Synthetic structural modifications of neurosteroid pregnanolone sulfate: Assessment of neuroprotective effects in vivo

0534367 - FGÚ 2021 RIV NL eng J - Journal Article
Chvojková, Markéta - Rambousek, Lukáš - Chodounská, Hana - Kudová, Eva - Valeš, Karel
Synthetic structural modifications of neurosteroid pregnanolone sulfate: Assessment of neuroprotective effects in vivo.
European Journal of Pharmacology. Roč. 881, Aug 15 (2020), č. článku 173187. ISSN 0014-2999. E-ISSN 1879-0712
R&D Projects: GA TA ČR(CZ) TE01020028; GA ČR(CZ) GBP304/12/G069; GA ČR(CZ) GA18-09296S; GA ČR(CZ) GA14-20613S; GA MZd(CZ) NU20-04-00389
Institutional support: RVO:67985823 ; RVO:61388963
Keywords : NMDA receptor * neuroactive steroid * behavior * neuroprotection * excitotoxicity * cognitive functions
OECD category: Neurosciences (including psychophysiology; Organic chemistry (UOCHB-X)
Impact factor: 4.432, year: 2020
Method of publishing: Limited access
https://doi.org/10.1016/j.ejphar.2020.173187

Neuroactive steroid 20-oxo-5 beta-pregnan-3 alpha-yl L-glutamyl 1-ester (PA-Glu), a synthetic analogue of naturally occurring 20-oxo-5 beta-pregnan-3 alpha-yl sulfate (pregnanolone sulfate, PA-S), inhibits N-methyl-D-aspartate (NMDA) receptors and possesses neuroprotective properties and minimal adverse effects. Herein, we report in vivo effects of new structural modifications of the PA-S molecule: a nonpolar modification of the steroid D-ring (5 beta-androstan-3 alpha-yl L-glutamyl 1-ester, AND-Glu), attachment of a positively charged group to C3 (20-oxo-5 beta-pregnan-3 alpha-yl L-argininate dihydrochloride salt, PA-Arg) and their combination (5 beta-androstan-3 alpha-yl L-argininate dihydrochloride salt, AND-Arg). The first aim of this study was to determine the structure-activity relationship for neuroprotective effects in a model of excitotoxic hippocampal damage in rats, based on its behavioral correlate in Carousel maze. The second aim was to explore side effects of neuroprotective steroids on motor functions, anxiety (elevated plus maze) and locomotor activity (open field) and the effect of their high doses in mice. The neuroprotective properties of PA-Glu and AND-Glu were proven, with the effect of the latter appearing to be more pronounced. In contrast, neuroprotective efficacy failed when positively charged molecules (PA-Arg, AND-Arg) were used. AND-Glu and PA-Glu at the neuroprotective dose (1 mg/kg) did not unfavorably influence motor functions of intact mice. Moreover, anxiolytic effects of AND-Glu and PA-Glu were ascertained. These findings corroborate the value of research of steroidal inhibitors of NMDA receptors as potential neuroprotectants with slight anxiolytic effect and devoid of behavioral adverse effects. Taken together, the results suggest the benefit of the nonpolar D-ring modification, but not of the attachment of a positively charged group to C3.
Permanent Link: http://hdl.handle.net/11104/0312575