Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat

Two relatively well characterised kinase signalling pathways are those invo lving MAPK/ERK and p38/SAPK2, that are known to be activated in vitro by va rious factors known to increase following stroke, such as glutamate, IL-1 a nd TNF. The present study was designed to investigate the activation and ce llular distribution of phosphorylated-ERK1/2, -p38 and the transcription fa ctor CREB following focal cerebral ischaemia using phosphospecific antibodi es. Up to 24 h following transient MCAO (90 min) and 6 h following permanen t MCAO, phospho-ERK1/2 staining was markedly increased within the cytoplasm of neuronal perikarya in 'penumbral-like' regions. In contrast, phospho-p3 8 immunostaining was markedly increased in cells with astrocyte-like morpho logy in both 'core' and 'penumbral-like' regions. Phospho-p38 staining was also detected in some neurones within 'penumbral-like' regions up to 24 h f ollowing transient MCAO. CREB activation was confined to neurones in 'penum bral-like' regions. Increased phospho-p38 immunoreactivity was detected in astrocyte-like cells present in the subcortical white matter ipsilateral to the occluded MCAO, while phospho-CREB and -ERK1/2 staining was localised t o cells with the morphological appearance of oligodendrocytes. This study d emonstrates phosphorylation, indicative of activation, of both the MAPK and p38 pathways following transient and permanent MCAO. However, each pathway shows a distinct cellular and spatial distribution within ischaemic tissue . Together these data indicate that neuroprotection offered by agents direc ted towards the ERK1/2 pathway may act directly through protection of neuro nes and oligodendrocytes, while those directed towards the p38 pathway kina se signalling pathways may be indirectly via inhibition of cytokines and ot her mediators involved in the brains response to injury. (C) 2000 Elsevier Science B.V. All rights reserved.