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Neurosteroid analogues. 16. A new explanation for the lack of anesthetic effects of ?(16)-alphaxalone and identification of a ?(17(20)) analogue with potent anesthetic activity.

ABSTRACT: This study addresses the hypothesis that the lack of anesthetic activity for (3?,5?)-3-hydroxypregn-16-ene-11,20-dione (?(16)-alphaxalone) is explained by the steroid ?(16) double bond constraining the steroid 20-carbonyl group to a position that prevents it from favorably interacting with ?-aminobutyric acid type A (GABA(A)) receptors. A series of ?(16) and ?(17(20)) analogues of ?(16)-alphaxalone was prepared to evaluate this hypothesis in binding, electrophysiological, and tadpole anesthesia experiments. The results obtained failed to support the hypothesis. Instead, the results indicate that it is the presence of the C-21 methyl group in ?(16)-alphaxalone, not the location of the constrained C-20 carbonyl group, that prevents ?(16)-alphaxalone from interacting strongly with the GABA(A) receptor and having anesthetic activity. Consistent with this conclusion, a ?(17(20)) analogue of ?(16)-alphaxalone without a C-21 methyl group was found to be very similar to the anesthetic steroid (3?,5?)-3-hydroxypregnane-11,20-dione (alphaxalone) with regard to time of onset and rate of recovery from anesthesia when administered to mice by tail vein injection.

SUBMITTER: Stastna E

PROVIDER: S-EPMC3794474 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Neurosteroid analogues. 16. A new explanation for the lack of anesthetic effects of δ(16)-alphaxalone and identification of a δ(17(20)) analogue with potent anesthetic activity.

Stastna Eva E Krishnan Kathiresan K Manion Brad D BD Taylor Amanda A Rath Nigam P NP Chen Zi-Wei ZW Evers Alex S AS Zorumski Charles F CF Mennerick Steven S Covey Douglas F DF

Journal of medicinal chemistry 20110506 11

This study addresses the hypothesis that the lack of anesthetic activity for (3α,5α)-3-hydroxypregn-16-ene-11,20-dione (Δ(16)-alphaxalone) is explained by the steroid Δ(16) double bond constraining the steroid 20-carbonyl group to a position that prevents it from favorably interacting with γ-aminobutyric acid type A (GABA(A)) receptors. A series of Δ(16) and Δ(17(20)) analogues of Δ(16)-alphaxalone was prepared to evaluate this hypothesis in binding, electrophysiological, and tadpole anesthesia ...[more]

PMID: 21504158

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Project description:Background: Preterm birth can lead to brain injury and currently there are no targeted therapies to promote postnatal brain development and protect these vulnerable neonates. We have previously shown that the neurosteroid-analogue ganaxolone promotes white matter development and improves behavioural outcomes in male juvenile guinea pigs born preterm. Adverse side effects in this previous study necessitated this current follow-up dosing study, where a focus was placed upon physical wellbeing during the treatment administration and markers of neurodevelopment at the completion of the treatment period. Methods: Time-mated guinea pigs delivered preterm (d62) by induction of labour or spontaneously at term (d69). Preterm pups were randomized to receive no treatment (Prem-CON) or ganaxolone at one of three doses [0.5 mg/kg ganaxolone (low dose; LOW-GNX), 1.0 mg/kg ganaxolone (mid dose; MID-GNX), or 2.5 mg/kg ganaxolone (high dose; HIGH-GNX) in vehicle (45% β-cyclodextrin)] daily until term equivalence age. Physical parameters including weight gain, ponderal index, supplemental feeding, and wellbeing (a score based on respiration, activity, and posture) were recorded throughout the preterm period. At term equivalence, brain tissue was collected, and analysis of hippocampal neurodevelopment was undertaken by immunohistochemistry and RT-PCR. Results: Low and mid dose ganaxolone had some impacts on early weight gain, supplemental feeding, and wellbeing, whereas high dose ganaxolone significantly affected all physical parameters for multiple days during the postnatal period when compared to the preterm control neonates. Deficits in the preterm hippocampus were identified using neurodevelopmental markers including mRNA expression of oligodendrocyte lineage cells (CSPG4, MBP), neuronal growth (INA, VEGFA), and the GABAergic/glutamatergic system (SLC32A1, SLC1A2, GRIN1, GRIN2C, DLG4). These deficits were not affected by ganaxolone at the doses used at the equivalent of normal term. Conclusion: This is the first study to investigate the effects of a range of doses of ganaxolone to improve preterm brain development. We found that of the three doses, only the highest dose of ganaxolone (2.5 mg/kg) impaired key indicators of physical health and wellbeing over extended periods of time. Whilst it may be too early to see improvements in markers of neurodevelopment, further long-term study utilising the lower doses are warranted to assess functional outcomes at ages when preterm birth associated behavioural disorders are observed.

Dataset Information

Neurosteroid analogues. 16. A new explanation for the lack of anesthetic effects of ?(16)-alphaxalone and identification of a ?(17(20)) analogue with potent anesthetic activity.

Publications

Neurosteroid analogues. 16. A new explanation for the lack of anesthetic effects of δ(16)-alphaxalone and identification of a δ(17(20)) analogue with potent anesthetic activity.

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