ABSTRACT
We and others have shown that insulin-like growth factor-1 (IGF-1) is neuroprotective when administered systemically shortly following stroke. In the current study, we addressed the hypothesis that microglia mediate neuroprotection by IGF-1 following ischemic stroke. Furthermore, we investigated whether IGF-1 modulates pro- and anti-inflammatory mediators in ischemic brain with a special reference to microglia. Ischemic stroke was induced in normal conscious Wistar rats by infusing the vasoconstrictor, endothelin-1 (Et-1), next to middle cerebral artery (MCA). IGF-1 (300⯵g) was injected subcutaneously (SC) at 30 and 120â¯min following stroke. Microglial inhibitor, minocycline, was injected intraperitoneally (IP) at 1â¯h before stroke (25â¯mg/kg) and 11â¯h after stroke (45â¯mg/kg). Post-stroke IGF-1 treatment reduced the infarct size and increased the sensorimotor function which coincided with an increase in the number of ameboid microglia in the ischemic cortex. Minocycline treatment abrogated the increase in ameboid microglia by IGF-1, while the effect of IGF-1 in the reduction of infarct size was only partially affected. IGF-1 suppressed mRNA expression of inducible nitric oxide synthase (iNOS) and interleukin (IL)-1ß in the ischemic hemisphere, while in purified microglia, only iNOS expression levels were reduced. Our findings show that microglia are a target for IGF-1 and that neuroprotection by IGF-1 coincides with down-regulation of inflammatory mediators which could be instrumental to the beneficial effects.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Brain Ischemia/drug therapy , Inflammation/drug therapy , Insulin-Like Growth Factor I/pharmacology , Animals , Brain/drug effects , Brain/metabolism , Brain Ischemia/metabolism , Disease Models, Animal , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/metabolism , Inflammation/metabolism , Insulin-Like Growth Factor I/metabolism , Male , Neuroprotective Agents/pharmacology , Nitric Oxide Synthase Type II/drug effects , Nitric Oxide Synthase Type II/metabolism , Rats, WistarABSTRACT
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.