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Published on: September 12, 2016
Pharmacological Inhibition of Microglial Proliferation Supports Blood-Brain Barrier Integrity in Experimental
Nozha Borjini1,2,3,4, Mercedes Fernandez2,5, Luciana Giardino5,6
1Research & Development, Chiesi Farmaceutici S.p.A, via Palermo 26/A, 43100 Parma, Italy.
Abstract:
Blood-brain barrier dysfunction (BBB) is a primary characteristic of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS). We have previously shown that blocking microglial proliferation using GW2580, a selective inhibitor of CSF1R (Colony stimulating factor 1 receptor), reduced disease progression and severity and prevented the relapse phase. However, whether this was due to effects of GW2580 on the functional integrity of the BBB was not determined. Therefore, here, we examine BBB properties in rats during EAE under GW2580 treatment. Our data suggest that blocking early microglial proliferation through selective targeting of CSF1R signaling has a therapeutic effect in EAE by protecting BBB integrity and reducing peripheral immune cell infiltration. Taken together, our results identify a novel mechanism underlying the effects of GW2580, which could offer a novel therapy for MS.
Insights
Blocking microglial proliferation with GW2580 protects blood-brain barrier integrity in experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis model. This suggests GW2580 may offer a novel therapy for MS by preserving BBB function.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Blood-Brain Barrier Research
Background:
- Blood-brain barrier (BBB) dysfunction is a hallmark of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS).
- Previous studies demonstrated that inhibiting microglial proliferation with GW2580, a CSF1R inhibitor, ameliorates EAE severity and prevents relapse.
- The specific impact of GW2580 on BBB integrity during EAE remained undetermined.
Purpose of the Study:
- To investigate the effects of GW2580 on blood-brain barrier properties in rats with EAE.
- To determine if GW2580's therapeutic benefits in EAE are mediated by protection of the BBB.
Main Methods:
- EAE was induced in rats, and GW2580 was administered to inhibit Colony stimulating factor 1 receptor (CSF1R) signaling and microglial proliferation.
- Blood-brain barrier integrity was assessed in EAE rats treated with GW2580.
- Peripheral immune cell infiltration into the central nervous system was quantified.
Main Results:
- GW2580 treatment protected the integrity of the blood-brain barrier in rats during EAE.
- Inhibition of early microglial proliferation via CSF1R signaling reduced peripheral immune cell infiltration into the brain.
- GW2580 demonstrated a therapeutic effect in EAE by preserving BBB function.
Conclusions:
- Targeting early microglial proliferation with GW2580 offers a therapeutic strategy for EAE.
- Protecting blood-brain barrier integrity is a key mechanism by which GW2580 exerts its beneficial effects in EAE.
- GW2580 represents a potential novel therapeutic agent for multiple sclerosis by preserving BBB integrity.
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