQX. Rats were intraperitoneally (i.p.) injected with pentylenetetrazole (PTZ, 50 mg/kg) for 28 consecutive days to establish chronic epilepsy models. Subsequently, NBQX (20 mg/kg, i.p.) was injected for 3 days for the observation of behavioral measurements of epilepsy. The Wisteria floribundi agglutinin (WFA)-labeled PNNs were measured by immunohistochemical staining to evaluate the PNNs. The levels of three components of PNNs such as tenascin-R, aggrecan and neurocan were assayed by Western blot assay. The results showed that there are reduction of PNNs and decrease of tenascin-R, aggrecan and neurocan in the medial prefrontal cortex (mPFC) in the rats injected with PTZ. However, NBQX treatment normalized PNNs, tenascin-R, aggrecan and neurocan levels. NBQX was sufficient to decrease seizures through increasing the latency to seizures, decrease the duration of seizure onset, and reduce the scores for the severity of seizures. Furthermore, the degradation of mPFC PNNs by chondroitinase ABC (ChABC) exacerbated seizures in PTZ-treated rats. Finally, the anti-epileptic effect of NBQX was reversed by pretreatment with ChABC into mPFC. These findings revealed that PNNs degradation in mPFC is involved in the pathophysiology of epilepsy and enhancement of PNNs may be effective for the treatment of epilepsy.
Highlights
Epilepsy is a serious life-shortening neurological disorder, which affects approximately 1% of general population [1] and leads to an increase of disability and mortality in the world [2]
Two-way analysis of variance (ANOVA) showed significant effects of PTZ (F1,28 = 66.7, p < 0.001) and chondroitinase ABC (ChABC) (F1,28 = 51.8, p < 0.001), and a PTZ × ChABC interaction (F1,28 = 5.6, p < 0.05) on the scores for the severity of seizures. These results revealed that degradation of Perineuronal nets (PNNs) in the medial prefrontal cortex (mPFC) exacerbated the epileptic seizure induced by PTZ, suggesting that the dysfunction of PNNs might be involved in the induction of epilepsy
Our results revealed that chronic epilepsy induced a reduction of components of PNNs, tenascin-R, aggrecan and neurocan in mPFC, while AMPA receptor antagonist NBQX increased the levels of these proteins, suggesting that PNNs might be essential for the functionality of synaptic transmission
Summary
Epilepsy is a serious life-shortening neurological disorder, which affects approximately 1% of general population [1] and leads to an increase of disability and mortality in the world [2]. Glutamate is a predominant neurotransmitter released from excitatory neurons related to the fast synaptic excitation [5]. AMPA receptors regulate the fast synaptic excitation in brain regions that are related to epilepsy [7]. AMPA receptor antagonists markedly reduce epileptiform and inhibit spread of epileptic discharges in both animal seizure models and human epilepsy [8,9]. Rodent models of epilepsy is used and it showed that perampanel, a potent, selective, orally active non-competitive AMPA receptor antagonist, exhibited a strong antiseizure activity in the maximal electroshock seizure test, and the 6 Hz seizure test [10,11]. NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzoquinoxaline-2,3-dione) is a competitive AMPA receptor antagonist and has a property that suppressed focal electrographic seizures in epileptic mice [9]. Noncompetitive AMPA antagonist perampanel improved the performance of partial seizures, suggesting a remarkable antiepileptogenic effect [16]
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