Imatinib, a cancer treatment, stopped an injury response mechanism of the central nervous system (CNS) from activating, damage to which is a hallmark of multiple sclerosis (MS), an early study reported.
Treatment with imatinib lessened immune cell infiltration and eased disease progression in mouse models of MS. Study researchers suggested that treatments with a similar mechanism of action might be of benefit in neurological diseases marked by BBB disruption.
The study “Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier” was published in the journal Nature Scientific Reports.
Disruption of the BBB and subsequent entry of immune cells to the CNS (brain and spinal cord) is a hallmark of various disorders, including MS. This barrier is a natural, highly selective membrane that shields the CNS from insults that can be carried in the blood.
Researchers at the Karolinska Institute, in Sweden, evaluated whether the loss of brain-blood barrier’s integrity would change during the different stages of MS — specifically, its preclinical (before symptoms evident), progression, and remission stages.
They first performed a genetic analysis of endothelial cells — which line the interior of blood vessels — isolated from vessels in the spinal cords of an established animal model of MS, the experimental autoimmune encephalomyelitis (EAE) mouse model. Cells from EAE mice were recovered at each of these disease phases, as were cells from control mice without EAE.
Analysis revealed gene activity changed significantly at all three phases in the EAE mice compared with control mice. Changes were detected in 59 genes during the preclinical, 1,571 during the progression, and 781 during the remission stage. Of note, 26 of these genes were common for all three disease stages.
In a previous study in a rat EAE model, the researchers showed that treatment with imatinib, approved to treat certain types of leukemia (a cancer that begins in white blood cells) and other cancers, preserved BBB integrity and ameliorated clinical symptoms of the disease. Imatinib inhibits a common injury response mechanism of the CNS that is mediated by the activation of the platelet-derived growth factor receptor alpha (PDGFR-alpha) signaling.
Based on these earlier data, the team included in their analysis EAE mice treated with imatinib at the different stages of MS, and observed that the treatment mostly affected genes of the BBB during the progression phase of EAE — with 858 genes being modulated.
Looking more closely at the pathways modulated at each stage, researchers found that the presymptomatic or preclinical phase was marked by an increase in genes linked with the activation of endothelial cells and leukocyte (white blood cell) adhesion. This continued in the progression phase, which showed additional immune-related pathways being activated. In the remission phase, a lessening in the activation of endothelial cell genes, as well as immune cell recruitment was seen compared with the progressive stage.
Imatinib’s use during the progression phase reduced the activity of genes linked with endothelial cell activation and the recruitment and infiltration of immune cells, as well as the formation of new blood vessels (a process called angiogenesis).
Using a fluorescent dye, researchers confirmed that early signs of a leaking BBB were already apparent in the preclinical phase, and marked leaking was visible at the progressive stage of EAE. The BBB was almost completely restored at the remission phase, and imatinib treatment lessened BBB leakage during EAE progression stage.
Further experiments using a different neutralizing antibody, one that mimics the action of imatinib and halts PDGFR-alpha signaling, resulted in a preserved BBB integrity and eased EAE symptoms.
To confirm the results obtained in mice, the team analyzed brain tissue from deceased MS patients. This work showed that PDGFR-alpha signaling is indeed increased in MS lesions, supporting the therapeutic potential of agents that block this pathway.
These findings suggest that blocking PDGFR-alpha signaling “leads to amelioration of a MS-like neuroinflammation through restoration of BBB function and integrity,” the researchers wrote.
Since PDGFR-alpha signaling is also important for other neurological diseases, “agents blocking this pathway are likely to attain larger therapeutic range than currently indicated,” the team suggested.
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