Lack of Therapeutic Efficacy of Trazodone, Dibenzoylmethane, and Tauroursodeoxycholic Acid in a Mouse Model of Marinesco-Sjögren Syndrome

Core Concepts

Trazodone, dibenzoylmethane, and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in a mouse model of Marinesco-Sjögren syndrome.

Abstract

The study investigated the therapeutic potential of three compounds - trazodone, dibenzoylmethane (DBM), and tauroursodeoxycholic acid (TUDCA) - in the woozy mouse model of Marinesco-Sjögren syndrome (MSS). Key highlights: Trazodone and DBM partially inhibit the PERK branch of the unfolded protein response (UPR), which is chronically activated in MSS. TUDCA is a chemical chaperone that can alleviate ER stress. Chronic treatment with these compounds starting from a presymptomatic stage did not prevent the development of motor dysfunction or Purkinje cell degeneration in woozy mice. Trazodone slightly improved performance on the beam walking test, but this was not associated with inhibition of PERK signaling or neuroprotection. Pharmacokinetic analysis showed no major differences in trazodone metabolism between woozy and control mice, excluding altered drug exposure as the reason for the lack of efficacy. The results indicate that trazodone, DBM, and TUDCA, at the tested dosing regimens, do not have a disease-modifying effect in this preclinical model of MSS.

Stats

There were no significant differences in beam walking performance between the different groups of mice up to six weeks of age. From seven weeks, the number of hindfoot missteps and the time to traverse the beam increased significantly in vehicle-treated woozy mice compared to WT controls. Trazodone-treated woozy mice performed better, making significantly fewer missteps and taking less time to traverse the beam than vehicle treated woozy mice. There was no effect of trazodone, DBM or TUDCA on rotarod performance in woozy mice. Immunohistochemistry found no reduction in the number of CHOP-positive Purkinje cells or increased Purkinje cell survival in the treated woozy mice. CHOP mRNA levels in laser capture microdissected Purkinje cells were similarly increased in vehicle- and trazodone-treated woozy mice compared to WT.

Quotes

"Trazodone slightly boosted beam walking performance. However, immunohistochemistry found no reduction in the number of CHOP-positive PCs, or increased PC survival, indicating no neuroprotective inhibition of PERK signaling." "These results indicate that trazodone, DBM and TUDCA, at dosing regimens active in other neurodegenerative disease mouse models, have no disease-modifying effect in a preclinical model of MSS."

Key Insights Distilled From

Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice

by Lavigna,G., ... at www.biorxiv.org 05-03-2024

https://www.biorxiv.org/content/10.1101/2024.04.30.591862v1

Deeper Inquiries

What other pharmacological strategies could be explored to inhibit the PERK pathway in a non-toxic manner for the treatment of Marinesco-Sjögren syndrome?

In light of the findings that trazodone, DBM, and TUDCA did not show efficacy in inhibiting the PERK pathway in the woozy mouse model, alternative pharmacological strategies could be explored. One potential approach could involve the modulation of physical interaction between PERK and eIF2α by enhancing Akt-mediated phosphorylation of PERK threonine residue 799. This strategy aims to reduce eIF2α binding to the PERK kinase domain, thereby inhibiting PERK signaling without systemic toxicity. By focusing on this specific mechanism, researchers may be able to fine-tune PERK signaling in a more targeted and effective manner for the treatment of Marinesco-Sjögren syndrome.

How do the findings from this study on the lack of efficacy of trazodone, DBM, and TUDCA in the woozy mouse model compare to their reported benefits in other neurodegenerative disease models?

The findings from this study, which demonstrated the lack of efficacy of trazodone, DBM, and TUDCA in the woozy mouse model of Marinesco-Sjögren syndrome, contrast with their reported benefits in other neurodegenerative disease models. In previous research, trazodone and DBM have shown neuroprotective effects by partially inhibiting the PERK signaling pathway downstream of eIF2α-P, without causing pancreatic toxicity. Additionally, TUDCA has demonstrated positive effects in various neurodegenerative disease models by facilitating protein folding and reducing ER stress-induced apoptosis. However, in the context of Marinesco-Sjögren syndrome, these compounds did not prevent motor dysfunction or neurodegeneration in the woozy mice, indicating a lack of disease-modifying effects specific to this syndrome.

Could gene therapy approaches aimed at restoring SIL1 function be a more promising therapeutic avenue for Marinesco-Sjögren syndrome compared to pharmacological interventions?

Given the lack of efficacy of trazodone, DBM, and TUDCA in the woozy mouse model, gene therapy approaches aimed at restoring SIL1 function could indeed be a more promising therapeutic avenue for Marinesco-Sjögren syndrome. Previous studies have shown that the reintroduction of a single wild-type Sil1 allele or transgenic expression of the SIL1 homologous 150-kDa oxygen-regulated protein (ORP150, also known as GRP170) fully rescues the woozy mouse phenotype. This suggests that restoring SIL1 function at the genetic level may have a more direct and effective impact on the disease pathology compared to pharmacological interventions targeting the PERK pathway or protein folding. Gene therapy approaches could offer a more targeted and sustainable solution for treating Marinesco-Sjögren syndrome by addressing the underlying genetic defect responsible for the disease.