Cilostazol Attenuates Gray and White Matter Damage in a Rodent Model of Focal Cerebral Ischemia

60 There is little published evidence for protection of white matter with neuroprotective drugs in animal models of stroke, yet white matter protection may be important in achieving clinical efficacy. We have examined the effects of NXY-059, a nitrone-based free radical trapping agent, on long-term functional disability in a primate model of stroke. We also examined histopathological effects, including analyses of grey and white matter damage. Five minutes after unilateral permanent middle cerebral artery occlusion, marmosets received a 1 ml i.v. infusion of saline (n=5) or NXY-059 (28 mg/kg) (n=6) and osmotic minipumps (model 2001D) were implanted s.c. to provide continuous drug or saline infusion for 48 h. Drug-filled pumps released NXY-059 at a rate of approximately 16 mg/kg/h. The plasma unbound drug concentration at 24 h was 76.3 ± 5.7 μM, a level well tolerated in acute stroke patients. The monkeys had been trained and tested on a variety of behavioral tasks before surgery. NXY-059-treated monkeys were significantly better at reaching with their contralesional arm than were saline-treated monkeys when re-tested 3 (p<0.01) and 10 weeks (p<0.01) after surgery. NXY-059-treatment also significantly reduced spatial neglect measured 3 weeks after surgery (p<0.01) compared with the saline group. After behavioral testing was complete, histopathological analysis showed NXY-059-treated monkeys had significantly smaller infarcts than saline-treated monkeys (F (1, 10)=5.21, p<0.05). NXY-059 reduced overall infarct size by 51%, damage to the cortex was reduced by 54%, white matter by 52%, caudate by 49%, and putamen by 33% compared with saline-treated monkeys. In conclusion, NXY-059 substantially lessened the functional disability in these monkeys. This drug protects not only cortical tissue, but also white matter and subcortical structures against ischemic damage. Together these findings bode well for advancing this drug to further clinical trials for its use in acute stroke.

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Abstract TMP30: M2 Microglia Derived Exosomes Promote White Matter Repair and Long-Term Functional Recovery After Focal Cerebral Ischemia in Mice

Stroke ◽

10.1161/str.51.suppl_1.tmp30 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Yongfang Li ◽

Longlong Luo ◽

Zhijun Zhang ◽

Yaohui Tang ◽

Guo-Yuan Yang

Keyword(s):

White Matter ◽

Cerebral Ischemia ◽

Focal Cerebral Ischemia ◽

Oligodendrocyte Precursor Cells ◽

Oligodendrocyte Precursor Cell ◽

M2 Microglia ◽

Oligodendrocyte Precursor ◽

White Matter Repair ◽

Exosomal Mirna

Objectives: White matter injury aggravates neurological and cognitive impairment in experimental ischemic stroke. M2 microglia promote oligodendrocyte precursor cells survival and differentiation, and further enhance white matter repair. However, the molecular mechanism is unclear. Here, we explored the effect and mechanism of M2 microglia-derived exosomes on white matter repair after focal cerebral ischemia in mice. Methods: Microglia BV2 cells were polarized to M2 phenotype by IL-4 stimulation. Exosomes were isolated from M2 microglia (M2-Exo) and unstimulated microglia as a control (M0-Exo). M2-Exo and M0-Exo (100 μg) were intravenously injected after 90-minute middle cerebral artery occlusion in mice (n=72). Brain atrophy volume and neuro behavioral outcomes were examined in 28 days following focal cerebral ischemia. Oligodendrocyte precursor cells survival, differentiation and white matter integrity were evaluated. Exosomal miRNA and target gene were further examined to explore molecular mechanism. Results: M2-Exo treatment promoted sensorimotor and memory function recovery ( p <0.05), and further reduced brain atrophy compared to the M0-Exo control group ( p <0.001). Immunostaining showed that M2-Exo increased the number of BrdU + /Pdgfr-α + and BrdU + /adenomatous polyposis coli + cells, enhanced myelin basic protein fluorescence-intensity compared to the control ( p <0.05). M2-Exo increased oligodendrocyte precursor cell survival under OGD in vi tro , ( p <0.05) and differentiation ( p <0.05). Exosomal miRNA sequencing and PCR identified that miR-23a-5p was enriched in M2-Exo. Conclusion: Our results showed that M2-Exo treatment enhanced oligodendrocyte precursor cell survival and differentiation, further promoted white matter repair and long-term functional recovery, suggesting that M2-Exo is a novel therapeutic strategy for the white matter repair after ischemic brain injury.

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