Protective Protein Drastically Reduced Following Brain Injury

KCCs normally lower intracellular chloride concentrations below the electrochemical equilibrium potential and depending on the chemical concentration gradients of potassium and chloride, KCC2 can operate as a net efflux or influx pathway. KCC2 is expressed at high levels in neurons throughout the nervous system and immunofluorescence has shown that the protein was localized at inhibitory synapses of the spinal cord. Previous studies had shown that the level of KCC2 dropped drastically after brain injury.

Investigators at the Université de la Méditerranée (Marseille, France) used primary hippocampal neuronal cultures to study KCC2 function. In this system, they could block the action of KCC2 either by an RNA interference approach or by using a dominant negative mutant. KCC2 activity was restored by gene therapy that overexpressed the active form of the KCC2, while overexpression of its nonactive mutant Y1087D was used as a control.

Results published in the May 15, 2011, issue of the Journal of Physiology revealed that the experimental silencing of endogenous KCC2 reduced neuronal resistance to toxic insults. In contrast, the artificial gain of KCC2 induced by overexpression of KCC2 gene function in the same neurons protected them from death. Overexpression of the nonactive mutant Y1087D had no protective effect.

"The death of neurons in the brain can be triggered by an imbalance of oxygen – known as oxidative damage, or where cells are incorrectly instructed to die by a neurotransmitter – a process known as excitotoxicity, " said senior author Dr. Igor Medina, professor of medicine at the Université de la Méditerranée. "KCC2 protects against both. It is really encouraging that we have identified a means of potentially protecting the brain from these common conditions. The destiny of neurons in a damaged brain depends on a tiny equilibrium between prosurvival and prodeath signals. We wanted to know what KCC2 was signaling for – was it killing neurons or protecting them after an injury? Our study has found that KCC2 actually rescues the damaged cells."

"Neuroprotective agents that may stem from this research would benefit the victims of car crashes, stroke, and those suffering with epilepsy, Parkinson's, and Alzheimer's – it is a major focus for further studies," said Dr Medina.

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