| Description: |
Allopregnanolone is a progesterone metabolite. Allopregnanolone is an allosteric modulator of the GABA receptor. |
| Target: |
Human Endogenous Metabolite |
| In Vivo: |
Allopregnanolone increases both the K+-evoked [3H]-glutamate and [3H]-GABA release in P rats. The neurosteroid also increases the basal release of [3H]-glutamate in VO rats in an effect that is dependent on the modulation of NMDA receptors as is reverted by Mg2+[2]. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels range between 34-51ng/mL by 30min[3]. Allopregnanolone-induced neurogenesis correlates with restoration of learning and memory function in a mouse model of Alzheimer's disease and is comparably efficacious in aged normal mice[4]. Progesterone and allopregnanolone has shown neuroprotective effects in different experimental models including stroke and spinal cord injury[5]. |
| In Vitro: |
Allopregnanolone induces a significant increase in proliferation of neuroprogenitor cells derived from the rat hippocampus and human neural stem cells derived from the cerebral cortex in a dose-dependent manner. Allopregnanolone increases the expression of genes that promote mitosis and inhibits the expression of genes that repress cell proliferation[1]. Its biosynthesis begins with progesterone, which is converted to dihydroprogesterone by the enzyme 5α-DHP and after that, the enzyme 3α-HSOR catalyses the reduction of dihydroprogesterone toward allopregnanolone[2] |
| Animal Administration: |
Rats: Allopregnanolone is dissolved in propylenglycol to a concentration of 0.6 mM and diluted in Krebs Ringer bicarbonate glucose (KRBG) Mg2+-free buffer at pH 7.4 to 120 nM. To antagonize GABA receptors, 120 nM allopregnanolone plus 9.8 μM Bic (Bic+Allo groups) or 9.8 μM Bic alone (Bic groups) is used[2]. Mice: Allopregnanolone is dissolved in 20%w/v HBCD solution at 2.5 mg/mL by brief sonication and is subcutaneously (SC) injected to mice at 0.5, 1, and 10 mg/kg. Additionally, allopregnanolone is dissolved in 6%w/v SBECD solution at 0.5 mg/mL and injected IV to mice at 0.1, 0.5, and 1 mg/kg. HBCD or SBECD alone are included as vehicle controls. Topical transdermal is applied on the shaved dorsal surface at 50mg/kg using a gel solution of 3.3% allopregnanolone (w/w), 45% DMSO, 30% EtOH, 2.5% Klucel MF, 19.2% PEG-300. Intranasal formulations are prepared in both 100% castor oil and 20% HBCD. Intramuscular formulation is administered to mice as allopregnanolone 1.5 mg/mL in 6% SBECD[3]. |
| References: |
[1]. Wang JM, et al. The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J Neurosci. 2005 May 11;25(19):4706-18.
[2]. Giuliani FA, et al. Allopregnanolone and puberty: modulatory effect on glutamate and GABA release and expression of 3α-hydroxysteroid oxidoreductase in the hypothalamus of female rats. Neuroscience. 2013 Jul 23;243:64-75.
[3]. Irwin RW, et al. Allopregnanolone Preclinical Acute Pharmacokinetic and Pharmacodynamic Studies to Predict Tolerability and Efficacy for Alzheimer’s Disease. PLoS One. 2015 Jun 3;10(6):e0128313.
[4]. Irwin RW, et al. Allopregnanolone as regenerative therapeutic for Alzheimer's disease: translational development and clinical promise. Prog Neurobiol. 2014 Feb;113:40-55.
[5]. Guennoun R, et al. Progesterone and allopregnanolone in the central nervous system: response to injury and implication for neuroprotection. J Steroid Biochem Mol Biol. 2015 Feb;146:48-61. |
