Modulation of the proteoglycan receptor PTPσ promotes white matter integrity and functional recovery after intracerebral hemorrhage stroke in mice.

BACKGROUND: Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality rates. However, extant investigations have mainly focused on gray matter injury within the primary injury site after ICH rather than on white matter (WM) injury in the brain and spinal cord. This focus partly accounts for the diminished therapeutic discovery. Recent evidence suggests that chondroitin sulphate proteoglycans (CSPG), which can bind to the neural transmembrane protein tyrosine phosphatase-sigma (PTPσ), may facilitate axonal regrowth and remyelination by ameliorating neuroinflammation. METHODS: A clinically relevant ICH model was established using adult C57BL/6 mice. The mice were then treated systemically with intracellular sigma peptide (ISP), which specifically targets PTPσ. Sensorimotor function was assessed by various behavioral tests and electrophysiological assessment. Western blot was used to verify the expression levels of Iba-1 and different inflammatory cytokines. The morphology of white matter tracts of brain and spinal cord was evaluated by immunofluorescence staining and transmission electron microscopy (TEM). Adeno-associated virus (AAV) 2/9 injection was used to assess the ipsilateral axonal compensation after injury. Parallel in vitro studies on the effects of CSPG interference on oligodendrocyte-DRG neuron co-culture explored the molecular mechanism through which ISP treatment promoted myelination capability. RESULTS: ISP, by targeting PTPσ, improved WM integrity and sensorimotor recovery via immunomodulation. In addition, ISP administration significantly decreased WM injury in the peri-hematomal region as well as cervical spinal cord, enhanced axonal myelination and facilitated neurological restoration, including electrophysiologically assessed sensorimotor functions. Parallel in vitro studies showed that inhibition of PTPσ by ISP fosters myelination by modulating the Erk/CREB signaling pathway. CONCLUSIONS: Our findings revealed for the first time that manipulation of PTPσ signaling by ISP can promote prolonged neurological recovery by restoration of the integrity of neural circuits in the CNS through modulation of Erk/CREB signaling pathway.

A previous hemorrhagic stroke protects against a subsequent stroke via microglia alternative polarization.

Microglia in hemorrhagic stroke contribute to both acute-phase exacerbation and late-phase attenuation of injury. Here, by using the mouse model, we reported that the shift in polarization of microglia from M1 to M2 phenotype could be altered by a past 'mini' stroke, resulting in better neurological function recovery, faster attenuation of lesion volume, and better survival. In mice with a previous stroke, M2 predominance appeared markedly in advance compared to mice without a previous stroke. Mechanistically, the RBC-mediated M2 polarization of microglia was synergistically enhanced by T cells: microglia cocultured with RBCs alone resulted in mild alterations to M2 markers, whereas in the presence of T cells, they expressed an early and sustained M2 response. These results suggest that by harnessing the microglia-mediated M2 polarization response, we could help mitigate devastating sequelae before a prospective hemorrhagic stroke even happens.

Vitamin D Enhances Hematoma Clearance and Neurologic Recovery in Intracerebral Hemorrhage.

BACKGROUND: Erythrophagocytosis by reparative monocyte-derived macrophage contributes to hematoma clearance and neurological recovery after intracerebral hemorrhage (ICH). Vitamin D (VitD) is a neuroprotective hormone and regulates the differentiation of monocyte-derived macrophage from monocytes. In this study, we examined the effects of VitD supplementation on monocyte-derived macrophage and hematoma clearance in rodent with ICH. METHODS: Neurobehavioral functions and hematoma volume were assessed using a collagenase injection model in both young- and middle-aged mice with or without VitD treatment given 2 hours post-ICH induction. We used flow cytometry to analyze CD36 expression and macrophage and undifferentiated monocyte cell numbers during in vivo erythrophagocytosis in collagenase and autologous blood injection models. Western blot analysis and immunofluorescence were used to assess the expression levels of the PPAR-γ (peroxisome proliferator-activated receptor γ)-CD36 axis and CD206. A macrophage differentiation study was conducted on murine bone marrow-derived monocytes. RESULTS: VitD promoted neurological recovery and facilitated hematoma clearance in both young- and middle-aged mice after ICH. Within the perihematomal region, mature macrophages, rather than undifferentiated monocytes, expressed higher levels of CD36 in driving erythrocyte clearance. VitD increased the macrophage number but decreased the monocyte number and elevated the levels of CD36 and PPAR-γ in the brain. In vitro, VitD accelerated the differentiation of reparative macrophages from bone marrow-derived monocytes. CONCLUSIONS: VitD promotes reparative macrophage differentiation, facilitates hematoma clearance, and improves neurobehavioral performance in mice with ICH, suggesting that VitD should be further examined as a potentially promising treatment for ICH.

Protracted Morphological Changes in the Corticospinal Tract Within the Cervical Spinal Cord After Intracerebral Hemorrhage in the Right Striatum of Mice.

Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality rates. Currently, there is no promising treatment that improves prognosis significantly. While a thorough investigation of the pathological process within the primary site of injury in the brain has been conducted by the research field, the focus was mainly on gray matter injury, which partly accounted for the failure of discovery of clinically efficacious treatments. It is not until recent years that white matter (WM) injury in the brain after subcortical ICH was examined. As WM tracts form networks between different regions, damage to fibers should impair brain connectivity, resulting in functional impairment. Although WM changes have been demonstrated in the brain after ICH, alterations distant from the initial injury site down in the spinal cord are unclear. This longitudinal study, for the first time, revealed prolonged morphological changes of the contralesional dorsal corticospinal tract (CST) in the spinal cord 5 weeks after experimental ICH in mice by confocal microscopy and transmission electron microscopy, implying that the structural integrity of the CST was compromised extensively after ICH. Given the important role of CST in motor function, future translational studies targeting motor recovery should delineate the treatment effects on CST integrity.