pexidartinib and Cerebral-Hemorrhage

Aged microglia display augmented inflammatory activity after neural injury. Although aging is a risk factor for poor outcome after brain insults, the precise impact of aging-related alterations in microglia on neural injury remains poorly understood. Microglia can be eliminated via pharmacological inhibition of the colony-stimulating factor 1 receptor (CSF1R). Upon withdrawal of CSF1R inhibitors, microglia rapidly repopulate the entire brain, leading to replacement of the microglial compartment. In this study, we investigated the impact of microglial replacement in the aged brain on neural injury using a mouse model of intracerebral hemorrhage (ICH) induced by collagenase injection. We found that replacement of microglia in the aged brain reduced neurological deficits and brain edema after ICH. Microglial replacement-induced attenuation of ICH injury was accompanied with alleviated blood-brain barrier disruption and leukocyte infiltration. Notably, newly repopulated microglia had reduced expression of IL-1β, TNF-α and CD86, and upregulation of CD206 in response to ICH. Our findings suggest that replacement of microglia in the aged brain restricts neuroinflammation and brain injury following ICH.

Topics: Aging; Aminopyridines; Animals; Blood-Brain Barrier; Brain; Brain Injuries; Cell Death; Cerebral Hemorrhage; Chemotaxis, Leukocyte; Disease Models, Animal; Mice; Microglia; Neuroinflammatory Diseases; Pyrroles; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor

Delayed cognitive decline commonly occurs following intracerebral hemorrhage (ICH), but the mechanisms underlying this phenomenon remain obscure. We therefore investigated the potential mechanisms responsible for impaired cognitive function in a mouse collagenase model of ICH. Following recovery of motor and sensory deficits in the chronic phase of ICH, we noted significant cognitive impairment, which was assessed by the Morris water maze. This finding was accompanied by reduced dendrite spine density of ipsilateral hippocampal CA1 neurons. Reduced synaptic plasticity, manifested by impaired long-term potentiation in hippocampal neurons, was also evident in both ipsilateral and contralateral hemispheres, suggesting that ICH also induces functional alterations in distal brain regions remote from the site of injury. In addition, the accumulation of microglia, infiltration of peripheral immune cells, and generation of reactive oxygen species were observed in both contralateral and ipsilateral hemispheres up to 5 wk post-ICH. Furthermore, depletion of microglia using PLX3397, which inhibits colony stimulating factor 1 receptor, ameliorated this delayed cognitive impairment. Collectively, these results suggest that persistent and diffuse brain inflammation may contribute to cognitive impairment in the chronic stage of ICH recovery.-Shi, E., Shi, K., Qiu, S., Sheth, K. N., Lawton, M. T., Ducruet, A. F. Chronic inflammation, cognitive impairment, and distal brain region alteration following intracerebral hemorrhage.

Topics: Aminopyridines; Animals; Brain; Cerebral Hemorrhage; Cognition; Cognitive Dysfunction; Disease Models, Animal; Fingolimod Hydrochloride; Flow Cytometry; Hippocampus; Inflammation; Male; Mice; Mice, Inbred C57BL; Microglia; Neuroimaging; Neuronal Plasticity; Pyrroles; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor

Microglia are the first responders to intracerebral hemorrhage, but their precise role in intracerebral hemorrhage remains to be defined. Microglia are the only type of brain cells expressing the colony-stimulating factor 1 receptor, a key regulator for myeloid lineage cells. Here, we determined the effects of a colony-stimulating factor 1 receptor inhibitor (PLX3397) on microglia and the outcome in the context of experimental mouse intracerebral hemorrhage. We show that PLX3397 effectively depleted microglia, and the depletion of microglia was sustained after intracerebral hemorrhage. Importantly, colony-stimulating factor 1 receptor inhibition attenuated neurodeficits and brain edema in two experimental models of intracerebral hemorrhage induced by injection of collagenase or autologous blood. The benefit of colony-stimulating factor 1 receptor inhibition was associated with reduced leukocyte infiltration in the brain and improved blood-brain barrier integrity after intracerebral hemorrhage, and each observation was independent of lesion size or hematoma volume. These results demonstrate that suppression of colony-stimulating factor 1 receptor signaling ablates microglia and confers protection after intracerebral hemorrhage.

Topics: Aminopyridines; Animals; Brain; Brain Edema; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Microglia; Neuroimaging; Pyrroles; Receptor, Macrophage Colony-Stimulating Factor; Species Specificity