Clinica Neurologica, Università degli Studi di Perugia, Ospedale S.Maria della Misericordia, Perugia, Italy.
Neurobiol Dis. 2011 Nov;44(2):185-91. doi: 10.1016/j.nbd.2011.06.015. Epub 2011 Jul 2.
Nitric oxide (NO) is an intercellular retrograde messenger involved in several physiological processes such as synaptic plasticity, hippocampal long-term potentiation (LTP), and learning and memory. Moreover NO signaling is implicated in the pathophysiology of brain ischemia. In this study, we have characterized the role of NO/cGMP signaling cascade in the induction and maintenance of post-ischemic LTP (iLTP) in rat brain slices. Moreover, we have investigated the possible inhibitory action of zonisamide (ZNS) on this pathological form of synaptic plasticity as well as the effects of this antiepileptic drug (AED) on physiological activity-dependent LTP. Finally, we have characterized the possible interaction between ZNS and the NO/cGMP/PKG-dependent pathway involved in iLTP. Here, we provided the first evidence that an oxygen and glucose deprivation episode can induce, in CA1 hippocampal slices, iLTP by modulation of the NO/cGMP/PKG pathway. Additionally, we found that while ZNS application did not affect short-term synaptic plasticity and LTP induced by high-frequency stimulation, it significantly reduced iLTP. This reduction was mimicked by bath application of NO synthase inhibitors and a soluble guanyl cyclase inhibitor. The effect of ZNS was prevented by either the application of a NO donor or drugs increasing intracellular levels of cGMP and activating PKG. These findings are in line with the possible use of AEDs, such as ZNS, as a possible neuroprotective strategy in brain ischemia. Moreover, these findings strongly suggest that NO/cGMP/PKG intracellular cascade might represent a physiological target for neuroprotection in pathological forms of synaptic plasticity such as hippocampal iLTP.
一氧化氮（NO）是一种细胞间逆行信使，参与多种生理过程，如突触可塑性、海马长时程增强（LTP）以及学习和记忆。此外，NO 信号转导与脑缺血的病理生理学有关。在这项研究中，我们研究了 NO/cGMP 信号级联在诱导和维持大鼠脑片缺血后 LTP（iLTP）中的作用。此外，我们还研究了佐尼沙胺（ZNS）对这种病理性突触可塑性的可能抑制作用以及这种抗癫痫药物（AED）对生理活动依赖性 LTP 的影响。最后，我们研究了 ZNS 与参与 iLTP 的 NO/cGMP/PKG 依赖性途径之间可能的相互作用。在这里，我们提供了第一个证据，表明缺氧和葡萄糖剥夺事件可以通过调节 NO/cGMP/PKG 途径在 CA1 海马切片中诱导 iLTP。此外，我们发现，尽管 ZNS 应用不影响高频刺激诱导的短期突触可塑性和 LTP，但它显著降低了 iLTP。NO 合酶抑制剂和可溶性鸟苷酸环化酶抑制剂的浴液应用可模拟这种减少。ZNS 的作用可以通过应用 NO 供体或增加细胞内 cGMP 水平并激活 PKG 的药物来预防。这些发现与 AED（如 ZNS）作为脑缺血的一种可能神经保护策略的可能用途一致。此外，这些发现强烈表明，NO/cGMP/PKG 细胞内级联可能是病理性突触可塑性（如海马 iLTP）中神经保护的生理靶点。
