U1141 PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, 48 boulevard Sérurier, 75019 Paris, France.
EA4475 - Pharmacologie de la Circulation Cérébrale, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, 4 avenue de l'Observatoire, 75006 Paris, France.
Brain Behav Immun. 2018 Oct;73:375-389. doi: 10.1016/j.bbi.2018.05.022. Epub 2018 May 28.
Neonatal acute ischemic stroke is a cause of neonatal brain injury that occurs more frequently in males, resulting in associated neurobehavioral disorders. The bases for these sex differences are poorly understood but might include the number, morphology and activation of microglia in the developing brain when subjected to stroke. Interestingly, poly (ADP-ribose) polymerase (PARP) inhibition preferentially protects males against neonatal ischemia. This study aims to examine the effects of PJ34, a PARP inhibitor, on microglial phenotypes at 3 and 8 days and on neurobehavioral disorders in adulthood for both male and female P9 mice subjected to permanent middle cerebral artery occlusion (pMCAo). PJ34 significantly reduced the lesion size by 78% and reduced the density of CX3CR1-labeled microglial cells by 46% when examined 3 days after pMCAo in male but not in female mice. Eight days after pMCAo, the number of Iba1/Cox-2 cells did not differ between male and female mice in the cortical peri-infarct region. In the amygdala, Iba1/Cox-2 (M1-like) cell numbers were significantly decreased in PJ34-treated males but not in females. Conversely, Iba1/Arg-1 (M2-like) and Arg-1/Cox-2 (Mtransitional) cell numbers were significantly increased in PJ34-treated females. Regarding neurobehavioral disorders during adulthood, pMCAo induced a motor coordination deficit and a spatial learning deficit in female mice only. PJ34 prevented MBP fibers, motor coordination and learning disorders during adulthood in female mice. Our data show significant sex differences in the effects of PARP inhibition on microglia phenotypes following neonatal ischemia, associated with improved behavior and myelination during adulthood in females only. Our findings suggest that modulating microglial phenotypes may play key roles in behavior disorders and white matter injury following neonatal stroke.
新生儿急性缺血性脑卒中是一种发生于男性的新生儿脑损伤病因，可导致相关神经行为障碍。这些性别差异的基础尚不清楚，但可能包括在发生脑卒中时，发育中的大脑中的小胶质细胞的数量、形态和激活情况。有趣的是，多聚（ADP-核糖）聚合酶（PARP）抑制剂优先保护雄性免受新生儿缺血的影响。本研究旨在探讨 PARP 抑制剂 PJ34 对雄性和雌性 P9 小鼠永久性大脑中动脉闭塞（pMCAo）后 3 天和 8 天的小胶质细胞表型以及成年后神经行为障碍的影响。PJ34 在雄性小鼠而非雌性小鼠 pMCAo 后 3 天检查时，显著将梗死体积缩小了 78%，并将 CX3CR1 标记的小胶质细胞密度降低了 46%。pMCAo 后 8 天，在皮质梗死周边区，雄性和雌性小鼠之间 Iba1/Cox-2 细胞的数量没有差异。在杏仁核中，PJ34 处理的雄性小鼠中 Iba1/Cox-2（M1 样）细胞数量显著减少，但雌性小鼠中则没有。相反，PJ34 处理的雌性小鼠中 Iba1/Arg-1（M2 样）和 Arg-1/Cox-2（M 过渡样）细胞数量显著增加。关于成年期的神经行为障碍，pMCAo 仅在雌性小鼠中引起运动协调缺陷和空间学习缺陷。PJ34 预防了成年期雌性小鼠的 MBP 纤维、运动协调和学习障碍。我们的数据显示，PARP 抑制对新生儿缺血后小胶质细胞表型的影响存在显著的性别差异，与成年期雌性小鼠行为和髓鞘形成的改善有关。我们的研究结果表明，调节小胶质细胞表型可能在新生儿脑卒中后行为障碍和白质损伤中发挥关键作用。
