Mechanism of progesterone neuroprotection of rat cerebellar Purkinje cells following oxygen–glucose deprivation

Abstract

The survival of rat Purkinje cell (PCs) cerebellar cultures was used to test the hypothesis that progesterone is protective againstoxygen-glucose deprivation through potentiation of GABA A receptor activity. Electrophysiological recordings confirm that PCs develop robust excitatory and inhibitory synapses in culture. Exposure of cultured PCs to increasing concentrations of progesterone during oxygen-glucose deprivation revealed a concentration-dependent protection by progesterone, with significant protection observed at physiological concentrations, as low as 10 nm. The concurrent application of the GABA A receptor antagonist picrotoxin (100 µm) completely abolished the neuroprotection afforded by progesterone, indicating that progesterone is neuroprotective through activation of GABA A receptors. Progesterone potentiates GABA A receptor activity indirectly through its metabolites, such as allopregnanolone (ALLO). Therefore, ALLO was applied to PC cultures and was observed to produce significant protection at all concentrations tested, from 10 to 1000 nm. Finally, the inhibition of progesterone metabolism with finasteride abolished the protection afforded by progesterone without having any effect on the neuroprotection caused by ALLO. These data indicate that progesterone protects cerebellar PCs at physiological concentrations through a GABA-active metabolite.

Glycyrrhizin attenuates rat ischemic spinal cord injury by suppressing inflammatory cytokines and HMGB1

“…It is important to note that the TUNEL assay does not distinguish between cell death mechanisms (necrosis or apoptosis); however, this method is useful for detecting damaged cells using light or fluorescence microscopy [30] . Furthermore, histopathological examinations of the spinal cords in our study revealed that there was significant neuronal loss in both 72-h I/R groups, when compared to the sham-operated groups.…”

“…These pathways lead to a cascade of inflammatory responses that can cause tissue damage and the release of inflammatory mediators. Secondly, the TUNEL assay is only useful for detecting dead cells, and this method does not distinguish between cell death mechanisms (necrosis or apoptosis) [30] . Because inflammatory responses can cause tissue damage and even death, Gly could reduce the number of TUNEL-positive cells by suppressing HMGB1 expression in this study.…”

Progesterone receptors: Form and function in brain

“…Support for an APα-mediated mechanism of P 4 neuroprotection is provided by the finding that i) APα is as effective as P 4 in seizure paradigms [107;109;110;111;112;113] and ii) molecular [114;115] or pharmacological [109;113;116;117] inhibition of P 4 metabolism to APα blocks the protective actions of P 4 . Interestingly, APα has also been implicated in the neuroprotective effects of P 4 following oxygen-glucose deprivation of rat Purkinje cells [118] and traumatic injury [23;119;120;121]. P 4 likely triggers multiple neuroprotective mechanisms.…”

17β-Estradiol protects the neonatal brain from hypoxia–ischemia

“…While our knowledge of the developmental actions of progesterone is incomplete (Golub et al, 2006), there is a growing body of literature on the neuroprotective potential of progesterone (for a review, see Stein et al, 2007). In the adult, progesterone protects against traumatic brain injury, stroke and oxygenglucose deprivation (Ardeshiri et al, 2006;Cutler et al, 2006). One potential mechanism of action is via activation of the GABA A receptor by the progesterone metabolite allopregnanolone (Ardeshiri et al, 2006).…”

“…In the adult, progesterone protects against traumatic brain injury, stroke and oxygenglucose deprivation (Ardeshiri et al, 2006;Cutler et al, 2006). One potential mechanism of action is via activation of the GABA A receptor by the progesterone metabolite allopregnanolone (Ardeshiri et al, 2006).…”