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.

The Role of Abnormal Hemostasis and Fibrinolysis in Morbidity and Mortality of Acute Promyelocytic Leukemia

“…By the end of the first week of treatment, fatal ICH was found to be six times higher with tPA. This serious adverse effect of tPA was an incentive for many recent studies [82][83][84][85][86] leading to several new findings on the role of fibrinolysis in ICH that can be applied to APL.…”

“…An exciting new finding is that PDGFRα can be inhibited by the Bcr-Abl tyrosine kinase inhibitors, imatinib, nilotinib, desatinib, and masitinib. 86 An ongoing phase 2 clinical trial of imatinib yield encouraging results of attenuating the adverse effect of tPA in acute ischemic stroke. 89 If successful, this can be applied to the strategy of reducing ICH in APL.…”

The PDGF pathway in breast cancer is linked to tumour aggressiveness, triple-negative subtype and early recurrence

“…In glioblastoma, autocrine signalling by PDGF-CC/PDGFRα has been proposed to have a role in tumour development and Lokker et al detected concomitant expression of PDGF-CC and PDGFRα in 6/6 tested glioblastoma cell lines, and 5/5 investigated primary glioblastoma tissue samples [ 26 ]. Furthermore, PDGF-CC has been shown to increase the permeability of the blood–brain barrier (BBB) [ 27 ], and the role of the PDGFRα/PDGF-CC pathway relative to BBB dysfunction in neurological disorders was recently reviewed [ 28 ]. In our cohort, patients who developed CNS metastases had primary tumours with high expression of tumour cell PDGFRα in 67%, PDGF-CC in 50% and concomitant high ligand/receptor expression in 33% of cases, indicating an active role of the PDGF pathway in these tumours.…”

The Central Role of Fibrinolytic Response in Trauma-Induced Coagulopathy: A Hematologist's Perspective

“…An exciting recent finding is that PDGFRα can be inhibited by Bcr-Abl tyrosine kinase inhibitors imatinib, nilotinib, dasatinib, and masitinib. 96 Imatinib has been shown to reduce BBB leakage in an animal model. 97 Encouraging preliminary results have also been seen in an ongoing phase 2 clinical trial of imatinib in acute ischemic stroke.…”