Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice.
There is no cure for Marinesco-Sjögren syndrome (MSS), a genetic multisystem disease linked to loss-of-function mutations in the SIL1 gene, encoding a BiP co-chaperone. Previously, we showed that the PERK kinase inhibitor GSK2606414 delays cerebellar Purkinje cell (PC) degeneration and the onset of...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2025-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0317404 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849315460939513856 |
|---|---|
| author | Giada Lavigna Anna Grasso Chiara Pasini Valentina Grande Laura Mignogna Elena Restelli Antonio Masone Claudia Fracasso Jacopo Lucchetti Marco Gobbi Roberto Chiesa |
| author_facet | Giada Lavigna Anna Grasso Chiara Pasini Valentina Grande Laura Mignogna Elena Restelli Antonio Masone Claudia Fracasso Jacopo Lucchetti Marco Gobbi Roberto Chiesa |
| author_sort | Giada Lavigna |
| collection | DOAJ |
| description | There is no cure for Marinesco-Sjögren syndrome (MSS), a genetic multisystem disease linked to loss-of-function mutations in the SIL1 gene, encoding a BiP co-chaperone. Previously, we showed that the PERK kinase inhibitor GSK2606414 delays cerebellar Purkinje cell (PC) degeneration and the onset of ataxia in the woozy mouse model of MSS. However, GSK2606414 is toxic to the pancreas and does not completely rescue the woozy phenotype. The present study tested trazodone and dibenzoylmethane (DBM), which partially inhibit PERK signaling with neuroprotective effects and no pancreatic toxicity. We also tested the chemical chaperone tauroursodeoxycholic acid (TUDCA), which protects MSS patients' cells from stress-induced apoptosis. Mice were chronically treated for five weeks, starting from a presymptomatic stage. Trazodone was given 40 mg/kg daily by intraperitoneal (ip) injection. DBM was given 0.5% in the diet ad libitum. TUDCA was given either 0.4% in the diet, or 500 mg/kg ip every three days. None of the treatments prevented motor dysfunction or PC degeneration in woozy mice, as assessed by beam walking, rotarod test, and calbindin immunohistochemistry. Only trazodone slightly boosted beam walking performance, but this effect was not related to inhibition of PERK signaling. Pharmacokinetic studies excluded that the lack of effect was due to altered drug metabolism in woozy mice. 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. This underscores the difficulty of translating neuroprotective strategies from other conditions to MSS, highlighting the need for more targeted therapeutic approaches. |
| format | Article |
| id | doaj-art-d7e7e477a4384592a7b51a294f7a3857 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-d7e7e477a4384592a7b51a294f7a38572025-08-20T03:52:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032025-01-01201e031740410.1371/journal.pone.0317404Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice.Giada LavignaAnna GrassoChiara PasiniValentina GrandeLaura MignognaElena RestelliAntonio MasoneClaudia FracassoJacopo LucchettiMarco GobbiRoberto ChiesaThere is no cure for Marinesco-Sjögren syndrome (MSS), a genetic multisystem disease linked to loss-of-function mutations in the SIL1 gene, encoding a BiP co-chaperone. Previously, we showed that the PERK kinase inhibitor GSK2606414 delays cerebellar Purkinje cell (PC) degeneration and the onset of ataxia in the woozy mouse model of MSS. However, GSK2606414 is toxic to the pancreas and does not completely rescue the woozy phenotype. The present study tested trazodone and dibenzoylmethane (DBM), which partially inhibit PERK signaling with neuroprotective effects and no pancreatic toxicity. We also tested the chemical chaperone tauroursodeoxycholic acid (TUDCA), which protects MSS patients' cells from stress-induced apoptosis. Mice were chronically treated for five weeks, starting from a presymptomatic stage. Trazodone was given 40 mg/kg daily by intraperitoneal (ip) injection. DBM was given 0.5% in the diet ad libitum. TUDCA was given either 0.4% in the diet, or 500 mg/kg ip every three days. None of the treatments prevented motor dysfunction or PC degeneration in woozy mice, as assessed by beam walking, rotarod test, and calbindin immunohistochemistry. Only trazodone slightly boosted beam walking performance, but this effect was not related to inhibition of PERK signaling. Pharmacokinetic studies excluded that the lack of effect was due to altered drug metabolism in woozy mice. 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. This underscores the difficulty of translating neuroprotective strategies from other conditions to MSS, highlighting the need for more targeted therapeutic approaches.https://doi.org/10.1371/journal.pone.0317404 |
| spellingShingle | Giada Lavigna Anna Grasso Chiara Pasini Valentina Grande Laura Mignogna Elena Restelli Antonio Masone Claudia Fracasso Jacopo Lucchetti Marco Gobbi Roberto Chiesa Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice. PLoS ONE |
| title | Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice. |
| title_full | Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice. |
| title_fullStr | Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice. |
| title_full_unstemmed | Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice. |
| title_short | Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice. |
| title_sort | trazodone dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in marinesco sjogren syndrome mice |
| url | https://doi.org/10.1371/journal.pone.0317404 |
| work_keys_str_mv | AT giadalavigna trazodonedibenzoylmethaneandtauroursodeoxycholicaciddonotpreventmotordysfunctionandneurodegenerationinmarinescosjogrensyndromemice AT annagrasso trazodonedibenzoylmethaneandtauroursodeoxycholicaciddonotpreventmotordysfunctionandneurodegenerationinmarinescosjogrensyndromemice AT chiarapasini trazodonedibenzoylmethaneandtauroursodeoxycholicaciddonotpreventmotordysfunctionandneurodegenerationinmarinescosjogrensyndromemice AT valentinagrande trazodonedibenzoylmethaneandtauroursodeoxycholicaciddonotpreventmotordysfunctionandneurodegenerationinmarinescosjogrensyndromemice AT lauramignogna trazodonedibenzoylmethaneandtauroursodeoxycholicaciddonotpreventmotordysfunctionandneurodegenerationinmarinescosjogrensyndromemice AT elenarestelli trazodonedibenzoylmethaneandtauroursodeoxycholicaciddonotpreventmotordysfunctionandneurodegenerationinmarinescosjogrensyndromemice AT antoniomasone trazodonedibenzoylmethaneandtauroursodeoxycholicaciddonotpreventmotordysfunctionandneurodegenerationinmarinescosjogrensyndromemice AT claudiafracasso trazodonedibenzoylmethaneandtauroursodeoxycholicaciddonotpreventmotordysfunctionandneurodegenerationinmarinescosjogrensyndromemice AT jacopolucchetti trazodonedibenzoylmethaneandtauroursodeoxycholicaciddonotpreventmotordysfunctionandneurodegenerationinmarinescosjogrensyndromemice AT marcogobbi trazodonedibenzoylmethaneandtauroursodeoxycholicaciddonotpreventmotordysfunctionandneurodegenerationinmarinescosjogrensyndromemice AT robertochiesa trazodonedibenzoylmethaneandtauroursodeoxycholicaciddonotpreventmotordysfunctionandneurodegenerationinmarinescosjogrensyndromemice |