Neurovascular unit transport responses to ischemia and common coexisting conditions: smoking and diabetes

Abstract

Transporters at the neurovascular unit (NVU) are vital for the regulation of normal brain physiology via ion, water, and nutrients movement. In ischemic stroke, the reduction of cerebral blood flow causes several complex pathophysiological changes in the brain, one of which includes alterations of the NVU transporters, which can exacerbate stroke outcome by increased brain edema (by altering ion, water, and glutamate transporters), altered energy metabolism (by altering glucose transporters), and enhanced drug toxicity (by altering efflux transporters). Smoking and diabetes are common risk factors as well as coexisting conditions in ischemic stroke that are also reported to change the expression and function of NVU transporters. Coexistence of these conditions could cause an additive effect in terms of the alterations of brain transporters that might lead to worsened ischemic stroke prognosis and recovery. In this review, we have discussed the effects of ischemic stroke, smoking, and diabetes on some essential NVU transporters and how the simultaneous presence of these conditions can affect the clinical outcome after an ischemic episode. Further scientific investigations are required to elucidate changes in NVU transport in cerebral ischemia, which can lead to better, personalized therapeutic interventions tailor-made for these comorbid conditions.

Keywords: glucose transporters; ion transporters; ischemic stroke; neurovascular unit.

Fig. 1.

A schematic representation of the cellular localization of transporters in neurovascular unit. KCa3.1, calcium-activated potassium channel-3.1; Bcrp, breast cancer resistance protein; Oatp1a4, organic anion transporting polypeptide; NCX, Na⁺/Ca²⁺ exchanger; P-gp, P-glycoprotein; NKCC, Na⁺-K⁺-2Cl⁻ cotransporter; SUR1, sulfonyl urea receptor-1-regulated nonselective cation channel; NHE, Na⁺/H⁺ exchanger; AQP4, aquaporin-4; MRP, multidrug resistance protein; GLT, glutamate transporter; GLUT, glucose transporter; SGLT, Na⁺-dependent glucose cotransporter.

Fig. 2.

A schematic representation of the effects of ischemic stroke on ion transporters at the neurovascular unit. Ischemic insult differentially affects the functions of these transporters, which regulate the movement of ions (Na⁺, K⁺, Ca²⁺) across brain cells. The combination of all these transporters’ functional changes results in an increased Na⁺, decreased K⁺, and increased Ca²⁺ level inside the brain cells after cerebral ischemia. These ion gradient changes contribute to cytotoxic brain edema and excitotoxic brain damage after stroke. NKCC, Na⁺-K⁺-2Cl⁻ cotransporter; SUR1/TRPM, sulfonyl urea receptor-1-regulated nonselective cation channel; NHE, Na⁺/H⁺ exchanger; NCX, Na⁺/Ca²⁺ exchanger; KCa3.1, calcium-activated potassium channel-3.1.

Fig. 3.

Radioactive deoxy-d-glucose uptake in primary cortical neurons in different conditions. OGD/R significantly increases neuronal glucose uptake compared with normoxia and OGD. Twenty-four hour pretreatment with nicotine and cotinine significantly decreases neuronal glucose uptake compared with control in OGD/R. OGD, 2 h oxygen-glucose deprivation; OGD/R, 2 h oxygen-glucose deprivation followed by 24 h reoxygenation. Data are expressed as means ± SE and represent 3–4 independent primary neuronal isolations with 3–6 replicate treatments per isolation. *P < 0.05, **P < 0.01, ****P < 0.0001.