Abstract
The role of insulin in the brain is still not completely understood. In the periphery, insulin can decrease inflammation induced by lipopolysaccharide (LPS); however, whether insulin can reduce inflammation within the brain is unknown. Experiments administrating intranasal insulin to young and aged adults have shown that insulin improves memory. In our animal model of chronic neuroinflammation, we administered insulin and/or LPS directly into the brain via the fourth ventricle for 4 weeks in young rats; we then analyzed their spatial memory and neuroinflammatory response. Additionally, we administered insulin or artificial cerebral spinal fluid (aCSF), in the same manner, to aged rats and then analyzed their spatial memory and neuroinflammatory response. Response to chronic neuroinflammation in young rats was analyzed in the presence or absence of insulin supplementation. Here, we show for the first time that insulin infused (i.c.v.) to young rats significantly attenuated the effects of LPS by decreasing the expression of neuroinflammatory markers in the hippocampus and by improving performance in the Morris water pool task. In young rats, insulin infusion alone significantly improved their performance as compared to all other groups. Unexpectedly, in aged rats, the responsiveness to insulin was completely absent, that is, spatial memory was still impaired suggesting that an age-dependent insulin resistance may contribute to the cognitive impairment observed in neurodegenerative diseases. Our data suggest a novel therapeutic effect of insulin on neuroinflammation in the young but not the aged brain.
Highlights
IntroductionThe consequences of neuroinflammation, associated with microglial activation, operating across a timescale of decades, are carefully regulated until, due to normal aging, there is a gradual shift to a non-equilibrium state that is permissive for neurodegenerative processes [5,6,7]
Aging is characterized by chronic low-level neuroinflammation [1,2,3,4]
Aged rats were not infused with LPS for three reasons: first, we have previously shown [41] that when LPS was chronically infused into the fourth ventricle of young and aged rats, only the young rats demonstrated impaired spatial memory performance in the Morris water maze task; the performance of aged rats was not further impaired by chronic infusion with LPS
Summary
The consequences of neuroinflammation, associated with microglial activation, operating across a timescale of decades, are carefully regulated until, due to normal aging, there is a gradual shift to a non-equilibrium state that is permissive for neurodegenerative processes [5,6,7]. Dysregulation of insulin signaling is associated with many age-related neurodegenerative diseases that present with chronic neuroinflammation and that may contribute to cognitive deficits [11,12,13]; the link between these two characteristics and their interaction in the neurodegenerative processes has not been fully investigated. PKCζ protein was shown to play a role in the activation of nuclear factor kappa B (NF-κB) pathway [17] which is necessary to enhance the inflammatory response. Insulin was reported to suppress the expression and activity of inducible nitric oxide synthase (iNOS) [18] and cyclooxygenase-2 (COX-2) [19] by diminishing the activation of the NF-κB pathway [20] with a consequent
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
