A critical role of NO/cGMP/PKG dependent pathway in hippocampal post-ischemic LTP: Modulation by zonisamide

NEUROBIOLOGY OF DISEASE

卷:44

Article

Costa, Cinzia^1,2  Tozzi, Alessandro^1,2  Siliquini, Sabrina^1,2  Galletti, Francesca^1,2  Cardaioli, Gabriela^1,2  Tantucci, Michela^1,2  Pisani, Francesco³  Calabresi, Paolo^1,2 

[1] Univ Perugia, Clin Neurol, Osped S Maria della Misericordia, I-06156 Perugia, Italy

[2] Fdn Santa Lucia, Ist Ricovero & Cura Carattere Sci, I-00143 Rome, Italy

[3] Univ Messina, Dipartimento Neurosci, Messina, Italy

关键词: Antiepileptic drugs;    Brain ischemia;    Excitatory synaptic transmission;    Long term potentiation;    Neuroprotection;    Nitric oxide;    Stroke;   

DOI  :  10.1016/j.nbd.2011.06.015

来源: Elsevier

【 摘 要 】

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 LIP. 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. (C) 2011 Elsevier Inc. All rights reserved.

【 授权许可】

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