Insulin-Like Growth Factor-1 Is Neuroprotective in Aged Rats With Ischemic Stroke

Did your doctor do one damn thing with these earlier posts on IGF-1? 

Or did your doctor DO NOTHING since everyone in stroke is

waiting for SOMEONE ELSE TO SOLVE THE PROBLEM?

• IGF-1 (8 posts to March 2014)

 

Insulin-Like Growth Factor-1 Is Neuroprotective in Aged Rats With Ischemic Stroke

Ahmad Serhan^1,2, Erik Boddeke² and Ron Kooijman^1*

• ¹Department of Experimental Pharmacology, Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium
• ²Department of Neuroscience, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

Post-stroke systemic injections of insulin-like growth factor-1 (IGF-1) exert neuroprotective effects in rats. In the current study, we aimed to test the efficacy of IGF-1 neuroprotection in aged rats (24–25 months old) and to compare the results with adult rats (6–7 months old). Furthermore, we addressed putative differences in microglial responses to IGF-1 in adult and aged rats. Rats were subjected to ischemic stroke while they were conscious by infusing endothelin-1 (Et-1) through a guide cannula that was implemented in the vicinity of the middle cerebral artery (MCA). Rats were given subcutaneous injections of IGF-1 (1 mg/kg) at 30 min and 120 min after the insult. Post-stroke IGF-1 treatment reduced the infarct size by 34% and 38% in aged and adult rats, respectively. The IGF-1 treated adult rats also showed significant improvement in sensorimotor function following stroke, while this function was not significantly affected in aged rats. Furthermore, aged rats displayed exaggerated activation of microglia in the ischemic hemisphere. Significant reduction of microglial activation by IGF-1 was only detected at specific regions in the ipsilateral hemisphere of adult rats. We show that IGF-1 reduced infarct size in aged rats with an ischemic stroke. It remains to be established, however, whether the age-related changes in microglial function affect the improvement in behavioral outcomes.

Introduction

Ischemic stroke is one of the most common causes of death and disability (Katan and Luft, 2018). Thrombolytic therapy with recombinant tissue plasminogen activator is still the most effective therapy for ischemic stroke (Lees et al., 2016; Alberts, 2017). However, many patients are not eligible for this therapy due to the narrow therapeutic window (Lees et al., 2016; Alberts, 2017).

In stroke patients, serum levels of insulin-like growth factor-1 (IGF-1) correlate positively with clinical outcome (Åberg et al., 2011, 2018; De Smedt et al., 2011; Saber et al., 2017) suggesting that IGF-1 may exert neuroprotective effects. IGF-1 is a polypeptide hormone that is involved in neonatal and postnatal development (Agrogiannis et al., 2014; Hellström et al., 2016; de Jong et al., 2017), but also acts as a survival factor for neurons in vitro (Ueno et al., 2013) and in vivo (Wine et al., 2009).

Moreover, post-stroke treatment with systemically injected IGF-1 induced neuroprotection in several rat models for ischemic stroke (Rizk et al., 2007; De Geyter et al., 2013, 2016; Bake et al., 2014). These observations indicate that IGF-1 may be effectively used as a neuroprotective agent in patients.

Many preclinical studies successfully identified neuroprotective drugs against ischemic stroke, but these drugs failed to exert significant effects in the clinic (Green, 2008; Veltkamp and Gill, 2016). One of the recommendations of the Stroke Therapy Academic Industry Roundtable (STAIR; Fisher et al., 2009) to facilitate translation to the clinic, is to include comorbidity factors such as aging in preclinical studies. Indeed, the incidence of stroke is higher in the elderly (Béjot et al., 2016). Therefore, we tested whether IGF-1 treatment is neuroprotective in aged rats and compared the results to the efficacy of IGF-1 in adult rats. Preliminary experiments in our laboratory revealed that neuroprotection by IGF-1 in rats with ischemic stroke is accompanied by microglial changes and a decrease in neuroinflammation. Since age correlates with an exaggerated activational state of microglia (Godbout et al., 2005; Norden and Godbout, 2013), we addressed the effects of IGF-1 on microglial activation.