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Susceptibility of the developing brain to acute hypoglycemia involving A₁ adenosine receptor activation

¹Section of Developmental Endocrinology and Biology, Yale Child Health Research Center, Department of Pediatrics, Yale University School of Medicine, New Haven Connecticut; and ²Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

Submitted 15 March 2005 ; accepted in final form 9 May 2005

It has been suggested that the developing brain is less vulnerable to the adverse effects of hypoglycemia than the mature brain; however, this issue remains controversial. We also do not know the magnitude or duration of hypoglycemia needed to trigger hypoglycemic brain injury during development. To address this issue a series of in vivo and in vitro studies were performed. First, we established an acute model of insulin-induced hypoglycemia in mice by administering 3 U/kg of neutral-protamine Hagadorn insulin subcutaneously. When we examined degenerating neurons in hippocampus and striatum by TUNEL labeling, injury was observed after 4 h of hypoglycemia in postnatal day (P)7 mice, and we observed more cell injury in animals rendered hypoglycemic at P7 than at P21. Studies of hippocampal slice cultures revealed that reduction in glucose concentration induced more neuronal injury in slices prepared from P3 and P7 than from P14 and P21 mice. Treatment of slices with an adenosine A₁ receptor (A₁AR) antagonist reduced the hypoglycemic damage, whereas agonists increased damage, particularly in slices prepared from very young pups. This suggests a critically important role for A₁ARs, which was further demonstrated by the reduction of hypoglycemic damage in hippocampal slices prepared from A₁AR^–/– mice. Furthermore, insulin-induced hypoglycemia in P7 A₁AR^–/– mice did not increase TUNEL-positive cells, but a major increase was seen in A₁AR^+/– mice. These observations show that the developing nervous system is indeed sensitive to acute hypoglycemic injury and that A₁AR activation contributes to damage induced by hypoglycemia, particularly in immature mouse brain.