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

Abstract

Neurological disorders account for a majority of non-malignant disability in humans and are often associated with dysfunction of the blood-brain barrier (BBB). Recent evidence shows that despite apparent variation in the origin of neural damage, the central nervous system has a common injury response mechanism involving platelet-derived growth factor (PDGF)-CC activation in the neurovascular unit and subsequent dysfunction of BBB integrity. Inhibition of PDGF-CC signaling with imatinib in mice has been shown to prevent BBB dysfunction and have neuroprotective effects in acute damage conditions, including traumatic brain injury, seizures or stroke, as well as in neurodegenerative diseases that develop over time, including multiple sclerosis and amyotrophic lateral sclerosis. Stroke and traumatic injuries are major risk factors for age-associated neurodegenerative disorders and we speculate that restoring BBB properties through PDGF-CC inhibition might provide a common therapeutic opportunity for treatment of both acute and progressive neuropathology in humans. In this review we will summarize what is known about the role of PDGF-CC in neurovascular signaling events and the variety of seemingly different neuropathologies it is involved in. We will also discuss the pharmacological means of therapeutic interventions for anti-PDGF-CC therapy and ongoing clinical trials. In summary: inhibition of PDGF-CC signaling can be protective for immediate injury and decrease the long-term neurodegenerative consequences.

Keywords: Blood–brain barrier; Neurodegeneration; PDGF-CC; Stroke; Traumatic brain injury; tPA.

Figure 1. Putative structure of the human PDGF-C CUB and GF domains

Domains are modeled separately and based on homology with human Cubulin (PDB: 3KQ4, residues 935–1042) and human PDGF-A (PDB: 3MJK, residues 118–179). The segment between CUB and GF domains is represented as dots with displayed cleavage site sequence. RV – predicted and KA – observed cleavage site (Gilbertson et al. JBC 2001), RKSR – putative processing site (Li et al. Nat. Cell. Biol. 2000), R²³¹ – essential for tPA-mediated cleavage (Fredriksson et al. JBC 2005). The disulfide bond-forming cysteines conserved in the GF domain of PDGF family are highlighted in orange.

Figure 2. Overview of PDGF-CC signaling

PDGFC gene expression in the signaling cell is regulated by the Egr-1 and Sp1 transcription factors. SNP rs28999109 disrupts the consensus binding sequence for Egr-1 and Sp1 and decreases promoter activity. In the extracellular matrix the inactive PDGF-CC homodimer containing the CUB domains is cleaved by tPA to release the active dimer consisting of growth factor domains. PAI-1 is a tPA inhibitor in plasma fibrinolysis and Neuroserpin inhibits tPA in the CNS parenchyma. PDGFR-α is present in the responding cell together with LRP1, a co-receptor that facilitates efficient cleavage of PDGF-CC by tPA. Upon ligand binding PDGFR-α becomes phosphorylated and activates intracellular signaling pathways including PI3K, Ras MAPK, p38 MAPK and Plc-γ.

Figure 3. Pharmacological means of inhibition for PDGF-CC – PDGFR-α signaling

Active PDGF-CC ligand can be targeted with neutralising antibodies to prevent receptor binding. In similar fashion ligand binding to PDGFR-α can be prevented by antibodies targeting the extracellular domains of the receptor. PDGFR-α intracellular domain phosphorylation and signaling activity can be reduced with tyrosine kinase inhibitors. For detailed description see Table 1.

Figure 4. Schematic diagram of the neurovascular unit in CNS injury

(I) Expression of tPA protein is induced and it becomes available in the extracellular matrix. (II) Proteolytically active tPA cleaves off the regulatory CUB domain (white) from the PDGF-CC dimer core (blue) yielding an active ligand. (III) Activation of PDGFR-α located on the perivascular astrocytes exerts influence on endothelial uptake by an unknown mechanism (IV) and results in BBB deregulation (V).