Neurosteroid
Neurosteroids have a wide range of potential clinical applications from sedation to treatment of epilepsy[6] and traumatic brain injury.
They act as positive allosteric modulators of the GABAA receptor (especially δ subunit-containing isoforms), and possess, in no particular order, antidepressant, anxiolytic, stress-reducing, rewarding,[10] prosocial,[11] antiaggressive,[12] prosexual,[11] sedative, pro-sleep,[13] cognitive and memory-impairing,[citation needed] analgesic,[14] anesthetic, anticonvulsant, neuroprotective, and neurogenic effects.
[3] Major examples include tetrahydrodeoxycorticosterone (THDOC), the androstane 3α-androstanediol, the cholestane cholesterol and the pregnanes pregnanolone (eltanolone), allopregnanolone (3α,5α-THP).
Also, many endogenous steroids, including pregnenolone, progesterone, corticosterone, deoxycorticosterone, DHEA, and testosterone, are metabolized into (other) neurosteroids, effectively functioning as so-called proneurosteroids.
[3] Some major known biological functions of neurosteroids include modulation of neural plasticity,[26] learning and memory processes,[27] behavior,[28][29] and seizure susceptibility,[30] as well as responses to stress, anxiety, and depression.
[32] This is similar to the case of endorphins, which are released in response to stress and physical pain and counteract the negative subjective effects of such states.
[34][35][36] In addition, it is thought that changes in neurosteroid levels may be involved in the changes in mood, anxiety, and sexual desire that occur during puberty in both sexes and during menopause in women.
[3][37][38] Elevated levels of inhibitory neurosteroids, namely allopregnanolone, can produce paradoxical effects, such as negative mood, anxiety, irritability, and aggression.
Hydroxydione proved to be a useful anaesthetic drug with a good safety profile, but was painful and irritating when injected probably due to poor water solubility.
The neurosteroid ganaxolone, an analog of the progesterone metabolite allopregnanolone, has been extensively investigated in animal models and is currently in clinical trials for the treatment of epilepsy.
[47][48] A randomized, placebo controlled, 10-week phase 2 clinical trial of orally administered ganaxolone in adults with partial onset seizure demonstrated that the treatment is safe, well tolerated and efficacious.
Researchers have suggested the use of so-called "neurosteroid replacement therapy" as a way of treating catamenial epilepsy with neuroactive steroids such as ganaxolone during the period of the menstrual cycle when seizure frequency increases.
[49] Allopregnanolone (SAGE-547) is under development as an intravenous therapy for the treatment of super-refractory status epilepticus, postpartum depression, and essential tremor.
