Category: Preclinical Development
Purpose: Tobacco smoke (TS) is a diverse mixture of over 4700 toxic, carcinogenic and mutagenic chemicals, as well as stable and unstable free radicals and reactive oxygen species (ROS) constituents. TS has been reported to enhance the risk of stroke and other cerebrovascular/neurological disorders like Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), depression, vascular dementia, and Huntington’s disease (HD). OS, inflammation and the resulting BBB impairmentare often the major prodromal factors. Even upon smoking cessation, former chronic smokers remain at considerable risk for neurovascular disorders such as stroke for several years. It is also well established that chronic smoking and diabetes carry similar risks for cerebrovascular diseases and stroke sharing similar pathogenic mechanisms, thus it is plausible that anti-diabetic drugs can prevent/ reduce BBB damage promoted by the chronic TS exposure. Herein, we investigated the role of rosiglitazone (RSG; family of thiazolidinedione class used oral anti-diabetic drug) against oxidative stress damage at the BBB by chronic TS exposure.
Methods: For this purpose, male C57BL/6J mice, age range 8–10 weeks were exposed to TS for two weeks and administered daily via intraperitoneal injections of dose levels of 10 or 20 mg/kg with dose volume of 20 ml/kg of RSG dissolved in DMSO/ sterile saline (1:10). Mice were sacrificed one day after the last day of CS exposure cycle, decapitated under anesthesia to collect brains for subsequent biochemical and molecular preparations. We then assessed the expression of the Nrf2 as a key antioxidant transcription factor, PPARγ and the effect of RSG on BBB integrity and inflammation using western blotting on homogenized brain tissues.
Results: The results revealed that RSG as a peroxisome proliferator-activated receptor gamma (PPARγ), activates counteractive mechanisms primarily associated with the Nrf2 and PPARγ pathway which reduced TS toxicity at the cerebrovascular level. The results also confirm the RSG’ role in the reduction of inflammation and oxidative stress and suppression of tight junction (TJ) proteins (ZO-1, Occludin, Claudin-5) downregulation and loss of BBB integrity induced by TS.
Conclusion: RSG could be considered as a promising therapeutic potential to prevent TS induced cerebrovascular dysfunction due to its protective effects which might be through PPARγ-dependent or PPARγ-independent Nrf2 pathway.
Luca Cucullo– Associate Professor, Texas Tech University HSC, Amarillo, Texas