Keelan, Julie; (1997) A study of the effects of glucose and oxygen deficiency on the function of synaptosomes: A model for ischaemia in immature and adult rat brain. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Immature animals show a heightened resistance to episodes of ischaemia in comparison with fully matured animals. Although this phenomenon has been observed for a number of decades, the underlying physiological and biochemical mechanisms allowing this increased resistance remain obscure. This study has concentrated on comparing a number of biochemical responses of neonatal and adult nerve terminals to episodes of in vitro ischaemia and reperfusion. Under such conditions of metabolic stress it was found that adult and neonatal isolated nerve terminals (synaptosomes) behaved very differently. Adult synaptosomes exhibited a decrease in adenosine triphosphate (ATP) levels and an increase in cytosolic calcium during ischaemia. Following a short recovery period there was a significant production of the free radical nitric oxide from adult synaptosomes. Increased calcium levels and increased free radicals have been implicated as causative factors in mitochondrial dysfunction. There was a significant decrease in the activities of two enzymes of the mitochondrial respiratory chain, namely complex II-III and complex IV after ischaemia in the adult synaptosomes. Neonatal synaptosomes did not exhibit increased cytosolic calcium or nitric oxide production. Furthermore there was no significant decrease in the activity of any of the enzymes of the mitochondrial respiratory chain after ischaemia/reperfusion in these neonatal synaptosomes. Oxidative stress of adult and neonatal synaptosomes was induced by the addition of exogenous peroxynitrite - a highly damaging reactive oxygen species which is widely implicated in oxidative damage. Adult synaptosomes exhibited the same pattern of mitochondrial dysfunction as that occurring after ischaemia/reperfusion. Furthermore, neonatal synaptosomes once again showed no such dysfunction. The total antioxidant status of adult and neonatal synaptosomes was found to be similar, however neonatal synaptosomes showed a two-fold greater concentration of the antioxidant peptide reduced glutathione. Interestingly, measured glutathione levels were also found to significantly increase in neonatal synaptosomes following ischaemia, but not in adult synaptosomes. it is concluded that oxidative damage to nerve terminals may have a role in the increased susceptibility of adult animals to episodes of ischaemia/reperfusion, and that glutathione could have an important role in protection.

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