The effects induced by the sulphonylurea glibenclamide on the neonatal rat spinal cord indicate a novel mechanism to control neuronal excitability and inhibitory neurotransmission.
OBJECTIVE
Using the neonatal rat spinal cord in vitro, we investigated the action of glibenclamide, a drug possessing dual pharmacological effects, namely block of K(ATP) channels and of the cystic fibrosis transmembrane conductance regulator (CFTR).


METHODS
Intra- and extracellular recordings were performed on motoneurons and interneurons. RT-PCR and western immunoblotting were used to determine gene and protein expression.


RESULTS
Glibenclamide (50 microM) facilitated mono- and polysynaptic reflexes, hyperpolarized motoneuron resting potential, increased action potential amplitude, decreased Renshaw cell-mediated recurrent inhibition, and increased network excitability by depressing GABA- and glycine-mediated transmission. The action of glibenclamide was mimicked by tolbutamide (500 microM) or the CFTR blocker diphenylamine-2,2-dicarboxylic acid (500 microM). The action of glibenclamide was independent from pharmacological inhibition of the Na(+)-K(+) pump with strophanthidin (4 microM) and was associated with a negative shift in the extrapolated reversal potential for CI(-) dependent synaptic inhibition. On interneurons, intracellularly-applied 8-bromo-cAMP elicited an inward current and resistance decrease; effects antagonized by the selective CFTR antagonist, CFTR(inh)-172 (5 microM). RT-PCR and western immunoblotting indicated strong expression of the CFTR in neonatal rat spinal cord.


CONCLUSIONS
These data suggest the CFTR expressed in motoneurons and interneurons of the neonatal spinal cord is involved in the control of Cl(-) homeostasis and neuronal excitability. CFTR appeared to contribute to the relatively depolarized equilibrium potential for synaptic inhibition, an important process to control hyperexcitability and seizure-predisposition in neonates.
Ostroumov
K
K
Neurobiology Sector and SPINAL Project, International School for Advanced Studies (SISSA), Trieste 34014, Italy.
Grandolfo
M
M
Nistri
A
A
D000818:Animals; D000831:Animals, Newborn; D005905:Glyburide / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*
D005905:Glyburide