The developing cerebellum is extremely vulnerable to hypoxia which can damage the Purkinje neurons. We hypothesized that this might be mediated by tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) derived from activated microglia as in other brain areas. One-day-old rats were subjected to hypoxia following, which the expression changes of various proteins in the cerebellum including hypoxia inducible factor-1 alpha, TNF-alpha, IL-1 beta, TNF-R-1 and IL-1R(1) were analyzed. Following hypoxic exposure, TNF-alpha and IL-1 beta immunoexpression in microglia was enhanced coupled by that of TNF-R-1 and IL-1R(1) in the Purkinje neurons. Along with this, hypoxic microglia in vitro showed enhanced release of TNF-alpha and IL-1 beta whose receptor expression was concomitantly increased in the Purkinje neurons. In addition, nitric oxide (NO) level was significantly increased in the cerebellum and cultured microglia subjected to hypoxic exposure. Moreover, cultured Purkinje neurons treated with conditioned medium derived from hypoxic microglia underwent apoptosis but the incidence was significantly reduced when the cells were treated with the same medium that was neutralized with TNF-alpha/IL-1 beta antibody. We conclude that hypoxic microglia in the neonatal cerebellum produce increased amounts of NO, TNF-alpha and IL-1 beta which when acting via their respective receptors could induce Purkinje neuron death.
[1]Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Anat, Singapore 117597, Singapore.
[2]Kunming Med Univ, Fac Basic Med Sci, Dept Anat, Kunming 650500, Peoples R China.
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