On the other hand, high-dose glucocorticoid pretreatment interferes with apoptotic death in glioma cells and oligodendrocytes and reduces ischemic brain damage and retinal light damage ( Tuor, 1997 Gorman et al., 2000 Melcangi et al., 2000 Wenzel et al., 2001 Limbourg et al., 2002). The situation may be similar in the CNS : on the one hand, glucocorticoids enhance neuronal cell death ( Behl et al., 1997a), and glucocorticoid receptor antagonists are protective, for example, during oxidative stress ( Behl et al., 1997b McCullers et al., 2002). For example, glucocorticoids induce apoptosis in inflammatory and immune cells such as thymocytes, myeloma cells, and peripheral blood monocytes, whereas concomitantly they protect those cells and tissues in which the inflammation takes place (for review, see Amsterdam et al., 2002). Glucocorticoids act as a double-edged sword in the regulation of apoptosis. We identify p21 Waf1/Cip1 as a novel antiapoptotic factor for postmitotic neurons and implicate p21 Waf1/Cip1 as the molecular target of neuroprotection by high-dose glucocorticoids. Both germline and somatically induced p21 Waf1/Cip1 deficiency abrogate the neuroprotection by corticosterone, whereas overexpression of p21 Waf1/Cip1 suffices to protect neurons from apoptosis. Corticosterone-mediated upregulation of p21 Waf1/Cip1 and neuroprotection are completely abolished by glucocorticoid and mineralocorticoid receptor antagonists as well as inhibitors of PI3- and Akt-kinase. These effects of AF64A are reversed by pretreatment with corticosterone. Exposure of neurons to the neurotoxin ethylcholine aziridinium (AF64A) results in activation of caspase-3 and a dramatic loss of p21 Waf1/Cip1 preceding apoptosis in neurons. In primary cortical neurons, corticosterone leads to a dose- and Akt-kinase-dependent upregulation with enhanced phosphorylation and cytoplasmic appearance of p21 Waf1/Cip1 at Thr 145. Here, we demonstrate that corticosterone protects neurons from apoptosis by a mechanism involving the cyclin-dependent kinase inhibitor p21 Waf1/Cip1. Sunshine hours, however, peak in July and August at 10.2 hours, tailing off to a low of 3.1 hours by December.The role of glucocorticoids in the regulation of apoptosis remains incongruous. Regarding daylight hours, these increase from 9.7 hours in January, peaking at 15 hours in June, and decrease steadily thereafter. Snowfall is exclusively a feature of the colder months, commencing slightly in November at 2.01" and escalating to 5.31" by January. While the average rainfall days go about the same pattern, they peak in May at 19.2 days and drop to their lowest in November at 11.1 days, indicating a more pronounced and extended wet period between March and September and a shorter dry period from October to February. Precipitation yields a different pattern, increasing steadily from 2.36" in January and February to a peak of 3.19" in April, and then decreasing gradually to 1.77" by September, before picking up again towards the end of the year. Concurrently, the levels of relative humidity remain relatively stable, with average readings fluctuating between 78 to 85%. Fluctuations in temperature range from 19☏ in January to a peak of 81.5☏ in July. Tucked in the heartland of Ohio, USA, the town experiences highly variable weather, year-round. Millersburg enjoys a humid continental climate pattern, with no dry season and hot summer months, as classified by Koppen's climate classification (Dfa).
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