<scp>N</scp>europrotection by <scp>S</scp>ildenafil: <scp>N</scp>euronal <scp>N</scp>etworks <scp>P</scp>otentiation in <scp>A</scp>cute <scp>E</scp>xperimental <scp>S</scp>troke

<jats:title>Summary</jats:title><jats:sec><jats:title>Aims</jats:title><jats:p>Sildenafil, a phosphodiesterase type 5 inhibitor, has been found to produce functional recovery in ischemic rats by increasing the c<jats:styled-content style="fixed-case">GMP</jats:styled-content> level and triggering neurogenesis. The aim of this study was to investigate further sildenafil mechanisms.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Male <jats:styled-content style="fixed-case">S</jats:styled-content>prague‐<jats:styled-content style="fixed-case">D</jats:styled-content>awley rats underwent middle cerebral artery occlusion and reperfusion, followed by intraperitoneal or intravenous treatment of sildenafil starting 2 h later. Behavioral tests were performed on day 1 or day 7 after reperfusion, while cerebral infarction, edema, <jats:styled-content style="fixed-case">N</jats:styled-content>issl staining, <jats:styled-content style="fixed-case">F</jats:styled-content>luoro‐<jats:styled-content style="fixed-case">J</jats:styled-content>ade <jats:styled-content style="fixed-case">B</jats:styled-content> staining, and electron microscopy studies were carried out 24 h poststroke. The c<jats:styled-content style="fixed-case">GMP</jats:styled-content>‐dependent <jats:styled-content style="fixed-case">N</jats:styled-content>ogo‐66 receptor (<jats:styled-content style="fixed-case">N</jats:styled-content>ogo‐<jats:styled-content style="fixed-case">R</jats:styled-content>) pathway, synaptophysin, <jats:styled-content style="fixed-case">PSD</jats:styled-content>‐95/neuronal nitric oxide synthases (n<jats:styled-content style="fixed-case">NOS</jats:styled-content>), brain‐derived neurotrophic factor (<jats:styled-content style="fixed-case">BDNF</jats:styled-content>)/tropomyosin‐related kinase <jats:styled-content style="fixed-case">B</jats:styled-content> (<jats:styled-content style="fixed-case">T</jats:styled-content>rk<jats:styled-content style="fixed-case">B</jats:styled-content>), and nerve growth factor (<jats:styled-content style="fixed-case">NGF</jats:styled-content>)/tropomyosin‐related kinase <jats:styled-content style="fixed-case">A</jats:styled-content> (<jats:styled-content style="fixed-case">T</jats:styled-content>rk<jats:styled-content style="fixed-case">A</jats:styled-content>) were measured.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Sildenafil enhanced neurological recovery and inhibited infarction, even following delayed administration 4 h after stroke onset. Furthermore, sildenafil reduced the loss of neurons and modulated the expressions of the c<jats:styled-content style="fixed-case">GMP</jats:styled-content>‐dependent <jats:styled-content style="fixed-case">N</jats:styled-content>ogo‐<jats:styled-content style="fixed-case">R</jats:styled-content> pathway. Moreover, sildenafil protected the structure of synapses and mediated the expressions of synaptophysin, <jats:styled-content style="fixed-case">PSD</jats:styled-content>‐95/n<jats:styled-content style="fixed-case">NOS</jats:styled-content>,<jats:styled-content style="fixed-case"> BDNF</jats:styled-content>/<jats:styled-content style="fixed-case">T</jats:styled-content>rk<jats:styled-content style="fixed-case">B</jats:styled-content>, and <jats:styled-content style="fixed-case">NGF</jats:styled-content>/<jats:styled-content style="fixed-case">T</jats:styled-content>rk<jats:styled-content style="fixed-case">A</jats:styled-content>.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Sildenafil produces significant neuroprotective effects on injured neurons in acute stroke, and these are mediated by the c<jats:styled-content style="fixed-case">GMP</jats:styled-content>‐dependent <jats:styled-content style="fixed-case">N</jats:styled-content>ogo‐<jats:styled-content style="fixed-case">R</jats:styled-content> pathway, <jats:styled-content style="fixed-case">NGF</jats:styled-content>/<jats:styled-content style="fixed-case">T</jats:styled-content>rk<jats:styled-content style="fixed-case">A</jats:styled-content>, and <jats:styled-content style="fixed-case">BDNF</jats:styled-content>/<jats:styled-content style="fixed-case">T</jats:styled-content>rk<jats:styled-content style="fixed-case">B</jats:styled-content>.</jats:p></jats:sec>