Central Insulin-Like Growth Factor-1-Induced Anxiolytic and Antidepressant Effects in a Rat Model of Sporadic Alzheimer's Disease Are Associated with the Peripheral Suppression of Inflammation

Abstract

(1) Insulin-like growth factor-1 (IGF-1) is a neurotrophin with anti-inflammatory properties. Neuroinflammation and stress activate peripheral immune mechanisms, which may contribute to the development of depression and anxiety in sporadic Alzheimer's disease (sAD). This study aims to evaluate whether intracerebroventricular (ICV) premedication with IGF-1 in a rat model of streptozotocin (STZ)-induced neuroinflammation can prevent the emergence of anhedonia and anxiety-like behavior by impacting the peripheral inflammatory responses. (2) Male Wistar rats were subjected to double ICVSTZ (total dose: 3 mg/kg) and ICVIGF-1 injections (total dose: 2 µg). We analyzed the level of anhedonia (sucrose preference), anxiety (elevated plus maze), peripheral inflammation (hematological and cytometric measurement of leukocyte populations, interleukin (IL)-6), and corticosterone concentration at 7 (very early stage, VES), 45 (early stage, ES), and 90 days after STZ injections (late stage, LS). (3) We found that ICVIGF-1 administration reduces behavioral symptoms: anhedonia (ES and LS) and anxiety (VES, ES), and peripheral inflammation: number of leukocytes, lymphocytes, T lymphocytes, monocytes, granulocytes, IL-6, and corticosterone concentration (LS) in the rat model of sAD. (4) The obtained results demonstrate beneficial effects of central IGF-1 administration on neuropsychiatric symptoms and peripheral immune system activation during disease progression in the rat model of sAD.

Keywords: anhedonia; anxiety; insulin-like growth factor-1; peripheral inflammation; sporadic Alzheimer’s disease model.

Figure 1

Scheme of procedures and group assignments. Explanations: SPT—sucrose preference test; EPM—elevated plus maze; ICVIGF-1—intracerebroventricular (ICV) injections of insulin-like growth factor-1 (IGF-1, total dose: 2 µg, divided into two injections on days 1 and 3, 0.5 µg/2 µL/ventricle, neurotrophin treatment); ICVSAL—intracerebroventricular (ICV) injections of saline (SAL, 2 µL/ventricle); ICVSTZ—intracerebroventricular (ICV) injections of streptozotocin (STZ, total dose: 3 mg/kg, divided into two injections on days 2 and 4, 0.75 mg/kg/2 µL/ ventricle, induction of sporadic Alzheimer’s disease model); ICVVEH—intracerebroventricular (ICV) injections of vehicle (VEH, 2 µL/ventricle), B—blood collection, B/SA—blood collection and sacrifice of animals; very early stage—stage of sporadic Alzheimer’s disease progression starting 7 days after ICV injections; early stage—stage of sporadic Alzheimer’s disease progression starting 45 days after ICV injections; and late stage—stage of sporadic Alzheimer’s disease progression starting 90 days after ICV injections.

Figure 2

The effect of insulin-like growth factor-1 (IGF-1) treatment on behavioral activity associated with anhedonia in the sucrose preference test at the baseline conditions, at the very early, early, and late stages after intracerebroventricular injections of streptozotocin and saline (STZ SAL), streptozotocin and insulin-like growth factor-1 (STZ IGF-1), citrate buffer and saline (VEH SAL), and citrate buffer and insulin-like growth factor-1 (VEH IGF-1). Data are presented as the mean ± SD and were analyzed by using the Mann–Whitney U test. Explanations: * in a black circle—p < 0.05, ** in a black circle—p < 0.01, indicating the significance of differences between STZ SAL and STZ IGF-1; $$ above the lines—p < 0.01, indicating the significance of differences to VEH SAL.

Figure 3

The effect of insulin-like growth factor-1 (IGF-1) treatment on behavioral activity associated with anxiety presented as the time spent in the open arms (a), the center (b), and the closed arms (c) of the elevated plus maze (EPM) at the baseline conditions, at the very early, early, and late stages after intracerebroventricular injections of streptozotocin and saline (STZ SAL), streptozotocin and insulin-like growth factor-1 (STZ IGF-1), citrate buffer and saline (VEH SAL), and citrate buffer and insulin-like growth factor-1 (VEH IGF-1). Data are presented as mean ± SD and were analyzed using a Mann–Whitney U test. Explanations: * in a black circle—p < 0.05, ** in a black circle—p < 0.01, indicating the significance of differences between STZ SAL and STZ IGF-1; $ above the lines—p < 0.05, $$ above the lines—p < 0.01, indicating the significance of differences to the VEH SAL group; ^ above the lines—p < 0.05, ^^ above the lines—p < 0.01, indicating the significance of differences between the STZ IGF-1 and VEH IGF-1 groups.

Figure 4

The effect of insulin-like growth factor-1 (IGF-1) treatment and time (stage) on the number of leukocytes (a), lymphocytes (b), monocytes (c), and granulocytes (d) at the early and late stages after intracerebroventricular injections of streptozotocin and saline (STZ SAL), streptozotocin and insulin-like growth factor-1 (STZ IGF-1), citrate buffer and saline (VEH SAL), and citrate buffer and insulin-like growth factor-1 (VEH IGF-1) in the peripheral blood. Data are presented as mean ± SD and were analyzed using the Mann–Whitney U test. Explanations: * in a black circle—p < 0.05, ** in a black circle—p < 0.01, indicating the significance of the differences between the STZ SAL and STZ IGF-1 groups; $ above the lines—p < 0.05, $$ above the lines—p < 0.01, indicating the significance of differences to the VEH SAL group; ^^ above the lines—p < 0.01, indicating the significance of differences between the STZ IGF-1 and VEH IGF-1 groups; and &—p < 0.05, &&—p < 0.01, indicating the significance of differences between the early and late stages of disease progression.

Figure 5

The effect of insulin-like growth factor-1 (IGF-1) treatment on the number of T CD3⁺ (a), Th CD4⁺ (b), Tc CD8⁺ (c), B CD45RA⁺ lymphocytes (e), NK cell CD161a⁺ (f), and ratio of CD4⁺/CD8⁺ lymphocytes (d) at the late stage after intracerebroventricular injections of streptozotocin and saline (STZ SAL), streptozotocin and insulin-like growth factor-1 (STZ IGF-1), citrate buffer and saline (VEH SAL), and citrate buffer and insulin-like growth factor-1 (VEH IGF-1) in the peripheral blood. Data are presented as mean ± SD and were analyzed using the Mann–Whitney U test. Explanations: * in a black circle—p < 0.05, ** in a black circle—p < 0.01, indicating the significance of differences between the STZ SAL and STZ IGF-1 groups; $ above the lines—p < 0.05, $$ above the lines—p < 0.01, indicating the significance of differences to the VEH SAL group.

Figure 6

The effect of insulin-like growth factor-1 (IGF-1) treatment and time (stage) on the concentrations of interleukin-6 (IL-6) (a), interleukin-10 (IL-10) (b), and corticosterone (CORT) (c) at the early and late stages after intracerebroventricular injections of streptozotocin and saline (STZ SAL), streptozotocin and insulin-like growth factor-1 (STZ IGF-1), citrate buffer and saline (VEH SAL), and citrate buffer and insulin-like growth factor-1 (VEH IGF-1) in plasma. Data are presented as mean ± SD and were analyzed using the Mann–Whitney U test. Explanations: * in a black circle—p < 0.05, indicating, the significance of differences between STZ SAL and STZ IGF-1; $ above the lines—p < 0.05, $$ above the lines—p < 0.01, indicating the significance of differences to the VEH SAL group; ^ above the lines—p < 0.05, indicating the significance of differences between the STZ IGF-1 and VEH IGF-1 groups; and &—p < 0.05, &&—p < 0.01, indicating the significance of differences between the early and late stages of disease progression.