Anti-Diabetic Countermeasures Against Tobacco Smoke-Dependent Cerebrovascular Toxicity: Use and Effect of Rosiglitazone.

Farzane Sivandzade,Luca Cucullo

doi:10.3390/ijms20174225

Abstract

Tobacco smoking (TS) is one of the most addictive habit sand a main public health hazards, impacting the vascular endothelium through oxidative stress (OS) stimuli, exposure to nicotine, and smoking-induced inflammation in a dose-dependent manner. Increasing evidence also suggested that TS increases glucose intolerance and the risk factor of developing type-2 diabetes mellitus (2DM), which, along with TS, is connected to blood–brain barrier (BBB) injuries, and heightens the risk of cerebrovascular disorders. Although the exact mechanism of rosiglitazone (RSG) is unknown, our previous in vitro work showed how RSG, an oral anti-diabetic drug belonging to the family of thiazolidinedione class, can protect BBB integrity through enhancement of nuclear factor erythroid 2-related factor (Nrf2) activity. Herein, we have validated the protective role of rosiglitazone against TS-induced BBB impairment in vivo. Our results revealed that RSG as a peroxisome proliferator-activated receptor gamma (PPARγ), activates counteractive mechanisms primarily associated with the upregulation of Nrf2 and PPARγ pathways which reduce TS-dependent toxicity at the cerebrovascular level. In line with these findings, our results show that RSG reduces inflammation and protects BBB integrity. In conclusion, RSG offers a novel and promising therapeutic application to reduce TS-induced cerebrovascular dysfunction through activation of the PPARγ-dependent and/or PPARγ-independent Nrf2 pathway.

Highlights

A vast number of deaths worldwide, are attributed to smoking, as a consequence of its effects on the vascular system in the body [1,2]
The mechanism of vascular damage induced by cigarette smoking is multifaceted; dysfunction of the blood–brain barrier (BBB) through activation of oxidative, inflammatory and immune responses leads to pathogenesis and progression of cerebrovascular and neurodegenerative disorders, including stroke, Alzheimer’s disease (AD), Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), depression, vascular dementia and Huntington’s disease (HD) [1,2,5,8,9,10,11,12,13]
The protective effect of RSG against tobacco smoke (TS)-induced damages was investigated in a rodent model with the scope to validate previous in vitro results [2]

Summary

Introduction

A vast number of deaths worldwide, are attributed to smoking, as a consequence of its effects on the vascular system in the body [1,2]. In the recent work of our group, the involvement of common pathogenic modulators of BBB impairment was confirmed so that chronic cigarette smoking and hyperglycemia (HG) carried similar risks for cerebrovascular diseases and stroke, sharing similar pathogenic mechanisms [20,21,22]. This result accounts for the reason for the possible application of anti-diabetic drugs to prevent/reduce BBB damage promoted by the chronic TS exposure. The aim of the present study is to validate and assess the previous results using animal models in vivo and to confirm RSG’s role in the activation of counteractive antioxidative mechanisms to reduce TS toxicity at the BBB

Objectives

Methods

Findings

Conclusion