A Pilot Study On MyD88-dependent Neuroprotection Against Cerebral Hypoperfusion

Brain injury following ischemia develops from a series of pathophysiological events that evolve over time and space.The reduction in cerebral blood flow restricts the energy supply that is required to maintain ionic gradients,causing neurons to depolarize and then suffer from excitotoxicity.At a late stage,over-activation of inflammation and apoptosis further aggravates brain injury in a larger scale.Since no new treatments have been approved to protect neurons from ischemic injury effectively,the focus should shift to depicting brain's capacity of self-preservation.It is reported that the sensitivity of mammalian central nervous system(CNS)to ischemia is region-specific.CA1 pyramidal neurons in the hippocampus degenerate after transient forebrain ischemia,whereas neurons in the CA3 subfield and cortex are resistant to the cerebral hypoperfusion.However,the mechanisms underlying this differential vulnerability remain largely unclear.Here we report that myeloid differentiation factor 88(My D88),a key adaptor of the Toll-like receptors(TLRs),plays a crucial role in resistance to cerebral hypoperfusion.Our results show that My D88 expression levels in different regions in the CNS are in accordance with the region's sensitivity to ischemia.Moreover,we find that reducing My D88 aggravates bilateral common carotid artery occlusion(BCCAo)-induced ischemic injury in the CA3 area,leading to a loss of habituation in an open field.Furthermore,we have developed an early ischemic model based on BCCAo,in which slightly increased intraoperative body temperature(38 ± 0.2°C)leads to pyknosis of CA1 pyramidal neurons at 8 h after ischemia before microgial cells are activated.Taking advantages of this model,we confirm that My D88 protects neurons in the early phase of ischemia.Taken together,these results indicate My D88 is an endogenous protective molecule,and its protective effect may not be related to the activation of TLR-mediated immune pathways,but to the suppression of the ischemic excitotoxicity.