Effect of Intranasally Administered Insulin on Metabolic Parameters and Inflammation Factors in Control and Diabetic Rats under Conditions of Cerebral Ischemia and Reperfusion

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Abstract

The search for natural biologically active substances that have a neuroprotective effect on cerebral ischemia-reperfusion is one of the urgent problems of modern neuroscience and medicine. Intranasally administered insulin (IAI) has a pronounced restorative effect on various neurodegenerative diseases, but the mechanisms of its action and therapeutic effects in cerebral ischemia have not been studied well, including in type 2 diabetes mellitus (DM2), which increases the risk of cerebrovascular dysfunction. The aim of the work was to study the effect of IAI on metabolic parameters and inflammatory factors in male rats with DM2 subjected to the two-vessel ischemia and prolonged forebrain reperfusion, in comparison with non-diabetic animals. A long-term high-fat diet with an injection of a low dose of streptozotocin (25 mg/kg) to rats was used to induce DM2, and a model of the global forebrain two-vessel ischemia induced by occlusion of both common carotids with prolonged reperfusion (IR) for 7 days was used to study cerebral ischemia. Two hours after the end of ischemia, rats were treated with IAI at a dose of 0.5 or 2.0 IU/rat, after which the drug was administered in the same doses daily for 7 subsequent days. It was found that IAI prevents body weight loss in both nondiabetic and diabetic rats that underwent IR, and also increases the total cholesterol level and the proportion of epididymal fat in rats without DM2 after IR. In DM2 rats that underwent IR, IAI in the explored doses reduces the level of postprandial glucose and insulin content in the blood, which indicates an improvement of glucose tolerance, and also reduces the levels of inflammatory factors in the blood – C-reactive protein (at a dose of 0.5 IU/rat/day) and tumor necrosis factor-α (in a dose of 2 IU/rat/day), which reveals its anti-inflammatory potential. Thus, the course treatment with IAI after induction of cerebral ischemia followed by reperfusion leads to an improvement of metabolic parameters and weakens inflammatory reactions in rats with DM2, which may be in demand in the correction of ischemic stroke in patients with DM2.

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About the authors

I. I. Zorina

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

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

A. S. Pechalnova

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

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

E. E. Chernenko

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

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

K. V. Derkach

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

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

A. O. Shpakov

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

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

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Supplementary files

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2. Fig. 1. Body weight loss in rats with and without DM2, who underwent double-vascular ischemia and reperfusion, 3 (a) and 7 (b) days after the start of reperfusion and the effect of intranasally administered insulin on it. The loss of body weight in % of total body weight on the 3rd (a) and 7th (b) days of reperfusion is presented. The designation of the groups: C-SO – falsely operated rats without DM2; C–IR – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion; C–IR-0.5 – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/ day; DM2-SO – falsely operated rats with DM2; DM2-IR – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion; DM2-IR-0.5 – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/day; DM2-IR-2 – rats with DM2, who underwent bicascular forebrain ischemia and reperfusion and received IVI at a dose of 2 IU/rat/day. The data is presented in the form of M ± SEM (n = 6 in

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3. Fig. 2. The proportion of visceral (a) and epididymal (b) fat in rats undergoing forebrain ischemia and 7-day reperfusion, with and without DM2, and the effect of intranasally administered insulin on them. The proportion of adipose tissue in % of total body weight is presented. The designation of the groups: C-SO – falsely operated rats without DM2; C–IR – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion; C–IR-0.5 – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/ day; DM2-SO – falsely operated rats with DM2; DM2-IR – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion; DM2-IR-0.5 – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/day; DM2-IR-2 – rats with DM2, who underwent bicascular forebrain ischemia and reperfusion and received IVI at a dose of 2 IU/rat/day. The data are presented in the form of M ± SEM (n = 6 in all groups).

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4. Fig. 3. Postprandial glucose levels in the blood of rats with and without DM2 who underwent forebrain ischemia and reperfusion, and the effect of intranasally administered insulin on them on the 3rd and 7th days of reperfusion. The designation of the groups: C-SO – falsely operated rats without DM2; C–IR – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion; C–IR-0.5 – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/ day; DM2-SO – falsely operated rats with DM2; DM2-IR – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion; DM2-IR-0.5 – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/day; DM2-IR-2 – rats with DM2, who underwent bicascular forebrain ischemia and reperfusion and received IVI at a dose of 2 IU/rat/day.a – differences are significant compared with C-SO at p < 0.05;b – differences are significant compared with C–IR at p < 0.05;c – differences are significant

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5. Fig. 4. The level of postprandial insulin in the blood of rats with and without DM2 who underwent forebrain ischemia and reperfusion for 7 days, and the effect of intranasally administered insulin on it. The designation of the groups: C-SO – falsely operated rats without DM2; C–IR – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion; C–IR-0.5 – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/ day; DM2-SO – falsely operated rats with DM2; DM2-IR – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion; DM2-IR-0.5 – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/day; DM2-IR-2 – rats with DM2, who underwent bicascular forebrain ischemia and reperfusion and received IVI at a dose of 2 IU/rat/day. The data are presented in the form of M ± SEM (n = 6 in all groups).

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6. Fig. 5. Levels of total cholesterol (a) and triglycerides (b) in the blood of rats with and without DM2 who underwent double-vascular ischemia reperfusion for 7 days, and the effect of intranasally administered insulin on them. The designation of the groups: C-SO – falsely operated rats without DM2; C–IR – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion; C–IR-0.5 – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/ day; DM2-SO – falsely operated rats with DM2; DM2-IR – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion; DM2-IR-0.5 – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/day; DM2-IR-2 – rats with DM2, who underwent bicascular forebrain ischemia and reperfusion and received IVI at a dose of 2 IU/rat/day. The data are presented in the form of M ± SEM (n = 6 in all groups).

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7. Fig. 6. Levels of TNFa (a) and C-reactive protein (CRP) (b) in the blood of rats with and without DM2, who underwent dvuvascular ischemia, on the 3rd day of reperfusion, and the effect of intranasally administered insulin on them. The designation of the groups: C-SO – falsely operated rats without DM2; C–IR – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion; C–IR-0.5 – rats without DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/ day; DM2-SO – falsely operated rats with DM2; DM2-IR – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion; DM2-IR-0.5 – rats with DM2 who underwent bicavascular forebrain ischemia and reperfusion and received IVI at a dose of 0.5 IU/rat/day; DM2-IR-2 – rats with DM2, who underwent bicascular forebrain ischemia and reperfusion and received IVI at a dose of 2 IU/rat/day. The data are presented in the form of M ± SEM (n = 6 in all groups).

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