In the past decade a number of alternative vaping products have hit the market, rapidly gaining consumers among adults and, especially, adolescents. Electronic nicotine delivery systems or e-cigarettes (e-Cigs) have become the sought-after product due to the belief that they are much safer than traditional cigarettes. Moreover, tobacco smoking (TS) is associated with vascular endothelial dysfunction in a causative and dose dependent manner primarily related to the TS content of reactive oxygen species (ROS), nicotine, and oxidative stress (OS) -driven inflammation. Current scientific opinion considers OS-mediated pathways to play a major role in the pathogenesis of these disorders, especially stroke. Preclinical studies (and preliminary data presented herein) have shown that nicotine (the principal e-liquid's ingredient) can cause OS, exacerbation of cerebral ischemia and secondary brain injury. Likewise, chronic e-Cig vaping could be prodromal to cerebrovascular impairment and promote cerebrovascular conditions that favor the onset of stroke and post- ischemic brain injury, suggested by our initial findings. The health impact of e-Cig vaping is currently unknown and the limited research and dearth of regulatory guidelines for the content of the vaping solution for e-Cigs (various harmful compounds including aldehydes, nitrosamines etc. have been detected in the e-Cig vapors) has become a critical public and regulatory concern we also want to address with this research. Further, we and others have found that TS promotes glucose intolerance and increases the risk of developing type-2 diabetes mellitus (2DM) with which it shares other pathogenic traits including the high risk of cerebrovascular and neurological disorders like stroke via ROS generation, inflammation, and blood-brain barrier (BBB) impairment. Recent in vitro findings and preliminary data from our group, supports an additive release pattern of angiogenic, oxidative and inflammatory factors by BBB endothelial cells in response to hyperglycemia (HG) and/or stroke conditions with comcomitant exposure to cigarette smoke extracts (CSE), thus suggesting the involvement of common pathogenic modulators of BBB impairment. To this end, metformin (MF; a widely prescribed, firstline anti-diabetic drug) before and after stroke injury has been shown to reduces stress and inhibits inflammatory responses 88. Recent preliminary data revealed that MF activates counteractive mechanisms which drastically reduce TS toxicity at the level of the BBB. These beneficial effects have been shown to be mediated by MF activation of nuclear factor erythroid 2-related factor (Nrf2) 51. Our hypothesis is that excessive OS caused by TS and e- Cigs dysregulation of the cellular antioxidant response system is the linking underling mechanism prodromal to cerebrovascular toxicity and highten risk and/or severity of stroke In this respect we will: 1) Assess the potential cerebrovascular pathogenic impact of e-Cig vaping vs. TS through a side by side comparative study as per a recent call to action to investigate e-Cig toxicity by the regulatory agency and the Surgeon General; 2) Assess the molecular mechanisms (Nrf2/mitochondrial focused) driving TS-dependent impairment of the BBB and enhanced risk stroke and 3) Assess the viability and effectiveness of metformin (MF) to prevent/reduce TS and possibly e-Cig vaping-induced BBB damage and subsequent ischemic stroke injury. This is of outmost importance since chronic smoking carry high risks for cardiovascular diseases (CVD) and stroke but care treatment(s) only begins upon clinical manifestation of a disease. For chronic smokers (including early stage former smokers for whom the risk of stroke is still very high) there are no prophylactic options available.
Our preliminary in vitro and in vivo findings strongly suggest that BBB impairment and increased risk for stroke by tobacco smoke (TS) closely resemble that of type-2 diabetes (2DM) and develop largely in response to common key modulators such oxidative stress (OS), inflammation and perhaps, alterations of the endogenous antioxidative response system. Preclinical studies (and preliminary data presented herein) have shown that nicotine (the principal e-liquid's ingredient) can cause OS, exacerbation of cerebral ischemia and secondary brain injury 52-54. Likewise, chronic e-Cig vaping could be prodromal to cerebrovascular impairment and promote the onset of stroke and post- ischemic brain injury as also suggested by our initial findings. However, the health impact of e-Cigs vaping is currently unknown and the substantial lack of toxicological and comparative research has become a critical public concern which greatly hinders the development of FDA regulatory/safety guidelines and need to be addressed. In this respect the Surgeon General issued a new report raising public health concerns about e?Cig use among US youth and young adults and a call to action to expand research efforts related to e?Cigs?. The bulk of research data on TS toxicity at the cerebrovascular system originated by our group during the current funding period along with the methodological approaches we developed to address the study needs in the same continuum afford us a unique position to tackle this issue. Furthermore, recent reports have shown that metformin (MF) treatment before and after ischemic injury reduces stress and inhibits inflammatory responses. Recent preliminary data reveals that MF promotes the activation of counteractive mechanisms mediated by the activation of nuclear factor erythroid 2-related factor (Nrf2) which drastically reduce TS toxicity at the brain and cerebrovascular levels and protect BBB integrity. Therefore we will be assessing whether MF could be used to reduce the risk of cerebrovascular damage promoted by TS and possibly e-Cig vaping. Potential benefit of MF could be extended as prophylactic care during the time window required for the renomalization of the risk levels of stroke following smoking cessation. Based on these premises, the overarching hypothesis is that excessive OS caused by TS and e-Cig dysregulation of the cellular antioxidant response system is the linking underling mechanism prodromal to cerebrovascular toxicity and highten risk and/or severity of stroke. Therefore, the objectives of our study are:1) Assess the potential cerebrovascular pathogenic impact of e-Cig vaping in respect to TS through a side by side comparative study and inform the regulatory agency (FDA) accordingly; 2)Assess the molecular mechanisms (Nrf2/mitochondrial focused) driving TS-dependent impairment of the BBB and enhanced risk stroke; 3) Assess the viability and effectiveness of MF to prevent/reduce TS and possibly e-Cig vaping-induced BBB damage and subsequent ischemic stroke injury. The proposed studies will benefit the millions of chronic smokers (including early stage former smokers and vapers) which are on the rise in US. Specifically we will: A) Assess the potential cerebrovascular pathogenic impact of e-Cig vaping and TS in a side by side comparative study (both in vitro and in vivo). B) Evaluate in vivo the effect of prophylactic versus therapeutic (post-ischemic) administration of metformin in reducing TS or e-Cig vaping - promoted cerebrovascular impairment and/or post-ischemic neuronal damage.
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