Sex differences in the effects of PARP inhibition on microglial phenotypes following neonatal stroke

Abstract

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^gfp-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.

Keywords: Amygdala; Cortex; Microglial phenotype; Neonatal stroke; Neurobehavioral deficits; Poly (ADP-ribose) polymerase inhibitor.