Chloride co‐transporters as possible therapeutic targets for stroke

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 unfolds in the subsequent hours and days, so it is critical to identify new therapeutic targets that could reduce 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 of 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 for promoting neuroprotection and neurorehabilitation following an ischaemic insult. Finally, we mention the likely importance of combining different strategies in order to achieve more effective therapies.

Preferential activation of HIF-2α adaptive signalling in neuronal-like cells in response to acute hypoxia

“…Given the current interested in the chloride co-transporters (CCC) and their potential role in neuronal adaptation to ischaemic stroke [ 32 ], expression of neuron-specific enolase (NSE)[ 33 ] and the neuronal specific chloride co-transporter, KCC2 [ 34 ], were analyzed by immunoblotting ( Fig 1E ). Low basal KCC2 and NSE expression was detected in both PC12 and NT2 cells ( Fig 1E ) and a striking increase in expression of both markers was observed upon differentiation, particularly KCC2.…”

Inhibition of Nkcc1 promotes axonal growth and motor recovery in ischemic rats

“…NKCC1 is predominately expressed in immature neurons (Young et al, 2011;Ge et al, 2006). Interestingly, focal cerebral ischemia leads to increased expression of NKCC1 and decreased expression of KCC2 (Jaenisch et al, 2010;Wang et al, 2014;Martin-Aragon Baudel et al, 2017). The disruption of neuronal chloride homeostasis results in a shift of the chloride equilibrium potential, which triggers GABA-mediated depolarization.…”

Shrm4 contributes to autophagy inhibition and neuroprotection following ischemic stroke by mediating GABA B receptor activation

“…26 The activation not just of GABA B , receptors, but also GABA A receptors are protective against ischemic neuronal damage. 11,12,27,28 In addition, activation of GABA A and GABA B receptors provided neuroprotection in the context of ischemia in vitro and in vivo through the PI3K/Akt signaling pathway. 29 More importantly, GABA B receptor activators/agonists such as baclofen are readily available for further research.…”

“…GABA B agonists commonly present with sedative, anxiolytic, anticonvulsant, and muscle relaxant effects 26 . The activation not just of GABA B , receptors, but also GABA A receptors are protective against ischemic neuronal damage 11,12,27,28 . In addition, activation of GABA A and GABA B receptors provided neuroprotection in the context of ischemia in vitro and in vivo through the PI3K/Akt signaling pathway 29 .…”