Survival Time

It has long been recognized that neuron populations differ with respect to the time course of detectable injury, with relatively rapid progression in striatum and cortex (5) but characteristic delayed neuronal death in the CA1 region of hippocampus (4-6,170,171). Most other vulnerable neuron populations that have been examined in any detail, e.g., dentate hilus (5,7 ) and thalamic reticular nucleus (7,20), also show overt damage within 1 day or less. Factors affecting the timing of cell loss have therefore been extensively studied for CA1 neurons. The rate at which pathology evolves can be influenced by the severity of the initial insult, as suggested by observations that the "maturation" of CA1 neuronal damage is more rapid after ischemic insults of longer duration in the gerbil (4). A reexamination of the issue in the rat supported the same conclusion, showing maximal damage within 3 days after long occlusions (15 or 30 min), at which time animals subjected to 5-min ischemia had achieved approximately half of their eventual CA1 neuronal loss (172). Some studies have made specific use of short insults and efforts to avoid hyperthermia to produce a model that exhibits slow CA1 degeneration in the gerbil (173). However, this is not a particularly robust phenomenon, and recent experiments have identified negligible change in the depolarization threshold for CA1 injury in rats evaluated at survival times of 1 week or longer (80 ).

In contrast, a 1-week survival interval is not sufficient in the context of protection studies. Adrenalectomy slowed, but did not prevent, the evolution of hippocampal damage in a gerbil model (174). Similarly, an acute ischemic preconditioning protocol demonstrated protection at 3 days that was lost by 1 week (175). Brief postischemic cooling that was protective at 3-day survival (176) showed some residual attenuation of injury at 1 week that was completely lost by 2 months (177). Progressive neuronal loss was suggested to occur over many weeks in preconditioned animals (178,179), and this has been rigorously confirmed in recent depolarization-monitored studies in both gerbils (6) and rats (80). Although sustained lesion evolution between 1 and 3 months was suggested in previously preconditioned rats, injury progress occurred most markedly between 1 and 2 weeks (80). Available results therefore suggest a minimum standard of 2-week survival for future intervention studies.

Increased neurogenesis occurs in the dentate gyrus after global ischemia in gerbils (180,181), and some evidence suggests that proliferating cells can also be found in CA1 (182). However, long-term evaluations of hippocampal morphology after ischemia have typically shown either no change in the CA1 neuron population (183) or very small increases in neuronal density that may correlate with overall tissue shrinkage (184). However, one report described detectable CA1 repopulation at long survival intervals after severe ischemia in a rat model of

4-VO plus hypotension that becomes more robust with supplementary growth factor treatments (75). CA1 neuronal recovery by 3 months was also suggested in a more variable 2-VO model (185), and very recently, striking increases in CA1 neuron number were described by 90 days in a 2-VO model using halothane-induced hypotension (186). In contrast, it is certain that no such recovery occurs within the same interval after depolarization-monitored 4-VO (80). Resolution of the sources of variability underlying these conflicting observations requires a new generation of very long-term survival studies, for which highly controlled and predictable models will be essential.

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