Agomelatine promotes differentiation of oligodendrocyte precursor cells and preserves white matter integrity after cerebral ischemic stroke

Abstract

White matter injury contributes to neurological disorders after acute ischemic stroke (AIS). The repair of white matter injury is dependent on the re-myelination by oligodendrocytes. Both melatonin and serotonin antagonist have been proved to protect against post-stroke white matter injury. Agomelatine (AGM) is a multi-functional treatment which is both a melatonin receptor agonist and selective serotonin receptor antagonist. Whether AGM protects against white matter injury after stroke and the underlying mechanisms remain elusive. Here, using the transient middle cerebral artery occlusion (tMCAO) model, we evaluated the therapeutic effects of AGM in stroke mice. Sensorimotor and cognitive functions, white matter integrity, oligodendroglial regeneration and re-myelination in stroke hemisphere after AGM treatment were analyzed. We found that AGM efficiently preserved white matter integrity, reduced brain tissue loss, attenuated long-term sensorimotor and cognitive deficits in tMCAO models. AGM treatment promoted OPC differentiation and enhanced re-myelination both in vitro, ex vivo and in vivo, although OPC proliferation was unaffected. Mechanistically, AGM activated low density lipoprotein receptor related protein 1 (LRP1), peroxisome proliferator-activated receptor γ (PPARγ) signaling thus promoted OPC differentiation and re-myelination after stroke. Inhibition of PPARγ or knock-down of LRP1 in OPCs reversed the beneficial effects of AGM. Altogether, our data indicate that AGM represents a novel therapy against white matter injury after cerebral ischemia.