title: A critical role of NO/cGMP/PKG dependent pathway in hippocampal post-ischemic LTP: modulation by zonisamide.
abstract: 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.
authors.affiliation: Clinica Neurologica, Università degli Studi di Perugia, Ospedale S.Maria della Misericordia, Perugia, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Costa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Tozzi
authors.forename: Sabrina
authors.initials: S
authors.lastname: Siliquini
authors.forename: Francesca
authors.initials: F
authors.lastname: Galletti
authors.forename: Gabriela
authors.initials: G
authors.lastname: Cardaioli
authors.forename: Michela
authors.initials: M
authors.lastname: Tantucci
authors.forename: Francesco
authors.initials: F
authors.lastname: Pisani
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D006152:Cyclic GMP / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007555:Isoxazoles / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000078305:Zonisamide
chemical_list: D000927:Anticonvulsants; D007555:Isoxazoles; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D000078305:Zonisamide; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP