title: 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.
authors.affiliation: Tissue Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles v. 2, 17177, Stockholm, Sweden. Electronic address: sebastian.lewandowski@ki.se.
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Lewandowski
authors.affiliation: Vascular Biology Groups, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles v. 2, 17177, Stockholm, Sweden; Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, 7301 Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0644, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Fredriksson
authors.affiliation: Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan Medical School, 7301 Medical Science Research Building III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0644, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.affiliation: Tissue Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Scheeles v. 2, 17177, Stockholm, Sweden. Electronic address: ulf.pe.eriksson@ki.se.
authors.forename: Ulf
authors.initials: U
authors.lastname: Eriksson
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000473:pathology; D015195:Drug Design; D006801:Humans; D008222:Lymphokines / Q000378:metabolism*; D051379:Mice; D058990:Molecular Targeted Therapy; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D012307:Risk Factors; D015398:Signal Transduction
chemical_list: D008222:Lymphokines; D018696:Neuroprotective Agents; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C
keywords: Blood–brain barrier; Neurodegeneration; PDGF-CC; Stroke; Traumatic brain injury; tPA