Evaluation of Z-VAD-FMK as an anti-apoptotic drug to prevent granulosa cell apoptosis and follicular death after human ovarian tissue transplantation.

Abstract

PURPOSE:

To evaluate the efficiency of ovarian tissue treatment with Z-VAD-FMK, a broad-spectrum caspase inhibitor, to prevent follicle loss induced by ischemia/reperfusion injury after transplantation.

METHODS:

In vitro, granulosa cells were exposed to hypoxic conditions, reproducing early ischemia after ovarian tissue transplantation, and treated with Z-VAD-FMK (50 μM). In vivo, cryopreserved human ovarian fragments (n = 39) were embedded in a collagen matrix containing or not Z-VAD-FMK (50 μM) and xenotransplanted on SCID mice ovaries for 3 days or 3 weeks.

RESULTS:

In vitro, Z-VAD-FMK maintained the metabolic activity of granulosa cells, reduced HGL5 cell death, and decreased PARP cleavage. In vivo, no improvement of follicular pool and global tissue preservation was observed with Z-VAD-FMK in ovarian tissue recovered 3-days post-grafting. Conversely, after 3 weeks of transplantation, the primary follicular density was higher in fragments treated with Z-VAD-FMK. This improvement was associated with a decreased percentage of apoptosis in the tissue.

CONCLUSIONS:

In situ administration of Z-VAD-FMK slightly improves primary follicular preservation and reduces global apoptosis after 3 weeks of transplantation. Data presented herein will help to guide further researches towards a combined approach targeting multiple cell death pathways, angiogenesis stimulation, and follicular recruitment inhibition.

• Authors: Maïté Fransolet, Laure Noël, Laurie Henry, Soraya Labied, Silvia Blacher, Michelle Nisolle, Carine Munaut
• Journal: Journal of assisted reproduction and genetics (J Assist Reprod Genet) Vol. 36 Issue 2 Pg. 349-359 (Feb 2019) ISSN: 1573-7330 [Electronic] Netherlands
• PMID: 30390176 (Publication Type: Journal Article)

Chemical References

• Amino Acid Chloromethyl Ketones
• Caspase Inhibitors
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone

Topics

• Amino Acid Chloromethyl Ketones (administration & dosage)
• Animals
• Apoptosis (drug effects)
• Caspase Inhibitors (administration & dosage)
• Female
• Granulosa Cells (drug effects)
• Humans
• Mice, SCID
• Ovarian Follicle (physiopathology, transplantation)
• Reperfusion Injury (drug therapy, physiopathology)
• Transplantation, Heterologous (adverse effects)