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. 2022 Dec 18;23(24):16160.
doi: 10.3390/ijms232416160.

Ranolazine Attenuates Brain Inflammation in a Rat Model of Type 2 Diabetes

Velia Cassano  1 , Martina Tallarico  2 , Giuseppe Armentaro  1 , Caterina De Sarro  3 , Michelangelo Iannone  4 , Antonio Leo  2 , Rita Citraro  2 , Emilio Russo  2 , Giovambattista De Sarro  2 , Marta Letizia Hribal  1 , Angela Sciacqua  1
Affiliations

Ranolazine Attenuates Brain Inflammation in a Rat Model of Type 2 Diabetes

Velia Cassano et al. Int J Mol Sci. .

Abstract

Recent studies suggest a pathogenetic association between metabolic disturbances, including type 2 diabetes (T2DM), and cognitive decline and indicate that T2DM may represent a risk factor for Alzheimer's disease (AD). There are a number of experimental studies presenting evidence that ranolazine, an antianginal drug, acts as a neuroprotective drug. The aim of the present study was to evaluate the effects of ranolazine on hippocampal neurodegeneration and astrocytes activation in a T2DM rat model. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ) injection. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine and NCD + Metformin. The presence of neurodegeneration was evaluated in the hippocampal cornus ammonis 1 (CA1) region by cresyl violet staining histological methods, while astrocyte activation was assessed by western blot analysis. Staining with cresyl violet highlighted a decrease in neuronal density and cell volume in the hippocampal CA1 area in diabetic HFD/STZ + Vehicle rats, while ranolazine and metformin both improved T2DM-induced neuronal loss and neuronal damage. Moreover, there was an increased expression of GFAP in the HFD/STZ + Vehicle group compared to the treated diabetic groups. In conclusion, in the present study, we obtained additional evidence supporting the potential use of ranolazine to counteract T2DM-associated cognitive decline.

Keywords: Alzheimer’s; neurodegeneration; ranolazine; type 2 diabetes mellitus.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Representative images of histological analysis. Magnification 20x. Cresyl violet staining was performed on a section from the hippocampal CA1 region in (A) HFD/STZ + Vehicle group, (B) HFD/STZ + Ranolazine group, (C) HFD/STZ + Metformin group, (D) NCD + Vehicle group, (E) NCD + Ranolazine group, (F) NCD + Metformin group. HFD = high fat diet; NCD = normocaloric diet; STZ = streptozotocin.
Figure 2
Figure 2
Neuronal count in the hippocampal CA1 region of the six study groups. Values are the mean ± SD (n = 6 per group). * p = 0.0011 HFD/STZ + Vehicle vs. HFD/STZ + Ranolazine, ** p = 0.039 HFD/STZ + Vehicle vs. HFD/STZ + Metformin, # p < 0.0001 HFD/STZ + Vehicle vs. NCD + Vehicle (Sidak’s test). HFD = high fat diet; NCD = normocaloric diet; STZ = streptozotocin.
Figure 3
Figure 3
(a) Representative western blot images of glial fibrillary acidic protein (GFAP) (upper panel) and β-actin (lower panel). (b) Graph of GFAP variation in each experimental group. Data values are the mean ± SE (standard error) after normalization for β-actin, and expressed as fold variation over NCD + Vehicle group. (n = 3–4 per group). HFD = high fat diet; NCD = normocaloric diet; STZ = streptozotocin; Ran = ranolazine; Met = metformin; GFAP= glial fibrillary acidic protein. * p = 0.046 NCD + Vehicle vs. HFD/STZ + Vehicle, ** p = 0.04 HFD/STZ + Metformin vs. HFD/STZ + Vehicle.
Figure 4
Figure 4
TNFα in each experimental group. Data values are the mean ± SE (standard error) after normalization for 18S levels, and expressed as fold variation over NCD + Vehicle group. (n = 3–4 per group.) HFD = high fat diet; NCD = normocaloric diet; STZ = streptozotocin; Ran = ranolazine; Met = metformin; GFAP= glial fibrillary acidic protein. ** p = 0.01 HFD/STZ + Vehicle vs. NCD + Vehicle, # p= 0.01 HFD/STZ + Metformin and HFD/STZ + Ranolazine vs. HFD/STZ + Vehicle.
Figure 5
Figure 5
Schematic diagram of the experimental protocol.
See this image and copyright information in PMC

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