Allopregnanolone
Encyclopedia
Allopregnanolone is a prototypic neurosteroid present in the blood and also the brain. It is a metabolite of progesterone
and potent
modulator of GABAA receptors. While allopregnanolone, like other GABAA receptor active neurosteroids such as allotetrahydrodeoxycorticosterone (3α,21-dihydroxy-5α-pregnan-20-one; THDOC), positively modulates all GABAA receptor isoforms, those isoforms containing δ-subunits
exhibit greater magnitude potentiation. Allopregnanolone has pharmacological properties similar to other positive modulators of GABAA receptors, including anxiolytic and anticonvulsant activity.
The biosynthesis
of allopregnanolone starts with the converting of progesterone into 5α-dihydroprogesterone
by 5α-reductase type I. After that, 3α-hydroxysteroid oxidoreductase isoenzymes (also referred to as 3α-hydroxysteroid dehydrogenase) converts this intermediate into allopregnanolone. Anxiety
and depression
are common side effect
s of 5α-reductase inhibitors such as finasteride
and dutasteride
, and they are believed to be caused, in part, by the prevention of the endogenous production of allopregnanolone.
The 5β-epimer of this compound (pregnanolone; 3α-hydroxy-5β-pregnan-20-one) has similar properties to allopregnanolone, and the 3β-methyl analogue, ganaxolone
, is under development to treat epilepsy
and other conditions.
Allopregnanolone aids neurogenesis
and has been found to reverse neuron creation and cognitive deficit
s in mouse model of Alzheimer’s disease.
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
and potent
Potency (pharmacology)
In the field of pharmacology, potency is a measure of drug activity expressed in terms of the amount required to produce an effect of given intensity. A highly potent drug evokes a larger response at low concentrations, while a drug of lower potency evokes a small response at low concentrations...
modulator of GABAA receptors. While allopregnanolone, like other GABAA receptor active neurosteroids such as allotetrahydrodeoxycorticosterone (3α,21-dihydroxy-5α-pregnan-20-one; THDOC), positively modulates all GABAA receptor isoforms, those isoforms containing δ-subunits
GABRD
Gamma-aminobutyric acid receptor subunit delta is a protein that in humans is encoded by the GABRD gene....
exhibit greater magnitude potentiation. Allopregnanolone has pharmacological properties similar to other positive modulators of GABAA receptors, including anxiolytic and anticonvulsant activity.
The biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
of allopregnanolone starts with the converting of progesterone into 5α-dihydroprogesterone
5α-Dihydroprogesterone
5α-Dihydroprogesterone is a steroid hormone. It is an intermediate in the production of allopregnanolone from progesterone....
by 5α-reductase type I. After that, 3α-hydroxysteroid oxidoreductase isoenzymes (also referred to as 3α-hydroxysteroid dehydrogenase) converts this intermediate into allopregnanolone. Anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
and depression
Depression
Depression or depress may refer to:-Medicine:* Depression , a state of low mood and aversion to activity** Mood disorder, a class of mental illnesses featuring depressed mood...
are common side effect
Side effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...
s of 5α-reductase inhibitors such as finasteride
Finasteride
Finasteride is a synthetic antiandrogen that inhibits type II 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone...
and dutasteride
Dutasteride
Dutasteride is a dual 5-a reductase inhibitor that inhibits conversion of testosterone to dihydrotestosterone ....
, and they are believed to be caused, in part, by the prevention of the endogenous production of allopregnanolone.
The 5β-epimer of this compound (pregnanolone; 3α-hydroxy-5β-pregnan-20-one) has similar properties to allopregnanolone, and the 3β-methyl analogue, ganaxolone
Ganaxolone
Ganaxolone is a steroid drug, with the molecular formula C22H36O2, related to allopregnanolone that has sedative, anxiolytic, and anticonvulsant effects. It is a potent and selective positive allosteric modulator of GABAA receptors. Ganaxolone protects against seizures in diverse animal models,...
, is under development to treat epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
and other conditions.
Allopregnanolone aids neurogenesis
Neurogenesis
Neurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
and has been found to reverse neuron creation and cognitive deficit
Cognitive deficit
Cognitive deficit, also known as cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to cognitive performance...
s in mouse model of Alzheimer’s disease.