Preclinical and clinical evidence of IGF-1 as a prognostic marker and acute intervention with ischemic stroke

Abstract

Ischemic strokes are highly prevalent in the elderly population and are a leading cause of mortality and morbidity worldwide. The risk of ischemic stroke increases in advanced age, corresponding with a noted decrease in circulating insulin growth factor-1 (IGF-1). IGF-1 is a known neuroprotectant involved in embryonic development, neurogenesis, neurotransmission, cognition, and lifespan. Clinically, several studies have shown that reduced levels of IGF-1 correlate with increased mortality rate, poorer functional outcomes, and increased morbidities following an ischemic stroke. In animal models of ischemia, administering exogenous IGF-1 using various routes of administration (intranasal, intravenous, subcutaneous, or topical) at various time points prior to and following insult attenuates neurological damage and accompanying behavioral changes caused by ischemia. However, there are some contrasting findings in select clinical and preclinical studies. This review discusses the role of IGF-1 as a determinant factor of ischemic stroke outcomes, both within the clinical settings and preclinical animal models. Furthermore, the review provides insight on the role of IGF-1 in mechanisms and cellular processes that contribute to stroke damage.

Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit

“…Animal models of circulating IGF-1 deficiency exhibit impaired neurovascular coupling, compromised blood-brain barrier integrity, and increased prevalence of micro hemorrhages (Toth et al, 2015;Tarantini et al, 2016bTarantini et al, , 2017Tarantini et al, , 2021aHayes et al, 2021). Increased reactive oxygen species (ROS) production, increased inflammation, and reduced glutamate and glucose handling machinery accompany the loss of circulating IGF-1 in these models (Toth et al, 2015(Toth et al, , 2017.…”

“…Insulin-like growth factor-1 is a pleiotropic neuroendocrine modulator that has been assessed in both clinical and preclinical studies of stroke [as reviewed by Hayes et al (2021) ]. Both humans and rodents exhibit age-related circulating declines of IGF-1 ( O’Connor et al, 1998 ; Sonntag et al, 2013 ).…”

“…While many studies associate reduced IGF-1 with increased neurodegeneration, some clinical studies of dementias and stroke see increased IGF-1 levels at the start of pathology, which may be an attempted compensatory mechanism designed to protect the brain ( Gubbi et al, 2018 ; Castilla-Cortazar et al, 2020 ). Preclinical studies suggest that IGF-1 plays a causal role in the stroke risk and recovery processes by directly regulating cell damage during ischemia [as reviewed by Hayes et al (2021) ]. IGF-1 supplementation in rodent models of middle cerebral artery occlusion and photothrombotic stroke reduces the size of infarcted tissue and the accompanying sensorimotor deficits, even when administered in the days after insult ( Liu et al, 2001 ; Bake et al, 2014 , 2016 ; Parker et al, 2017 ; Serhan et al, 2019 ; Hayes et al, 2021 ).…”

IGF-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit

“…Animal models of circulating IGF-1 deficiency exhibit impaired neurovascular coupling, compromised blood-brain barrier integrity, and increased prevalence of microhemorrhages (Toth et al, 2015a;Tarantini et al, 2016b;Tarantini et al, 2017;Hayes et al, 2021;Tarantini et al, 2021).…”

“…IGF-1 is a pleiotropic neuroendocrine modulator that has been assessed in both clinical and preclinical studies of stroke (as reviewed by (Hayes et al, 2021)). IGF-1 levels decline in advanced age, and the extent of this decline is associated with increased risk of stroke incidence, increased mortality, and worsened functional outcomes post-stroke in humans (Johnsen et al, 2004;De Smedt et al, 2011;Tang et al, 2014;Armbrust et al, 2017;Saber et al, 2017).…”