The Role of the Neuroprotective Factor Npas4 in Cerebral Ischemia

Abstract

Stroke is one of the leading causes of death and adult disability in the world. Although many molecules have been documented to have a neuroprotective effect, the majority of these molecules failed to improve the neurological outcomes for patients with brain ischemia. It has been proposed that neuroprotection alone may, in fact, not be adequate for improving the prognosis of ischemic stroke. Neuroprotectants that can regulate other processes which occur in the brain during ischemia could potentially be targets for the development of effective therapeutic interventions in stroke. Neuronal Per-Arnt-Sim domain protein 4 (Npas4) is an activity-dependent transcription factor whose expression is induced in various brain insults, including cerebral ischemia. It has been shown that Npas4 plays an important role in protecting neurons against many types of neurodegenerative insult. Recently, it was demonstrated that Npas4 indeed has a neuroprotective role in ischemic stroke and that Npas4 might be involved in modulating the cell death pathway and inflammatory response. In this review, we summarize the current knowledge of the roles that Npas4 may play in neuroinflammation and ischemia. Understanding how ischemic lesion size in stroke may be reduced through modulation of Npas4-dependent apoptotic and inflammatory pathways could lead to the development of new stroke therapies.

Keywords: Npas4; apoptosis; ischemic stroke; neuroinflammation; neuroprotection.

Figure 1

(A) The genomic structure of the mouse Npas4 gene. The Npas4-coding region is organized into eight exons and spans a genomic region of approximately 5.6 kb. Filled boxes represent exons, empty boxes represent UTRs and lines between filled boxes represent introns; (B) The domain structure of the mouse Npas4 protein showing the location of the basic Helix-Loop-Helix (bHLH), Per-Arnt-Sim (PAS) domains as well as the transactivation domain (TAD). Conservation of each domain to the domain consensus sequence is also indicated (percentage amino acid identity).

Figure 2

Model of Npas4 neuroprotective function following cerebral ischemia. Ischemic challenge induces Npas4 expression, which then limits brain damage via two mechanisms: (1) by modulating the cell death pathway such that damaged cells undergo apoptosis in preference to necrosis and (2) by suppressing inflammation.