Chloride co-transporters as possible therapeutic targets for stroke

Mart�n-Arag�n Baudel, Miguel A. S.; Mart�n-Arag�n Baudel, Miguel A S; Poole, Amy V.; Darlison, Mark G.

Abstract

Stroke is one of the major causes of death and disability worldwide. The major type of stroke is an ischaemic one, which is caused by a blockage that interrupts blood flow to the brain. There are currently very few pharmacological strategies to reduce the damage and social burden triggered by this pathology. The harm caused by the interruption of blood flow to the brain evolves during the following hours and days, so it is critical to identify new therapeutic targets that could reduce the neuronal death associated with the spread of the damage. Here we review some of the key molecular mechanisms involved in the progression of neuronal death, focusing on some new and promising studies. In particular, we focus on the potential of the chloride co-transporter (CCC) family of proteins, mediators of the GABAergic response, both during the early and later stages of stroke, to promote neuroprotection and recovery. Different studies on CCCs, during the chronic and recovery phases post-stroke, reveal the importance of timing when considering CCCs as potential neuroprotective and/or neuromodulator targets. The molecular regulatory mechanisms of the two main neuronal CCCs, NKCC1 and KCC2, are further discussed as an indirect approach to promote neuroprotection and neurorehabilitation following an ischaemic insult. Finally, we mention the likely importance of combining different strategies in order to achieve more effective therapies.

Citation

Martín-Aragón Baudel, M. A. S., Martín-Aragón Baudel, M. A. S., Poole, A. V., & Darlison, M. G. (2017). Chloride co-transporters as possible therapeutic targets for stroke. Journal of Neurochemistry, 140(2), 195-209. https://doi.org/10.1111/jnc.13901

• Journal Article Type: Article
• Acceptance Date: Nov 8, 2016
• Online Publication Date: Dec 22, 2016
• Publication Date: 2017-01
• Deposit Date: Nov 18, 2016
• Publicly Available Date: Dec 23, 2017
• Journal: Journal of Neurochemistry
• Print ISSN: 0022-3042
• Electronic ISSN: 1471-4159
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 140
• Issue: 2
• Pages: 195-209
• DOI: https://doi.org/10.1111/jnc.13901
• Keywords: brain ischaemia; chloride co-transporter; excitotoxicity; GABAA receptor; neuroprotection; therapy
• Public URL: http://researchrepository.napier.ac.uk/Output/426239
• Contract Date: Nov 18, 2016