The antagonism of prostaglandin FP receptors inhibits the evolution of spreading depolarization in an experimental model of global forebrain ischemia

NEUROBIOLOGY OF DISEASE

卷:137

Article

Varga, Daniel P.¹  Szabo, Irisz¹  Varga, Viktoria E.¹  Menhyart, Akos¹  Toth, Orsolya M.¹  Kozma, Mihaly²  Balint, Armand R.¹  Krizbai, Istvan A.^2,3  Bari, Ferenc¹  Farkas, Eszter¹ 

[1] Univ Szeged, Dept Med Phys & Informat, Fac Med, Koranyi Fasor 9, H-6720 Szeged, Hungary

[2] Biol Res Ctr, Inst Biophys, Mol Neurobiol Res Unit, Physiol & Pathol Blood Brain Barrier Res Grp, Temesvari Krt 62, H-6726 Szeged, Hungary

[3] Vasile Goldis Western Univ, Inst Life Sci, Revolutiei Blvd 94, Arad 310025, Romania

关键词: AL-8810;    Apoptosis;    Cerebral blood flow;    Cerebral ischemia;    FP receptor;    Microglia;    Neurodegeneration;    Neuropharmacology;    Spreading depolarization;    Stroke;   

DOI  :  10.1016/j.nbd.2020.104780

来源: Elsevier

【 摘 要 】

Spontaneous, recurrent spreading depolarizations (SD) are increasingly more appreciated as a pathomechanism behind ischemic brain injuries. Although the prostaglandin F2 alpha - FP receptor signaling pathway has been proposed to contribute to neurodegeneration, it has remained unexplored whether FP receptors are implicated in SD or the coupled cerebral blood flow (CBF) response. We set out here to test the hypothesis that FP receptor blockade may achieve neuroprotection by the inhibition of SD. Global forebrain ischemia/reperfusion was induced in anesthetized rats by the bilateral occlusion and later release of the common carotid arteries. An FP receptor antagonist (AL-8810; 1 mg/bwkg) or its vehicle were administered via the femoral vein 10 min later. Two open craniotomies on the right parietal bone served the elicitation of SD with 1 M KCl, and the acquisition of local field potential. CBF was monitored with laser speckle contrast imaging over the thinned parietal bone. Apoptosis and microglia activation, as well as FP receptor localization were evaluated with immunohistochemistry. The data demonstrate that the antagonism of FP receptors suppressed SD in the ischemic rat cerebral cortex and reduced the duration of recurrent SDs by facilitating repolarization. In parallel, FP receptor antagonism improved perfusion in the ischemic cerebral cortex, and attenuated hypoemic CBF responses associated with SD. Further, FP receptor antagonism appeared to restrain apoptotic cell death related to SD recurrence. In summary, the antagonism of FP receptors (located at the neuro-vascular unit, neurons, astrocytes and microglia) emerges as a promising approach to inhibit the evolution of SDs in cerebral ischemia.