Glucose and Other Physiologic Variables

Elevated blood glucose can worsen global ischemic injury in a number of rodent models (37,113,160-163), and it is an established practice to minimize this potential variability by fasting animals prior to an insult. However, the impact of glucose level is dependent on both insult duration and occlusion efficacy. Hippocampal CA1 neuronal loss after insults of moderate duration in the gerbil appears to be insensitive to the physiologic range of glucose variation between fed and fasted states (138). Pathology can be largely unaffected even by profound hyperglycemia after insults of several minutes' duration in either rats (135) or gerbils (164), although other studies have noted increased striatal injury after occlusions as short as 4 min (165). Importantly, a threshold of approximately 12 mM glucose must be exceeded to exacerbate injury in a standard rat model of 10-min 2-VO plus hypotension (166). This permits the use of normally fed animals in most global ischemia studies, which is a practical necessity in preconditioning paradigms that may involve insults repeated on successive days. To the extent that glucose effects can be attributed to greater acidosis under conditions of sustained substrate delivery (38,167), its potential impact will be minimized in models that involve short, effective occlusions.

Elevated glucose sustains anaerobic metabolism and prolongs the delay in ischemic depolarization (168), which might be expected to reduce the impact of very short occlusions. However, as noted above, a quite surprising report indicated that profound hyperglycemia, sufficient to completely prevent hippocampal depolarization during brief ischemia, nevertheless permitted detectable CA1 loss to occur (135). This would imply that neuronal damage could occur in the absence of overt ion fluxes associated with ischemic depolarization. A lingering technical concern is that different groups of animals were used to generate the physiologic and pathologic data in that study, and any differential cooling that might have occurred during the brain exposure necessary for physiologic recording would not have been present in the histopathology group. Nevertheless, this remains an intriguing observation, and the extent to which differences in blood glucose may contribute to the small residual heterogeneity in outcome in depolarization-monitored studies remains to be fully investigated.

Global ischemia models are relatively insensitive to variations in blood gases. Extreme hypercapnia can worsen ischemic injury when associated with reductions in pH comparable to those observed during hyperglycemic ischemia (169). Moderately reduced oxygenation has been observed to attenuate pharmacologic protection in one study (138 ).

In summary, modest variations in glucose and blood gases appear to have comparatively little impact under the conditions of severe CBF reduction and short insult duration that characterize current global ischemia models. No difficulties have been encountered with the use of fed, spontaneously respiring animals to define consistent depolarization thresholds for hippocampal injury in rats and gerbils (60,79,80). Nevertheless, it remains good practice to establish the impact of physiologic variables on outcome under specific conditions of model usage.

Metabolism Masterclass

Metabolism Masterclass

Are You Sick And Tired Of All The Fat-Burning Tricks And Trends That Just Don’t Deliver? Well, Get Set To Discover The Easy, Safe, Fast, And Permanent Way To Mega-Charge Your Metabolism And Lose Excess Fat Once And For All! This Weight Blasting Method Is Easy AND Natural… And Will Give You The Hot Body And Killer Energy Levels You’ve Been Dreaming Of.

Get My Free Ebook


Post a comment