Recently published in vitro and in vivo findings strongly suggest that blood-brain barrier (BBB) impairment and increased risk for stroke by tobacco smoke (TS) develop largely in response to common key modulators such oxidative stress (OS), inflammation and alterations of the endogenous antioxidative response system (ARE) regulated by the nuclear factor erythroid 2-related factor (Nrf2). Preclinical studies have also shown that nicotine (the principal e-liquid's ingredient used in e-cigarettes) can also cause OS, exacerbation of cerebral ischemia and secondary brain injury. Preliminary data from our laboratories provides evidence that likewise to TS; chronic e-Cigarette (e-Cig) vaping can promote loss of BBB integrity and vascular inflammation as well as act as a risk factor for the onset of stroke and worsening of post- ischemic brain injury. In addition, recent reports have shown that metformin (MF) treatment before and after ischemic injury reduce stress and inhibit inflammatory responses. Preliminary data provided in this grant suggests that MF promotes Nrf2-mediated counteractive mechanisms which drastically reduce TS toxicity at the brain and cerebrovascular levels while protecting BBB integrity. We provide additional in vivo evidence showing that MF can effectively reduce the oxidative and inflammatory risk for stroke and attenuate post-ischemic brain injury promoted by TS and e-Cig vaping. We propose that MF could be repurposed to prevent/reduce BBB damage and subsequent stroke injury by TS and e-Cig exposure in chronic smokers/vapors. Thus, the objectives of our study are: 1) Assess and validate the brain microvascular molecular mechanisms by which MF can protect the BBB from TS/e-Cig including ischemic/reperfusion (IR) injury. We will unravel the molecular target through which MF can positively impact the BBB and reduce the burden of ischemic stroke and cerebrovascular impairments in chronic smokers and vapors. 2) Evaluate in vivo the effect of prophylactic versus therapeutic (post-ischemic) administration of metformin in reducing TS/e-Cig - promoted cerebrovascular impairment and/or post-ischemic neuronal damage. In vivo investigations will define a mechanism of BBB transport and CNS entry for MF along with major ischemic injury endpoints; including infarction and edema volume, histological endpoints and behavioral recovery after stroke. Ultimately, we will characterize MF's efficacy and therapeutic time window for stroke treatment in mice exposed to TS or e-Cig vapor.
It is known that metformin (MF), a widely prescribed, firstline anti-diabetic drug, can positively modulate lipid, metabolic and inflammatory profiles. Interestingly, recent reports show that MF treatment before and after ischemic injury reduces stress and inhibits inflammatory responses. Recent published work by our group and as well as current preliminary data reveal that MF promotes the activation of counteractive mechanisms which drastically reduce tobacco smoke (TS) and e-cigarette (e-Cig) toxicity at both the brain and cerebrovascular levels, protects BBB integrity, and improves stroke outcome. Ultimately our data suggest that repurposing MF could provide a suitable prophylactic and/or post stroke therapeutic agent to be utilized for a high risk, stroke-prone populations of smokers and possibly early stage former smokers. To this end, the goal of our current research endevour is to understand further the mechanisms and extent to which metformin can prevent/reduce BBB damage and subsequent ischemic stroke injuries in high risk populations of smokers and vapers. We are concurrently exploring the inhibition of pathological mechanisms related to the dysregulation of Nrf2, which is similarly involved in TS/e-Cig cerebrovascular impairments.
