The Effect of Age on Susceptibility to Hypoxic-Ischemic Brain Damage

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Abstract

YAGER, J.Y. AND J.A. THORNHILL. The effect of age on susceptibility to hypoxic-ischemic brain damage. NEUROSCI BIOBEHAV REV 21 (2) 167–174, 1997.—Stroke occurs in all age groups, ranging from the new-born to the elderly. Our current understanding of the mechanisms of ischemic brain injury suggests that, despite age, the underlying cascade of events includes the rapid depletion of energy reserves, lactate accumulation, release of excitatory amino acids, high intracellular concentrations of Ca2+, and the production of oxygen free radicals. The extent to which these events affect brain injury, however, is profoundly influenced by age. Hyperglycemia for example, markedly enhances hypoxic-ischemic brain damage in adults, but has a protective effect in new-born rats. Insulin-induced hypoglycemia, on the other hand, protects the adult brain, but may be detrimental to the new-born. Substrate utilization of ketone bodies is markedly enhanced in the new-born, and has now been shown also to protect the brain. The immature brain is generally believed to be more resistant to the damaging effects of cerebrovascular compromise compared to the more mature brain. However, recent experiments suggest that the correlation between brain damage and age is not linear. To further clarify the effects of age and development on hypoxic-ischemic brain damage, we developed a model whereby rats of increasing age received identical cerebrovascular insults. Neuropathologic assessment at 7 days of recovery showed that brain damage was most severe in the 1- and 3-week-old animals followed by those that were 6 months. The 6- and 9-week-old groups had significantly less injury than the other three age groups. Hippocampal damage was most severe in the 3-week and 6-month-old rats compared to all other age groups. These findings contrast previously held beliefs regarding the enhanced tolerance of the immature brain to hypoxic-ischemic damage and demonstrate that the immature brain is, in fact, less resistant to hypoxic-ischemic brain damage than its adult counterpart. The results emphasize the need for a greater understanding of the effects of ontogeny on hypoxic-ischemic brain damage, particularly as it pertains to the development of therapeutic interventions. © 1997 Elsevier Science Ltd. All rights reserved.

Section snippets

INTRODUCTION

STROKE IS a health hazard most commonly associated with the elderly. In recent years, it has become evident, however, that this disease affects the lives of individuals of all age groups 4, 5. Annual incidence rates have suggested that as many as 65–90 per 100,000 people between the ages of 15 and 49 years experience an ischemic cerebral infarct [68]. Experience from the Lausanne Stroke Registry, which surveys patients in Switzerland, revealed that 12.3% of all individuals with a first-ever

DEVELOPMENT, SUBSTRATE UTILIZATION AND HYPOXIA-ISCHEMIA

While the fundamental mechanisms underlying hypoxic-ischemic brain injury are being increasingly well understood, the extent to which they affect the brain at different ages remains relatively unknown. Some insight into these differences comes from work in which the age-specific differences of hypoxic-ischemic injury to glucose supplementation were elucidated. In that regard, hyperglycemia has, for some time, been recognized as enhancing the brain damaging effects of hypoxia-ischemia. Myers et

AGING AND HYPOXIA-ISCHEMIA

It is clear from the above discussion that, while the basic mechanisms underlying hypoxic-ischemic injury may be similar in different age groups, the effects of these mechanisms on the neuropathological outcome may be vastly different. Until recently, the developing animal has been reported to be far more resistant to the damaging effects of hypoxia-ischemia than its adult counterpart. Duffy et al. [21]exposed new-born and adult rats to anoxia for variable lengths of time, and found that the

DISCUSSION

Many early reports showed younger animals to be more resistant to hypoxia/anoxia than their adult counterparts 2, 21, 23, 25. The phenomenon of an age related tolerance to hypoxic-ischemic brain damage in the young has, however, never been shown in in vivo preparations. Jilek et al. [36]produced stagnant ischemia of the brain in rats aged 10–180 days. As found by others, he found enhanced survival in the very young animals, with those aged 20–30 days doing least well. Histopathologically,

Acknowledgements

This research was supported by grants from the Heart & Stroke Foundation of Saskatchewan.

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