The FAAH inhibitor URB597 suppresses hippocampal maximal dentate afterdischarges and restores seizure-induced impairment of short and long-term synaptic plasticity.
The FAAH inhibitor URB597 suppresses hippocampal maximal dentate afterdischarges and restores seizure-induced impairment of short and long-term synaptic plasticity.
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DOI：
10.1038/s41598-017-11606-1
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发表时间：
2017-09-11
影响因子：
4.6
通讯作者：
Di Giovanni G
中科院分区：
文献类型：
--
作者：
Colangeli R;Pierucci M;Benigno A;Campiani G;Butini S;Di Giovanni G
合成大麻素和植物大麻素已在人类和实验性癫痫模型中显示出抑制癫痫发作的作用。然而，它们通常对记忆和与记忆相关的过程有不利影响。本研究比较了内源性大麻素（eCB）降解抑制与合成CB激动剂对最大齿状激活（MDA）急性点燃引起的边缘癫痫发作的影响。此外，我们还研究了naïve和mda点燃麻醉大鼠齿状回（DG）颗粒细胞的反应性和突触可塑性。我们发现脂肪酸酰胺水解酶（FAAH）抑制剂URB597和合成大麻素激动剂WIN55,212-2都具有am251敏感的抗癫痫作用。WIN55,212-2，剂量依赖性（0.5-2 mg/kg, i.p.）损害naïve大鼠穿孔通路- dg突触的短期可塑性（STP）和长期增强（LTP）。引人注目的是，在正常情况下，URB597 （1 mg/kg, i.p.）没有任何有害影响，而它可以防止癫痫引起的STP和LTP的改变。我们的证据表明，提高eCB的音调，而不是一般的CB1激活，可能代表了一种潜在的策略，可以开发一种新型药物，用于治疗癫痫发作和与癫痫相关的共病性记忆障碍。
Synthetic cannabinoids and phytocannabinoids have been shown to suppress seizures both in humans and experimental models of epilepsy. However, they generally have a detrimental effect on memory and memory-related processes. Here we compared the effect of the inhibition of the endocannabinoid (eCB) degradation versus synthetic CB agonist on limbic seizures induced by maximal dentate activation (MDA) acute kindling. Moreover, we investigated the dentate gyrus (DG) granule cell reactivity and synaptic plasticity in naïve and in MDA-kindled anaesthetised rats. We found that both the fatty acid amide hydrolase (FAAH) inhibitor URB597 and the synthetic cannabinoid agonist WIN55,212-2 displayed AM251-sensitive anti-seizure effects. WIN55,212-2, dose-dependently (0.5–2 mg/kg, i.p.) impaired short-term plasticity (STP) and long-term potentiation (LTP) at perforant path-DG synapses in naïve rats. Strikingly, URB597 (1 mg/kg, i.p.) was devoid of any deleterious effects in normal conditions, while it prevented seizure-induced alterations of both STP and LTP. Our evidence indicates that boosting the eCB tone rather than general CB1 activation might represent a potential strategy for the development of a new class of drugs for treatment of both seizures and comorbid memory impairments associated with epilepsy.
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影响因子：
25
作者：
Carlson, G;Wang, Y;Alger, BE
通讯作者：
Alger, BE
影响因子：
25
作者：
Chavez, Andres E.;Chiu, Chiayu Q.;Castillo, Pablo E.
通讯作者：
Castillo, Pablo E.
影响因子：
4.6
作者：
Marino Gammazza A;Colangeli R;Orban G;Pierucci M;Di Gennaro G;Lo Bello M;D'Aniello A;Bucchieri F;Pomara C;Valentino M;Muscat R;Benigno A;Zummo G;de Macario EC;Cappello F;Di Giovanni G;Macario AJ
通讯作者：
Macario AJ
影响因子：
38.1
作者：
Bell, Brian;Lin, Jack J.;Seidenberg, Michael;Hermann, Bruce
通讯作者：
Hermann, Bruce
影响因子：
3.7
作者：
Bhaskaran MD;Smith BN
通讯作者：
Smith BN