*Review* **Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke**

**Sunday Solomon Josiah, Nur Farah Meor Azlan and Jinwei Zhang \***

Hatherly Laboratories, Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter EX4 4PS, UK; josiahsos2014@gmail.com (S.S.J.); nm503@exeter.ac.uk (N.F.M.A.)

**\*** Correspondence: j.zhang5@exeter.ac.uk; Tel.: +44-(0)1392-72-3828

**Abstract:** Stroke is one of the major culprits responsible for morbidity and mortality worldwide, and the currently available pharmacological strategies to combat this global disease are scanty. Cationchloride cotransporters (CCCs) are expressed in several tissues (including neurons) and extensively contribute to the maintenance of numerous physiological functions including chloride homeostasis. Previous studies have implicated two CCCs, the Na+-K+-Cl<sup>−</sup> and K+-Cl<sup>−</sup> cotransporters (NKCCs and KCCs) in stroke episodes along with their upstream regulators, the with-no-lysine kinase (WNKs) family and STE20/SPS1-related proline/alanine rich kinase (SPAK) or oxidative stress response kinase (OSR1) via a signaling pathway. As the WNK-SPAK/OSR1 pathway reciprocally regulates NKCC and KCC, a growing body of evidence implicates over-activation and altered expression of NKCC1 in stroke pathology whilst stimulation of KCC3 during and even after a stroke event is neuroprotective. Both inhibition of NKCC1 and activation of KCC3 exert neuroprotection through reduction in intracellular chloride levels and thus could be a novel therapeutic strategy. Hence, this review summarizes the current understanding of functional regulations of the CCCs implicated in stroke with particular focus on NKCC1, KCC3, and WNK-SPAK/OSR1 signaling and discusses the current and potential pharmacological treatments for stroke.

**Keywords:** stroke; electroneutral transport; cation-chloride cotransporters; KCCs; NKCCs; WNK-SPAK/OSR1
