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Cerebellar granule neurons undergo apoptosis when deprived of chronic depolarization; serum deprivation has not been considered as a trigger of apoptosis in this culture. Here we report that serum removal triggers cell injury, which is characterized by signs of apoptosis. Actual cell death (trypan blue permeability) occurred 24 and 48 hr after serum removal. At earlier times (6 and 8 hr after serum removal) we found significant impairment of mitochondrial functioning [3‐(4,5‐dimethyl thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay] and an increase in the percentage of neurons showing signs of DNA fragmentation (in situ terminal deoxynucleotidyl transferase assay, fluorescent assay). Protection was obtained by inhibiting RNA synthesis with actinomycin D and by antioxidants [1 mM: 1,4‐diazobicyclo(2.2.2)octane, histidine, mannitol; 1% dimethyl sulfoxide; 0.01–1 μM ascorbic acid]. We also measured neuronal oxidation utilizing the oxidation‐sensitive fluorescent dye 2′,7′‐dichlorofluorescin diacetate, and found a significant increase in the rate of neuronal oxidation as early as 15 min after serum deprivation. The blockade of glutamate receptors by (+)‐5‐methyl‐10,11‐dihydroxy‐5H‐dibenzo(a,d)cyclohepten‐5,10‐imine (MK‐801) and 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione also provided neuroprotection. However, oxidative stress appears to precede glutamate receptor activation: within the 8 hr period of serum deprivation, mannitol was protective when present either during only the first or last 4 hr; MK‐801 was protective only when present for the entire 8 hr period or in the last, but not first 4 hr of serum deprivation. Serum deprivation of mature cerebellar granule neurons can be used to study mechanisms of oxidative stress‐induced apoptosis. © 1996 Wiley‐Liss, Inc.

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This study demonstrates that the photochemically induced model of stroke is an extremely viable method of inducing cerebral infarction in old animals. The lesions are reproducible both in terms of location and size and compatible with long-term survival of the animal. With this model we demonstrated, one week following surgery, a significantly larger infarct in rats 20 and 24 months of age compared to 4-month-old rats. The older rats also sustained greater neurologic deficits as assessed on a rotarod task. Older rats also were characterized by a glial response that was far less intense than in young animals. While the precise relationship between glia activation and cerebral damage remains to be determined, it would appear that a better understanding of those factors that contribute to the astrocytic response in the aged rat may be of particular benefit in designing therapeutic strategies aimed at reducing the pathologic consequences of cerebral infarction in elderly humans.

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