Inhibition of long-term potentiation by valproic acid through modulation of cyclic AMP
Inhibition of long-term potentiation by valproic acid through modulation of cyclic AMP
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DOI：
10.1111/j.1528-1167.2009.02412.x
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发表时间：
2010-08-01
期刊：
影响因子：
5.6
通讯作者：
Walker, Matthew C.
中科院分区：
文献类型：
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作者：
Chang, Pishan;Chandler, Kate E.;Walker, Matthew C.
目的：丙戊酸（Valproic acid，VPA）在临床上广泛用于癫痫、双相情感障碍、偏头痛等.在实验模型中，它也被证明具有神经保护和抗癫痫作用。然而，其在这些不同条件下的作用机制尚不清楚，但有一些证据表明VPA对蛋白激酶A（PKA）活性的影响。因此，我们问VPA是否调节环磷酸腺苷（cAMP）/PKA依赖的突触可塑性和这种模式的行动是否可以解释其anticonvulsant effect.Methods：我们首先测试VPA对PKA依赖的突触可塑性在苔藓纤维CA 3突触在大鼠海马切片非常高的频率刺激或应用的腺苷酸环化酶激活剂毛喉素的影响。使用生化测定，我们然后测试VPA是否对PKA活性有直接影响或通过调节cAMP产生的间接影响。最后，VPA和腺苷酸环化酶（SQ 22536）和PKA（H89）的抑制剂进行了测试，在体外模型中的癫痫样活动诱导的campal-entorhinal皮质切片使用戊四氮（2 mM）或低magnesium.Results：VPA（1 mm）抑制PKA依赖的长时程增强苔藓纤维CA 3锥体细胞的传输。然而，VPA不直接调节PKA活性，而是抑制cAMP的积累。在急性体外癫痫发作模型中，VPA的抗惊厥活性不是通过调节腺苷酸环化酶或PKA.Conclusions介导的：这些结果表明，VPA通过对cAMP积累的作用可以抑制突触可塑性，但这不能完全解释其抗惊厥作用。
P>Purpose:Valproic acid (VPA) is widely used clinically in epilepsy, bipolar disorder, and migraine. In experimental models, it has also been shown to have neuroprotective and antiepileptogenic effects. Its mechanisms of action in these diverse conditions are, however, unclear, but there is some evidence indicating an effect of VPA upon protein kinase A (PKA) activity. We, therefore, asked whether VPA modulates cyclic adenosine monophosphate (cAMP)/PKA-dependent synaptic plasticity and whether this mode of action could explain its anticonvulsant effect.Methods:We first tested the effects of VPA on PKA-dependent synaptic plasticity at mossy fiber to CA3 synapses in rat hippocampus slices following very high-frequency stimulation or application of the adenylyl cyclase activator forskolin. Using biochemical assays, we then tested whether VPA had a direct effect on PKA activity or an indirect effect through modulating cAMP production. Lastly, VPA and inhibitors of adenylyl cyclase (SQ22536) and PKA (H89) were tested in in vitro models of epileptiform activity induced in hippocampal-entorhinal cortex slices using either pentylenetetrazol (2 mM) or low magnesium.Results:VPA (1 mm) inhibited PKA-dependent long-term potentiation of mossy fiber to CA3 pyramidal cell transmission. However, VPA did not directly modulate PKA activity but rather inhibited the accumulation of cAMP. In acute in vitro seizure models, the anticonvulsant activity of VPA is not mediated through modulation of adenylyl cyclase or PKA.Conclusions:These results indicate that VPA through an action on cAMP accumulation can inhibit synaptic plasticity, but this cannot fully explain its anticonvulsant effect.