title: Metallothioneins I/II are involved in the neuroprotective effect of sildenafil in focal brain injury.
abstract: We recently reported that administration of the non-selective cyclic GMP-phosphodiesterase (cGMP-PDE) inhibitor zaprinast to cortically cryoinjured rats results three days post-lesion in reduced neuronal cell death that was associated to decreased macrophage/microglial activation and oxidative stress and increased astrogliosis and angiogenesis. Similar effects have been observed in cryoinjured animals overexpressing metallothioneins I/II (MT-I/II), metal-binding cysteine-rich proteins that are up-regulated in response to injury. In this work we have examined the effect of administration of the selective PDE5 inhibitor sildenafil (10mg/kg, sc) 2h before and 24 and 48h after induction of cortical cryolesion in wild-type and MT-I/II-deficient mice. Our results show that in wild-type animals sildenafil induces similar changes in glial reactivity, angiogenesis and antioxidant and antiapoptotic effects in the cryolesioned cortex as those observed in rats with zaprinast, indicating that inhibition of PDE5 is responsible for the neuroprotective actions. However, these effects were not observed in mice deficient in MT-I/II. We further show that sildenafil significantly increases MT-I/II protein levels in homogenates of lesioned cortex and MT-I/II immunostaining in glial cells around the lesion. Taken together these results indicate that cGMP-mediated pathways regulate expression of MT-I/II and support the involvement of these proteins in the neuroprotective effects of sildenafil in focal brain lesion.
authors.affiliation: Institute of Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Spain. judith.prado@uab.cat
authors.forename: Judith
authors.initials: J
authors.lastname: Prado
authors.forename: Paula
authors.initials: P
authors.lastname: Pifarré
authors.forename: Mercé
authors.initials: M
authors.lastname: Giralt
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
authors.forename: Agustina
authors.initials: A
authors.lastname: García
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001930:Brain Injuries / Q000188:drug therapy* / Q000473:pathology; D002540:Cerebral Cortex / Q000293:injuries / Q000473:pathology; D003080:Cold Temperature; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005911:Gliosis / Q000473:pathology; D007150:Immunohistochemistry; D008262:Macrophage Activation; D008668:Metallothionein / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects; D018696:Neuroprotective Agents; D018384:Oxidative Stress / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018696:Neuroprotective Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011688:Purinones; D013450:Sulfones; D008668:Metallothionein; D000068677:Sildenafil Citrate; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C011145:zaprinast