Identifying a therapeutic window for intranasal insulin administration in a two-vessel rat model of forebrain ischemia and investigating the mechanisms of its neuroprotective action

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Abstract

Cerebral ischemia is a significant medical and social issue, necessitating the development of effective treatment strategies. Due to the complex pathogenesis and prolonged recovery period associated with this condition, drugs with pleiotropic effects, such as intranasally administered insulin (IAI), are of the greatest interest. IAI sprayed in the nasal cavity enters the brain, regulating metabolism through central mechanisms, has neuroprotective and neuroregulatory effects. It has been proven to be effective in the treatment of neurodegenerative diseases, although data on its effectiveness in cerebral ischemia remain limited. The aim of the work was to search for a “therapeutic window” and evaluate the mechanisms of the
neuroprotective effect of IAI when used in rats with cerebral ischemia. Rats with two-vessel forebrain ischemia were administered IAI 2 and 4 hours after an episode of ischemia at a dose of 0.5 IU/rat/day, and then daily for a 7-day period after ischemia. It has been demonstrated that IAI is more effective if animals were treated 2 hours after the ischemic event, compared with administration after 4 hours, despite the subsequent 7-day of IAI treatment. When administered 2 hours after an ischemic event, IAI has been shown to support the expression of components of insulin signaling genes in the hippocampus and normalize the number of cells in the CA1 region. It also stimulates the expression of the anti-apoptotic Bcl-2 gene and reduces the expression of the Gfap and Aif1 genes, which are markers of astrocytes and microglia, and this indicates the anti-inflammatory effect of IAI. In addition, for the first time IAI has been found to stimulate the activity of the thyroid system and prevent the development of post-ischemic hypothyroidism. All these effects were less pronounced or not observed when IAI was administered 4 hours after the ischemic event. Thus, for the first time, we described a “therapeutic window” for the use of IAI in cerebral ischemia and evaluated some of the mechanisms underlying its neuroprotective effects.

About the authors

I. I. Zorina

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: zorina.inna.spb@gmail.com
Saint-Petersburg, Russia

A. S. Pechalnova

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: zorina.inna.spb@gmail.com
Saint-Petersburg, Russia

E. E. Chernenko

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: zorina.inna.spb@gmail.com
Saint-Petersburg, Russia

D. K. Avrova

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: zorina.inna.spb@gmail.com
Saint-Petersburg, Russia

K. V. Derkach

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Email: zorina.inna.spb@gmail.com
Saint-Petersburg, Russia

A. O. Shpakov

Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences

Author for correspondence.
Email: zorina.inna.spb@gmail.com
Saint-Petersburg, Russia

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