Abstract:

New clinical evidence suggests that pharmacological blockade of CCCs may improve [Cli] homeostasis dysregulation and restore endogenous GABAergic inhibition and glutamatergic excitability in neurological diseases with disturbed neuronal circuits, such as epilepsy and autism. The usage of the current CCC-targeting drugs in the preclinical studies, such as bumetanide, shows their potentials to reduce brain damage and accelerate neurological recovery in acute brain disorders that have secondary ionic disturbances including ischemic stroke. However, recent investigation of bumetanide pharmokinetics
shows rapid elimination and poor brain penetration, which may lead to negative side effects, such as clinical deficits in hearing and developmental delay in mice. Additional investigation of the long-term effects of the current CCC targeting drugs in the immature brain is warranted. Developing more selective and potent inhibitors of the CCCs with less adverse side effects is needed. Better understanding of roles of NKCC1 in the neurological diseases may lead to new alternative and more effective therapies.