CNS and Neurological Disorders 2014-01-01

Kv1.3 lymphocyte potassium channel inhibition as a potential novel therapeutic target in acute ischemic stroke.

Andras Folyovich, Eniko Biro, Csaba Orban, Anna Bajnok, Barna Vasarhelyi, Gergely Toldi

Index: CNS Neurol. Disord. Drug Targets 13(5) , 801-6, (2014)

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Abstract

Stroke-induced immunosuppression (SIIS) leads to severe complications in stroke patients, including an increased risk of infections. However, functional alterations of T lymphocytes during SIIS are poorly described in acute ischemic stroke (AIS). We aimed to characterize Ca(2+) influx kinetics in major lymphocyte subsets (CD4, Th1, Th2, CD8) in AIS patients without infection 6 hours and one week after the CNS insult. We also assessed the sensitivity of the above subsets to specific inhibition of the Kv1.3 and IKCa1 lymphocyte K(+) channels. We took peripheral blood samples from 12 non-stroke individuals and 12 AIS patients. We used an innovative flow cytometry approach to determine Ca(2+) influx kinetics and the surface expression of Kv1.3 channels. Our results indicate that Ca(2+) influx kinetics is altered in the Th2 and CD8 subsets in AIS which may play a role in the development of SIIS. Specific inhibition of Kv1.3 channels selectively decreased Ca(2+) influx in the CD8 and Th2 subsets of AIS patients. The surface expression of Kv1.3 channels is also altered compared to non-stroke individuals. Kv1.3 channel inhibition might have beneficial therapeutic consequences in AIS, selectively targeting two distinct T cell subsets at two different time points following the CNS insult. Within hours after the insult, it might prevent excessive tissue injury through the inhibition of CD8 cells, while at one week after the insult, it may improve the inflammatory response through the inhibition of Th2 cells, thus reducing the unwanted clinical consequences of SIIS.