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Editors Selection IGR 21-2

Basic Science: Neuroprotection 1

Comment by Dorota Skowronska-Krawczyk on:

86200 The neurosteroid allopregnanolone protects retinal neurons by effects on autophagy and GABRs/GABA receptors in rat glaucoma models, Ishikawa M; Takaseki S; Yoshitomi T et al., Autophagy, 2020; 0: 1-18

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Numerous laboratories focus their research on finding the strategies to protect RGCs from death. Despite the wealth of preclinical studies showing efficacy for drugs targeting these pathways, almost all failed translation to the clinic, so effective treatment remains a therapeutic challenge.

Several pieces of evidence show that dysfunctional autophagy recurs in neurodegenerative diseases making this process an attractive venue for neuroprotective drug discovery. Autophagy is a lysosome-mediated degradation system. Physiological levels of autophagy are essential for the maintenance of cellular homeostasis, and it is rapidly upregulated during various stress conditions. However, excessive, or uncontrolled levels of autophagy are able to induce autophagic cell death.

In the paper of Ishikawa et al.¹ the authors investigated the role of allopregnanolone (AlloP) in protecting RGCs, focusing on the effect of this natural neurosteroid on autophagy. While studies agree that autophagy is induced in RGCs in response to injury, autophagy has been found to either protect or promote cell death depending on the experimental model used.² In the ex-vivo and in-vivo glaucoma models in this study, the team measured the neurofilament layer thickness and number of damaged RGCs upon administering the AlloP or known factors that induce autophagy. The results of the study show that factors inducing autophagy, such as rapamycin and torin-2, are able to protect RGCs from death, but AlloP was more efficient. However, this activity was dependent on an intact ability to activate GABRs/GABA^A receptors. This suggests that GABAergic signaling may have a modulatory role and may enhance the neuroprotective effect of AlloP. The work of Ishikawa et al. contributes to our understanding of neurodegenerative signals and the role of autophagy in the neuroprotection.

Autophagy is a lysosome-mediated degradation system. Physiological levels of autophagy are essential for the maintenance of cellular homeostasis, and it is rapidly upregulated during various stress conditions.

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