Myo‐Inositol Improves Ischemic Stroke Outcome After both Nicotine Containing Electronic Cigarette and Tobacco Smoke Exposure

Abstract

Ischemic stroke occurs in 87% of all strokes and is the leading cause of disability in the United States. Smoking has been shown to increase brain edema after ischemic stroke and worsen long‐term clinical outcomes. Electronic nicotine delivery systems or e‐cigarettes (e‐Cigs) are gaining popularity over traditional tobacco smoke cigarettes, and have been reported influence stroke outcome. Previous work from our lab reported nicotine and e‐Cig exposure decreased glucose utilization in the brain in ischemic stroke models, further exacerbating the effects of ischemic injury. Myo‐inositol(MI), a major organic osmolyte that promotes cell membrane stability and various cellular functions, has been reported to reduce infarcted area and edema ratio in a diabetic ischemic mouse model. We also sought to understand the role of MI protection with regard to additional stroke comorbidities, such as e‐Cig or tobacco smoke exposure. In this study, we investigated the neuroprotective role of MI transporters during stroke and post‐stroke outcomes, especially related to the role of glial cells and post‐stroke reorganization. We hypothesize MI plays a role in increased recovery of motor function, after stroke, in animal groups exposed to tobacco smoke or e‐Cig vape. Primary astrocytes and primary neurons were used for in vitro studies and a middle cerebral artery occlusion (MCAO) mouse model for in vivo stroke studies. Immunocytochemistry (ICC) studies showed astrocytes express sodium dependent myo‐inositol transporter 1 (SMIT1) and sodium‐dependent glucose transporter 6 (SGLT6). Our data illustrated expression of both transporters increased in a time‐dependent manner during oxygen‐glucose deprivation (OGD), in tobacco smoke extract (TSE), and e‐Cig extract (ECE) treated cells. Further, this was confirmed by an increase of MI uptake in TSE treated astrocytes. Altered cell mitochondrial respiration levels were observed in astrocytes and neurons incubated for 24hr with TSE and ECE followed by OGD exposure using Seahorse XF Cell Mito Stress. Animal studies demonstrated post‐stroke administration of MI, reduced infarction size and edema ratios in tobacco smoke compared to non‐tobacco smoke animals. An improvement of motor function was also seen in selected behavioral tests. E‐cig exposed animals had a slight increase in infarction size compared to non‐e‐Cig animals. This preliminary data suggest myo‐inositol may have a neuroprotective role in ischemic stroke injury and could significantly improve stroke outcome in both tobacco smokers and e‐Cig users. Further investigation will include assessment of sex differences with regard to the neuroprotective mechanisms of MI in e‐Cig and tobacco smoke exposed animals.Support or Funding Information1R01DA0497375 and R01DA029121 to TJA and LC