Astrocyte‐specific insulin‐like growth factor‐1 gene transfer in aging female rats improves stroke outcomes

Abstract

Middle aged female rats sustain larger stroke infarction and disability than younger female rats. This older group also shows age-related reduction of insulin like growth factor (IGF)-1 in serum and in astrocytes, a cell type necessary for post stroke recovery. To determine the impact of astrocytic IGF-1 for ischemic stroke, these studies tested the hypothesis that gene transfer of IGF-1 to astrocytes will improve stroke outcomes in middle aged female rats. Middle aged (10–12 month old), acyclic female rats were injected with recombinant adeno-associated virus serotype 5 (AAV5) packaged with the coding sequence of the human (h)IGF-1 gene downstream of an astrocyte-specific promoter GFAP (AAV5-GFP-hIGF-1) into the striatum and cortex. The AAV5-control consisted of an identical shuttle vector construct without the hIGF-1 gene (AAV5-GFAP-control). Six to eight weeks later, animals underwent transient (90 mins) middle cerebral artery occlusion via intraluminal suture. While infarct volume was not altered, AAV5-GFAP-hIGF-1 treatment significantly improved blood pressure and neurological score in the early acute phase of stroke (2 days) and sensory-motor performance at both the early and late (5 days) acute phase of stroke. AAV5-GFAP-hIGF-1 treatment also reduced circulating serum levels of GFAP, a biomarker for blood brain barrier permeability. Flow cytometry analysis of immune cells in the brain at 24h post stroke showed that AAV5-GFAP-hIGF-1 altered the type of immune cells trafficked to the ischemic hemisphere, promoting an anti-inflammatory profile. Collectively, these studies show that targeted enhancement of IGF-1 in astrocytes of middle-aged females improves stroke-induced behavioral impairment and neuroinflammation.

Altered levels of circulating insulin-like growth factor I (IGF-I) following ischemic stroke are associated with outcome - a prospective observational study

“…If so, local IGF-I in the brain would not be an exacerbating agent, but instead a substance that could improve the clinical outcome of IS. From experimental studies, there is evidence that local astrocyte IGF-I expression mediates neuroprotection [ 21 ] and that locally delivered astrocyte IGF-I improves experimental stroke outcomes [ 22 ]. While the exact mechanisms are not known, they probably involve neuroprotection, as well as angiogenesis, neurogenesis, and neuronal sprouting (for reviews, see [ 1 , 2 ]).…”

Oligodendrocyte Response to Pathophysiological Conditions Triggered by Episode of Perinatal Hypoxia-Ischemia: Role of IGF-1 Secretion by Glial Cells

“…Among the investigated types of glial cells in the context of IGF-1 secretion, astrocytes attract a special attention. They were shown to express both IGF-1 and its receptors, which play a crucial role in regulating glucose uptake by these cells and thus providing neurons with metabolic substrates on demand [95][96][97][98][99]. The increased secretion of this growth factor by astrocytes exerted neuroprotective effect on hippocampal neurons after traumatic brain injury [100].…”

MicroRNA‐365 modulates astrocyte conversion into neuron in adult rat brain after stroke by targeting Pax6

“…For example, reactive astrocytes induced by ischemic injury can accelerate the formation of glial scars (Boda & Buffo, 2010). However, astrocytes also promote neuronal survival and neurogenesis by releasing various growth factors after ischemic stroke (Liu, Teschemacher, & Kasparov, 2017;Okoreeh, Bake, & Sohrabji, 2017;Vaccarino et al, 2007). Therefore, astrocytesbased therapies for stroke draw extensive attention of researchers (Li, Liu, Xin, & Chopp, 2014;Trendelenburg & Dirnagl, 2005).…”