Nicotine Exacerbates Brain Edema during In Vitro and In Vivo Focal Ischemic Conditions

Abstract

We have previously shown that nicotine, the addictive component of tobacco products, alters the blood-brain barrier (BBB) Na ϩ ,K ϩ ,2Cl Ϫ cotransporter (NKCC) during in vitro hypoxiaaglycemia exposure. Attenuation of abluminal NKCC suggests that accumulation of ions in the brain extracellular fluid would result in an increase of fluid or cytotoxic edema in the brain during hypoxia-aglycemia or stroke conditions. To further investigate whether nicotine products have the potential to worsen stroke outcome by increasing edema formation, two separate models to mimic stroke conditions were utilized to decipher the effects of short-term and long-term administrations of nicotine products on brain edema following stroke. Oxygen glucose deprivation (OGD) was studied in rat hippocampal slices with short-term or long-term exposure to nicotine and cigarette smoke constituents. During short-term exposure, the presence of nicotine at a concentration mimicking heavy smokers increased water content of hippocampal slices during OGD. Furthermore, long-term 1-week administration of nicotine increased water content in hippocampal slices that could be attenuated with nicotine acetylcholine receptor (nAChR) antagonists, suggesting nicotine increase edema during OGD via nAChRs. A second model of focal ischemia, middle cerebral artery occlusion, showed an increase of infarct size during short-term exposure to nicotine and an increase of edema during both short-term and long-term administration of nicotine, compared with saline controls. These findings support the paradigm that nicotine products not only increase the incidence of stroke but also have the potential to worsen stroke outcome by increased edema formation.

The Experimental Autoimmune Encephalomyelitis Disease Course Is Modulated by Nicotine and Other Cigarette Smoke Components

“…Pumps were incubated in saline at 37°C overnight (14-day pumps) or for at least 40 hours (28-day pumps) to ensure a steady pump rate (0.25 µl/hr) and then implanted subcutaneously in the back of the mice. At 14 or 28 days of infusion, the serum cotinine levels were measured at 83.8 ng/ml (14-day infusion) and 85.7 ng/ml (28-day infusion), which is comparable to that found in heavy smokers (80–100 ng/ml) [24]. The preparation of CSC is at 40 mg/ml in DMSO (Murty Pharmaceuticals).…”

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“…Similarly, Hawkins and coworkers confirmed that nicotine down regulated the expression of the ZO-1 tight junction protein in the BBB, the follow-on of increased permeability [53]. Furthermore, many other scientific communities revealed that nicotine alters the function of the BBB Na +À K +À 2Cl À co transporter through mediation of a7nAChR [54][55][56].…”

Nicotine aggravates the brain postischemic inflammatory response

“…It is known that nicotine alters the Na ϩ , K ϩ , 2Cl cotransporter 1 (NKCC1) on the abluminal (brain facing) surface of the BBB during in vitro hypoxia/ aglycemia conditions, affecting the development of both cytotoxic and vasogenic brain edema (1,16,29,49). Nicotine also affects the tight-junction complexes between brain endothelial cells, which may contribute to vasogenic brain edema (16).…”