Bumetanide - how a water pill can reduce autistic behaviours

Bumetanide is a loop diuretic that has been used for adults since 1976 and in children since 1986.  It has recently been successfully used to halt seizures in extremely young babies.  The use of Bumetanide for the control of such seizures was proposed in 2005 along with the suggested mechanism. 

 

A summary of that mechanism is that elevated intracellular levels of Cl^-  cause GABA to excite rather than inhibit inside the hippocampus.  But in the spinal cord GABA is already known to be inhibitory.  As a result non-convulsive seizures can occur in very young babies.  Because the GABA in spine is inhibitory there are no violent signs of convulsion, but in the hippocampus there is a seizure going on.

Bumetanide reduces intracellular levels of Cl^- , it inhibits the NKCC1 transporter so renders GABA inhibitory in the hippocampus . This action alone has been shown to make the loop diuretic a much more effective anticonvulsant than phenobarbital, which can actually exacerbate the seizure.

Research shows that during a brief period from just before to just after birth, maternal oxytocin (see note * below) temporarily renders GABA inhibitory, possibly by reducing NKCC1 activity.  

Thereafter, GABA remains excitatory until GABA itself causes a switch from excitation to inhibition of GABA by inducing expression of the mature chloride transporter, KCC2.  KCC2 transports chloride out of the cell, thereby reversing the concentration gradient of chloride.

Most anesthetic and indeed anticonvulsants are GABAergic.  It was found that giving such an anesthetic to a very young rat actually stimulated it, since GABA was still excitatory in the hippocampus.  For the same reason giving the GABAergic anticonvulsant  phenobarbital to a young baby only makes its seizure worse.

Valium is also GABAergic and so when its use in autitstic children demonstrates a stimulating rather than a calming role the question then arose as to the possibility of that elevated intracellular levels of Cl^- are causing GABA to remain excitatory rather than inhibitory in the autistic brain.

The logical question was than would reducing the level of Cl^- trip GABA back to being inhibitory and then this would manifest itself in measurable behavioural changes.

This hypothesis was first tested in a small trial in 2010 and then in full randomized controlled trial in 2012.


Merci beaucoup M.Lemonnier pour votre contribution à la science de l'autisme !
 

Note

*Oxytoxin may sound familiar. It is in Phase II clinical trials as a treatment for autism.

Coincidence ??