Identification of a neurovascular signaling pathway regulating seizures in mice

Abstract

ObjectiveA growing body of evidence suggests that increased blood–brain barrier (BBB) permeability can contribute to the development of seizures. The protease tissue plasminogen activator (tPA) has been shown to promote BBB permeability and susceptibility to seizures. In this study, we examined the pathway regulated by tPA in seizures.MethodsAn experimental model of kainate-induced seizures was used in genetically modified mice, including mice deficient in tPA (tPA−/−), its inhibitor neuroserpin (Nsp−/−), or both (Nsp:tPA−/−), and in mice conditionally deficient in the platelet-derived growth factor receptor alpha (PDGFRα).ResultsCompared to wild-type (WT) mice, Nsp−/− mice have significantly reduced latency to seizure onset and generalization; whereas tPA−/− mice have the opposite phenotype, as do Nsp:tPA−/− mice. Furthermore, interventions that maintain BBB integrity delay seizure propagation, whereas osmotic disruption of the BBB in seizure-resistant tPA−/− mice dramatically reduces the time to seizure onset and accelerates seizure progression. The phenotypic differences in seizure progression between WT, tPA−/−, and Nsp−/− mice are also observed in electroencephalogram recordings in vivo, but absent in ex vivo electrophysiological recordings where regulation of the BBB is no longer necessary to maintain the extracellular environment. Finally, we demonstrate that these effects on seizure progression are mediated through signaling by PDGFRα on perivascular astrocytes.InterpretationTogether, these data identify a specific molecular pathway involving tPA-mediated PDGFRα signaling in perivascular astrocytes that regulates seizure progression through control of the BBB. Inhibition of PDGFRα signaling and maintenance of BBB integrity might therefore offer a novel clinical approach for managing seizures.

Rat models of spinal cord injury: from pathology to potential therapies

“…In stroke, further neurological impairment can take place if thrombolytic treatment with recombinant tissue plasminogen activator (tPA) is administered beyond a narrow time window, owing to increased edema and vascular permeability. Investigations into the mechanism that underlies this unwanted side effect of tPA have revealed that tPA causes proteolytic activation of latent platelet-derived growth factor-CC (PDGF-CC), and that the loss of blood–brain-barrier integrity is a consequence of PDGF-CC activating PDGFR-α on astrocytic end-feet lining the capillary walls (Su et al, 2008, 2009; Fredriksson et al, 2015).

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Pharmacological targeting of the PDGF-CC signaling pathway for blood–brain barrier restoration in neurological disorders

“…In the adult CNS PDGF-CC, and later also PDGF-BB, have been shown to affect BBB permeability, the latter through maintenance of the pericyte-endothelial interaction (Armulik et al, 2010; Armulik, Genové, & Betsholtz, 2011; Su et al, 2008). Intraventricular injection of active PDGF-CC protein is sufficient to induce BBB opening (Su et al, 2008) and its inhibition was shown to reduce BBB dysfunction and indicated promising therapeutic effects in experimental ischemic stroke (Su et al, 2008), spinal cord injury (Abrams et al, 2012; Sharp, Yee, & Steward, 2014), TBI (Su et al, 2015), MS (Adzemovic, Zeitelhofer, Eriksson, Olsson, & Nilsson, 2013), seizures (Fredriksson et al, 2015) and ALS neurodegeneration (Lewandowski et al, 2016). In order to better understand the role of PDGF-CC in regulation of BBB integrity we will first describe its structure and mechanisms of activation.…”

“…Outside the CNS, tPA activity is mainly regulated through inhibition by plasminogen activator inhibitor-1 (PAI-1, SERPINE1 ) (Collen, 2001), whereas in the CNS, neuroserpin ( SERPINI1 ) was recently found to be the physiologic relevant inhibitor of tPA activity (Fredriksson et al, 2015) (Figure 2). In the CNS, where tPA is believed to exert unique functions distinct from its role in fibrinolysis, we have previously demonstrated that activation of PDGF-CC in the neurovascular interface requires existence of LDL receptor-related protein (LRP1) (Su et al, 2008) (Figure 2).…”

“…Intriguingly, tPA was one of the first genes recognized to be activated early after seizure onset (Qian, Gilbert, Colicos, Kandel, & Kuhl, 1993) and its genetic deficiency raises threshold for seizure induction (Tsirka, Gualandris, Amaral, & Strickland, 1995; Yepes et al, 2002). In a recent study we showed that imatinib delays onset and progression of kainate-induced seizures in wild-type mice but not in tPA knockout mice (Fredriksson et al, 2015). This lack of cumulative protection of imatinib treatment in tPA knockout mice suggests that during seizures both tPA and PDGFR-α operate in the same signaling pathway.…”

“…This lack of cumulative protection of imatinib treatment in tPA knockout mice suggests that during seizures both tPA and PDGFR-α operate in the same signaling pathway. Moreover, inducible deletion of recombinant PDGFR-α in perivascular astrocytes reduced progression of convulsive seizure behavior (Fredriksson et al, 2015) and indicates that intervention at the PDGFR-α, acting downstream of tPA, is sufficient to have an effect on seizure progression.…”