Estradiol-induced changes in the activity of hippocampal neurons in network culture are suppressed by co-incubation with gabapentin.
The ovarian steroid hormone estradiol, in addition to its function in the maintenance and regulation of reproductive capacity, can alter neuronal excitability. Estradiol is proconvulsant, increases neuronal excitability and decreases the threshold for seizure activity. Over one-third to one-half of women with epilepsy experience catamenial seizures, which are seizures influenced by cyclical hormone changes. These hormone-sensitive seizures respond to the anti-epileptic drug gabapentin, which is a structural analogue of the inhibitory amino acid neurotransmitter GABA. We studied the effects of 17-beta-estradiol alone and estradiol co-incubated with gabapentin on neuronal activity in network cultures of rat hippocampal neurons using a fluorescent calcium binding dye fluo-3 AM, FM 1-43 labeling of synaptic vesicles and electrophysiological recordings. Significant changes in the neuronal network activity were observed in the estradiol-treated neuronal cultures; the reactivity of the neurons to KCl depolarization induced intracellular calcium changes, and FM 1-43 destaining was increased as was the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSC). All these excitatory effects of estradiol were nullified by co-incubating the neurons with a combination of estradiol and gabapentin. This suggests that gabapentin can indeed affect the estradiol-induced changes in neuronal network hyperexcitability by influencing the neuronal calcium levels, exocytosis and synaptic activity. Our findings could provide an understanding of the cellular basis of hormone-sensitive seizure control by gabapentin.
Rao
Shilpa P
SP
Molecular Biophysics Unit, Indian Institute of Science, Bangalore-560012, India.
Sikdar
S K
SK
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000588:Amines / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003509:Cyclohexanecarboxylic Acids / Q000494:pharmacology*; D003952:Diagnostic Imaging; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D000077206:Gabapentin; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009415:Nerve Net / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010852:Picrotoxin / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D015763:2-Amino-5-phosphonovalerate; D000588:Amines; D002118:Calcium; D003509:Cyclohexanecarboxylic Acids; D004958:Estradiol; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D000077206:Gabapentin; D010852:Picrotoxin; D011189:Potassium Chloride; D011726:Pyridinium Compounds; D000644:Quaternary Ammonium Compounds; D005680:gamma-Aminobutyric Acid; C073804:FM1 43