Protective Effect And Underlying Mechanisms Of Moderate Hypothermia And Huperzine A On Neonatal Rats Brain After Hypoxia-ischemia

Perinatal asphyxia remains one of the most devastating neurologic processes leading to acute mortality and chronic neurological disability in survivors. Depending on the extent, duration, timing and location, mental retardation, cerebral palsy and disorders of sensorimotor coordination can develop in these children, which result in considerable impact on the affected children and their families. Despite of the severe clinical and social significance, few therapeutic interventions are available for clinical use, and the care of infants with HIE is largely limited to supportive measures. Currently experimental cerebral protective interventions for HIBD including pharmacologic agents (for examples:antagonists of excitatory amino acids, calcium channel blocker, free-radical scavengers, NO synthase inhibitor) and nonpharmacologic interventions (for example: moderate hypothermia).Moderate hypothermia referred to a slight lowering of body temperature (2-6℃) so as preduced a marked protection against hypoxic-ischemic damage in central neurons. There were increasing body of evidence showing that moderate hypothermia seems to be a promising therapy for acute hypoxic-ischemic brain injury as a result of acute perinatal asphyxia, because the mode of action of hypothermia is apparently non-specific and multi-focal in widely progressing cascade reactions in hypoxic-ischemic neurons; namely, suppressing: (1) glutamate surge followed by; (2) intraneuronal calcium mobilization; (3) sustained activation of glutamate receptors; (4) dysfunction of blood brain barrier; (5) proliferation of microglial cells; (6) production of superoxide anions and nitric oxide; and (7) inhibition of neuronal apoptosis. This non-specific and widely affecting manner plus its simple carrying-out, safety and economy might explain why hypothermia is superior to any medicine developed.Extensive studies, both in basic and clinical fields, have showen the specific inhibition of apoptosis after cerebral HI by moderate post-insult hypothermia, but the precise mechanisms are not well understood as yet. Apoptosis is an evolving active cell death process differencing from necrosis. Theoretically, apoptosis pathway is divided into three stages presented as a sequential series of events moving from initiation,commitment and execution and every stage has its characteritic events. The initiation stage consists of initial signal transduction pathway (MAPK) and activation of immediate early genes following an apoptotic stimulus. The commitment stage reprents the convergence of various apoptotic pathway onto mitochondria which play a pivotal role in regulating neuronal apoptosis and ends at the point cells commit to die. The commit point serves as an irreversible step for the cell-upstream of this point the cell death process can be reversed; however, downstream of this specific biochemical event the cell is committed to die. The excution stage begins with the pathway leading directly to the hallmark morphologic changes. This experiment was designed to explore the underlying mechanisms of specific inhibition effect of induced moderate hypothermia on neuronal apoptosis in neonatal rats after HI brain injury.Clinically, the prominent characteristic of HIE is the deterioration in memory and cognition, which is associated with a marked hypofunction of the cholinergic system resulting from degeneration of cholinergic neurons in the selective vulnerable region such as hippocampus, striatum and cortex. Hence, the anti-dementia agent with broad neuroprotection is supposed to be a promising candidate as the symptomatic treatment for this kind of disorder. Huperzine A (HupA), a novel Lycopodium alkaloid isolated from the Chinese herb, Huperzia serrata, is an effective cognition enhancer owing to its long-lasting inhibition of AChE, high oral availability and minimal peripheral side effects. Previous studies have shown that this agent exhibited memory-enhancing efficacy in a broad range of animal models of cognitive impairment, in Alzheimer's disease (AD) and in the aged...