Repurposing Metformin to Offset Stroke Risk and Injury in Comorbid Populations of Smokers

Abstract: 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.

Grant Number: 5R01NS117906-05
NIH Institute/Center: NIH
Principal Investigator: Thomas Abbruscato