Regulation of Neuregulin Expression in the Injured Rat Brain and Cultured Astrocytes

Abstract

In this report, we investigated whether reactive astrocytes produce neuregulins (glial growth factor 2/heregulin/acetylcholine receptor-inducing activity or neu differentiation factor) and its putative receptors, ErbB2 and ErbB3 tyrosine kinases, in the injured CNS in vivo. Significant immunoreactivities with antineuregulin, anti-ErbB2, and anti-ErbB3 antibodies were detected on astrocytes at the injured site 4 d after injury to the adult rat cerebral cortex. To elucidate the mechanisms for the upregulation of neuregulin expression in astrocytes, primary cultured astrocytes were treated with certain reagents, including forskolin, that are known to elevate the intracellular level of cAMP and induce marked morphological changes in astrocytes. Western blot analysis showed that the expression of a 52 kDa membrane-spanning form of a neuregulin protein was enhanced in cultured astrocytes after administration of forskolin. The upregulation of glial fibrillary acidic protein was also observed in astrocytes treated with forskolin. In contrast, inactivation of protein kinase C because of chronic treatment with phorbol ester 12-O-tetradecanoyl phorbol 13-acetate downregulated the expression of the 52 kDa isoform, although other splice variants with apparent molecular sizes of 65 and 60 kDa were upregulated. These results suggest that the enhancement of neuregulin expression at injured sites is induced, at least in part, by elevation in intracellular cAMP levels and/or a protein kinase C signaling pathway. The neuregulin expressed on reactive astrocytes may stimulate their proliferation and support the survival of neurons surrounding cortical brain wounds in vivo.

Neuregulin-1 Attenuates Neointimal Formation following Vascular Injury and Inhibits the Proliferation of Vascular Smooth Muscle Cells

“…The upregulation of NRG-1 and erbB receptors in the lesion area after injury may also account for the relatively lower concentrations of NRG-1 required in the in vivo studies compared with the amount required to block proliferation in the VSMC cultures. Similarly, the upregulation of NRG-1 and its erbB receptors has also been reported after ischemia and central nervous system injury [31,32,33,34,35,36]. As seen in the vascular injury model, we showed that administration of exogenous NRG-1 was neuroprotective and prevented inflammatory responses caused by ischemia [32, 37].…”

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

“…In the adult mouse cortex, erbB4 expression is detected at low levels in some astrocytes (Erlich et al, 2000). Astrocyte expression of erbB3 receptors is only reported during astrogliosis following injury of the rat adult cortex (Tokita et al, 2001).…”

Neuregulin in Cardiovascular Development and Disease

“…56,57 NRG-1 and its receptors are upregulated after traumatic brain injury in rat models. 58,59 NRG-1β exerts a cytoprotective effect against oxidant injury in multiple cell types in the brain, including the microvascular endothelial cell. 60 …”