AMPA Receptor antagonist NBQX attenuates later-life epileptic seizures and autistic-like social deficits following neonatal seizures

作者：Lippman Bell Jocelyn J; Rakhade Sanjay N; Klein Peter M; Obeid Makram; Jackson Michele C; Joseph Annelise; Jensen Frances E^*

来源：Epilepsia, 2013, 54(11): 1922-1932.

DOI：10.1111/epi.12378

• Hypoxic
• ischemic encephalopathy
• Epileptogenesis
• Autistic-like behavior
• AMPA receptor antagonists
• Early life seizures

PurposeTo determine whether AMPA receptor (AMPAR) antagonist NBQX can prevent early mammalian target of rapamycin (mTOR) pathway activation and long-term sequelae following neonatal seizures in rats, including later-life spontaneous recurrent seizures, CA3 mossy fiber sprouting, and autistic-like social deficits.
MethodsLong-Evans rats experienced hypoxia-induced neonatal seizures (HS) at postnatal day (P)10. NBQX (20mg/kg) was administered immediately following HS (every 12hx4 doses). Twelve hours post-HS, we assessed mTOR activation marker phosphorylated p70-S6 kinase (p-p70S6K) in hippocampus and cortex of vehicle (HS+V) or NBQX-treated post-HS rats (HS+N) versus littermate controls (C+V). Spontaneous seizure activity was compared between groups by epidural cortical electroencephalography (EEG) at P70-100. Aberrant mossy fiber sprouting was measured using Timm staining. Finally, we assessed behavior between P30 and P38.
Key FindingsPostseizure NBQX treatment significantly attenuated seizure-induced increases in p-p70S6K in the hippocampus (p<0.01) and cortex (p<0.001). Although spontaneous recurrent seizures increased in adulthood in HS+V rats compared to controls (3.221seizures/h; p=0.03), NBQX significantly attenuated later-life seizures (0.14 +/- 0.1seizures/h; p=0.046). HS+N rats showed less aberrant mossy fiber sprouting (115 +/- 8.0%) than vehicle-treated post-HS rats (174 +/- 10%, p=0.004), compared to controls (normalized to 100%). Finally, NBQX treatment prevented alterations in later-life social behavior; post-HS rats showed significantly decreased preference for a novel over a familiar rat (71.0 +/- 12s) compared to controls (99.0 +/- 15.6s; p<0.01), whereas HS+N rats showed social novelty preference similar to controls (114.3 +/- 14.1s).
SignificanceBrief NBQX administration during the 48h postseizure in P10 Long-Evans rats suppresses transient mTOR pathway activation and attenuates spontaneous recurrent seizures, social preference deficits, and mossy fiber sprouting observed in vehicle-treated adult rats after early life seizures. These results suggest that acute AMPAR antagonist treatment during the latent period immediately following neonatal HS can modify seizure-induced activation of mTOR, reduce the frequency of later-life seizures, and protect against CA3 mossy fiber sprouting and autistic-like social deficits.

• 出版日期2013-11