Neuronal and Astrocyte Insulin-like Growth Factor-1 Signaling Differentially Modulates Ischemic Stroke Damage

Abstract

Ischemic stroke is a leading cause of death and disability, as therapeutic options for mitigating the long-term deficits precipitated by the event remain limited. Acute administration of the neuroendocrine modulator insulin-like growth factor-1 (IGF-1) attenuates ischemic stroke damage in preclinical models, and clinical studies suggest IGF-1 can reduce the risk of stroke and improve overall outcomes. The cellular mechanism by which IGF-1 exerts this protection is poorly defined, as all cells within the neurovascular unit express the IGF-1 receptor. We hypothesize that the functional regulation of both neurons and astrocytes by IGF-1 is critical in minimizing damage in ischemic stroke. To test this, we utilized inducible astrocyte-specific or neuron-specific transgenic mouse models to selectively reduce IGF-1R in the adult mouse brain prior to photothrombotic stroke. Acute changes in blood brain barrier permeability, microglial activation, systemic inflammation, and biochemical composition of the brain were assessed 3 hours following photothrombosis, and significant protection was observed in mice deficient in neuronal and astrocytic IGF-1R. When the extent of tissue damage and sensorimotor dysfunction was assessed for 3 days following stroke, only the neurological deficit score continued to show improvements, and the extent of improvement was enhanced with additional IGF-1 supplementation. Overall, results indicate that neuronal and astrocytic IGF-1 signaling influences stroke damage but IGF-1 signaling within these individual cell types is not required for minimizing tissue damage or behavioral outcome.

A role for astrocytic insulin-like growth factor I receptors in the response to ischemic insult

“…Indeed, recent preliminary observations support a strong context-dependent role of IGF-I signaling in stroke, as time after stroke and type of stroke determine the role of IGF-IR in astrocytes. 50 These observations also support the use of targeted increase of IGF-IR activity in astrocytes as a therapeutic approach to improve resistance to ischemic injury. Indeed, these cells are important determinants of neurodegenerative processes, 77 and key mediators of neuroprotection after ischemia.…”

“…33 As a corollary, the role of IGF-IR in other types of brain cells in the response to injury should be examined, as suggested recently. 50 For instance, it cannot be excluded that IGF-IR in microglia 23 and brain endothelium 20,51 will play an important role in the response to stroke insult, as it is widely over-expressed in the region surrounding the lesion. 52 Recent data reinforce the need to separately analyze a possible differential role of IGF-IR in astrocytes and microglia in the response to stroke.…”

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

“…148 Astrocytes regulate KCC2 expression in neurons through the release of neurotrophic factors, such as BDNF and IGF-1, and inflammatory cytokines, such as TNF-α, IL-6, and IL-1β. [150][151][152][153] Astrocyte-released BDNF stimulates KCC2 expression in neurons by the activation of PI3K-AKT and Ras-MAPK pathways. 150,154,155 Astrocytes also maintain physiological levels of extracellular K+ and glutamate.…”