Many of the biological actions of progesterone are mediated through the progesterone receptor (PR), a nuclear transcription factor. Progesterone is well recognized to protect against seizures in animal models. Although this activity has been attributed to the progesterone metabolite allopregnanolone, a GABAA receptor-modulating neurosteroid with anticonvulsant properties, PRs could also play a ...

Benzodiazepines are the current first-line standard-of-care treatment for status epilepticus but fail to terminate seizures in about one third of cases. Synaptic GABAA receptors, which mediate phasic inhibition in central circuits, are the molecular target of benzodiazepines. As status epilepticus progresses, these receptors are internalized and become functionally inactivated, conferring benzo...

Generalized anxiety, panic, and posttraumatic stress disorder (PTSD) are debilitating conditions, which have an incidence of one in ten persons in the general population and epidemiological studies also report that these disorders often occur with depression (1-3). Anxiolytic benzodiazepines, including diazepam and alprazolam, remain the best and most used treatments for these conditions (4-7)....

BACKGROUND Animal studies have shown that neuroactive steroids modulate the activity of the gamma-aminobutyric acid type A/benzodiazepine receptor complex and that these steroids display anxiolytic or anxiogenic activity depending on their positive (e.g. allopregnanolone) or negative allosteric modulation (e.g. dehydroepiandrosterone sulphate) of this receptor. This study compared plasma levels...

Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is thought to result from deficient intracellular cholesterol and/or ganglioside trafficking. We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1(-/-) mi...

Allopregnanolone is an endogenous neurosteroid that acts in a rapid non-genomic manner to enhance the function of GABAA receptor (GABAAR), major inhibitory mammalian central nervous system (CNS). Consequently, allopregnanolone elicits anxiolytic, antidepressant, anticonvulsant, analgesic and sedative effects. Endogenous influences neural inhibition behaviour, with perturbed levels implicated de...

Neuroactive steroids can either potentiate or inhibit a variety of membrane channels. Most studies have suggested that the effects are mediated by specific association of the steroid with the affected channel. However, a recent study of the rho1 (GABA-C) receptor (Mol Pharmacol 66:56-69, 2004) concluded that the actions were consistent with an action of the steroid in the lipid bilayer to alter...

OBJECTIVES Painful diabetic neuropathy is associated with hyperexcitability and hyperactivity of spinal cord neurons. However, its underlying pathophysiological mechanisms have not been fully clarified. Induction of excitatory/inhibitory neurotransmission imbalance at the spinal cord seems to account for the abnormal neuronal activity in diabetes. Protective properties of neurosteroids have bee...

Although 3alpha-substituted metabolites of progesterone are well established to interact with GABA(A) receptor/Cl(-) channels, the nature of the interaction(s) remains uncertain. We used patch-clamp recording to study the interaction with GABA(A) receptor/Cl(-) channels expressed by embryonic hippocampal neurons differentiating in culture and nonneuronal cells transfected with GABA(A) receptor ...

..................................................................................................... 6 ABBREVIATIONS....................................................................................... 7 LIST OF ORIGINAL PAPERS............................................................ 8 INTRODUCTION .......................................................................................... ...