Neuroglobin: an endogenous neuroprotectant

Abstract

Cerebral hypoxia and ischemia trigger endogenous protective mechanisms that can prevent or limit brain damage. Understanding these mechanisms may lead to new therapeutic strategies for stroke and related disorders. Neuroglobin (Ngb), a recently discovered protein that is distantly related to hemoglobin and myoglobin, is expressed predominantly in brain neurons, and appears to modulate hypoxic-ischemic brain injury. Evidence includes the observations that neuronal hypoxia and cerebral ischemia induce Ngb expression, that enhancing Ngb expression reduces--and knocking down Ngb expression increases--hypoxic neuronal injury in vitro and ischemic cerebral injury in vivo, and that Ngb-overexpressing transgenic mice are resistant to cerebral infarction. However, the mechanisms that underlie hypoxic induction of Ngb and neuroprotection by Ngb are still unclear.

Figure 1

Neuronal localization of Ngb. Ngb immunoreactivity is associated preferentially with neuronal cell bodies (top) and processes (bottom).

Figure 2

Ngb expression is inducible by hypoxia and leads to neuroprotection, but the mechanisms for induction and protection are poorly understood. Induction might proceed by HIF-dependent or HIF-independent pathways, or both. Mechanisms proposed to mediate neuroprotective effects of Ngb in hypoxic or ischemic injury include O₂ transport, scavenging of reactive oxygen- (ROS) or nitrogen (RNS)-containing species, enhancing dissociation of Gα- from Gβγ-subunits of guanine nucleotide-binding proteins, and serving as an O₂ sensor that triggers downstream adaptations under hypoxic conditions.