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In Vitro Data Supporting a Role for p38 MAPK in Neurodegeneration

Much of the in vitro evidence for a role for p38 MAPK in neuronal cell death comes from studies with PC12 cells, a rat pheochromocytoma cell line which responds to nerve growth factor (NGF). Withdrawal of NGF from these cells results in apoptosis and a concomitant induction of p38a and JNK MAPK activity. Furthermore, these studies also demonstrated that this cell death could be inhibited by the p38a MAPK inhibitor PD169316 (Kummer et al. 1997). It is becoming clear from a number of studies that activation of p38a MAPK and its relative role in neuronal cell death is stimulus dependent. The induction of apoptosis by calyculin in cortical cultures could partially be reversed by PD169316, whereas the induction of excitotoxic cell death by N-methyl-d-aspartate (NMDA) was not (Ko et al. 2000). Furthermore, SB 203580 could not rescue apoptotic rat ganglion neurons deprived of neurotrophins (Maas et al. 1998), whereas in a separate study it did extend the survival of retinal ganglion neurons exposed to NMDA (Kikuchi et al. 2000). Most recently, Legos and colleagues demonstrated that the selective p38 MAPK inhibitor SB 239063 could confer neuroprotection to cultured primary neurons exposed to NMDA for 5 min, but not for 60 min (Legos et al. 2002).

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