Protective Effects Of Allopurinol And Moderate Hypothermia On Hypoxic-ischemic Brain Damage In Neonatal Rats

Hypoxic-ischemic brain damage ,HIBD resulted from birth asphyxia remains acommon causes leading to acute mortality and chronic neurological disability insurvivors. Few therapeutic interventions are available for clinical use. Currentlyexperimental cerebral protective interventions for HIBD including pharmacologicagents (for examples:antagonists of excitatory amino acids, calcium channel blocker,free-radical scavengers, NO synthase inhibitor) and nonpharmacologic interventions(for example: moderate hypothermia). Allopurinol is both an inhibitor of xanthine oxidase and a scavenger of freeradicals. It has been used successfully to reduce ischemic injury of theheart ,kidney,small intestine ,and adult rat brain. Allopurinol could have achieved thiseffect by either (1) improved cerebral blood flow,(2) preservation of purine bases forATP resynthesis,(3)facilitation of mitochondrial electron transfer , (4) antioxidantactivity or (5) inhibition of apoptosis . Studies have shown that allopurinoladministered subcutaneously before or after inducing hypoxia-ischemia reduces braininjury in 7-day-old rats. High dose of allopurinol was proved to have a goodprotective effect in neonatal infant with asphyxia and no poisonous side effects was found .Allopuriol was administered intraperitoneally in the present study,and its protective effects andmechanisms on HIBD in neonatal rat were investigated. Moderate hypothermia referred to a slight lowering of body temperature (2-6℃)which in turn preduce a marked protection against hypoxic-ischemic damage incentral neurons. There were increasing evidence showing that moderate hypothermiaseems to be a promising therapy for acute hypoxic-ischemic brain injury as a result ofacute perinatal asphyxia. The underlying mechanisms includ (1)decrease metabolicrate; (2) suppressing glutamate surge followed by; (3) intraneuronal calciummobilization; (4) sustained activation of glutamate receptors; (5) dysfunction of bloodbrain barrier; (6) proliferation of microglial cells; (7) production of superoxide anionsand nitric oxide; and (8) inhibition of neuronal apoptosis. This non-specific andwidely affecting manner plus its simple carrying-out, safety and economy mightexplain why hypothermia is superior to any medicine developed. Nowadays moderate hypothermia and other medicines combined together were VI复旦大学博士学位论文 别嘌呤醇和亚低温对新生大鼠缺氧缺血性脑损伤的保护作用used in the therapeutic interventions in adult animal HIBD and prominent effects wereobserved in most studies. Allopurinol combined with moderate hypothermia has notbeen reported so far. We propose that there may be a synergistic effect of allopurinol andmoderate hypothermia used in the treatment of HIBD. Periventricular leukomalacia (PVL) is a form of white matter disease found mostcommonly in premature infants with very low birth weight (<1500g). PVL in new-born infants is frequently associated with severe long-term neurological morbiditysuch as cerebral palsy, mental retardation and visual impairment. With appreciablyimproved perinatal care, the survival rate of premature infants is greatly increased,while the incidence of cerebral palsy in these infants remains high and is evenincreasing in some countries. It is essential to understand pathophysiological andmolecular mechanisms underlying PVL so that to develop strategies,which in turnprevent its occurrence or to ameliorate adverse consequences.Bilateral carotid arteryocclusion(BCAO) was used to establish animal models of white mater damage withpostnatal day 1 or 5 abroad. However, the kind of reports has not been reported inChina. In the present study, we performed the BCAO surgery in rat pups on postnatalday 1 to establish white matter damage model. Brain injury was examined onpostnatal days 7 and 14 by immunohistochemistry and other methods. The under...