The Study Of Mechanism And Therapeutic Effects Of Anakinra I.v. In Cerebral Ischemic Rat

Inflammatory reactions of central nerve system play an essential role in the pathophysiologic process of ischemic brain injury, especially during the enlargement of damage and the secondary damage after ischemia. Proinflammatory factor expression in ischemic brain has a close relationship with occurrence, development and prognosis of cerebral ischemia. There are huge cytokine expression and proinflammatory infiltration in damage area after ischemic brain injury, which aggravate brain injury especially in reperfusion. Interleukin (IL) is one of the most important factors among these proinflammatory factors. All kinds of interleukin take part in inflammatory reactions and play various effects. IL-1β is an inflammatory factor regulating the complex pathologic changes of acute cerebral ischemia. IL-1β mRNA protein level increases after cerebral ischemia and reperfusion. In a model of middle cerebral artery occlusion, IL-1β mRNA was expressed markedly at 15 min after ischemia, peaked at 3 hr and died away during four days suggesting IL-1β plays an important role in inflammation of local cerebral ischemia. IL-1β is relative with ischemic, excitatory and traumatic brain injury. There is a native interleukin-1 receptor antagonist (IL-1ra) in the body which is a glycosylated protein with 23～25 kDa molecular weight and a native inhibitor of IL-1 receptor antagonist (IL-1ra). IL-1ra competitively inhibits the binding of IL-1 to the IL-1R and produces no IL-1 signal transduction.Anakinra, a recombinant, non-glycosylated form of human interleukin-1 receptor antagonist (rhIL-1ra), is identical to a native IL-1 receptor antagonist except for a methionine residue that has been added to the beginning of the amino acid sequence. It is expressed in E. coli, form of 153 amino acids and the molecular weight is 17.3 kDa which is recommended to treat rheumatoid arthritis. It cannot pass through the blood brain barrier in normal animals. There is no article about animal studies of Anakinra being administered iv in cerebral ischemia . We have analysed therapeutic effect and therapeutic time window of Anakinra on cerebral ischemia in several experimental models and its mechanism for therapy of cerebral ischemia at molecular level. This study provides evidence for the treatment of cerebral ischemia by inhibiting inflammatory reaction. We also searched therapy for cerebral ischemia with longer time window and investigated permeability of blood brain barrier system for biological macromolecules in cerebral ischemia, which represents a more scientific, more impersonal and more modern approach to the treatment of ischemic brain injury.In this study, we produced ischemic brain injury by permanent or ischemia-reperfusion model of middle cerebral artery occlusion (MCAO). Anakinra was injected intravenously at 3,6,12 hr after ischemia. It was found that Anakinra obviously reduced the damage of nervous function and brain, which indicated Anakinra could cross blood brain barrier for treatment in cerebral ischemia. The therapeutic time window of previous drugs for the treatment of cerebral...