Abstract
Currently, there is no effective treatment for the fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. In this pilot study, we evaluated whether allopregnanolone, a natural neurosteroid that exerts beneficial effects in neurodegenerative diseases, nervous system injury, and peripheral neuropathies, could improve lymphocytic bioenergetics and plasma pharmacometabolomics in six males with FXTAS (68 ± 3 years old; FMR1 CGG repeats 94 ± 4; FXTAS stages ranging from 3 to 5) enrolled in a 12-week open-label intervention study conducted at the University of California Davis from December 2015 through July 2016. Plasma pharmacometabolomics and lymphocytic mitochondria function were assessed at baseline (on the day of the first infusion) and at follow-up (within 48 h from the last infusion). In parallel, quantitative measurements of tremor and ataxia and neuropsychological evaluations of mental state, executive function, learning, memory, and psychological symptoms were assessed at the same time points. Allopregnanolone treatment impacted significantly GABA metabolism, oxidative stress, and some of the mitochondria-related outcomes. Notably, the magnitude of the individual metabolic response, as well as the correlation with some of the behavioral tests, was overwhelmingly carrier-specific. Based on this pilot study, allopregnanolone treatment has the potential for improving cognitive and GABA metabolism in FXTAS aligned with the concept of precision medicine.
| Original language | English (US) |
|---|---|
| Journal | Molecular Neurobiology |
| DOIs | |
| State | Accepted/In press - Jan 1 2018 |
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Keywords
- Allopregnanolone
- Bioenergetics
- FXTAS
- GABA
- Lymphocytes
- Pharmacometabolomics
ASJC Scopus subject areas
- Neuroscience (miscellaneous)
- Neurology
- Cellular and Molecular Neuroscience
Cite this
Allopregnanolone Treatment Improves Plasma Metabolomic Profile Associated with GABA Metabolism in Fragile X-Associated Tremor/Ataxia Syndrome : a Pilot Study. / Napoli, Eleonora; Schneider, Andrea; Wang, Jun Yi; Trivedi, Aditi; Carrillo, Nika Roa; Tassone, Flora; Rogawski, Michael A; Hagerman, Randi J; Giulivi, Cecilia R.
In: Molecular Neurobiology, 01.01.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Allopregnanolone Treatment Improves Plasma Metabolomic Profile Associated with GABA Metabolism in Fragile X-Associated Tremor/Ataxia Syndrome
T2 - a Pilot Study
AU - Napoli, Eleonora
AU - Schneider, Andrea
AU - Wang, Jun Yi
AU - Trivedi, Aditi
AU - Carrillo, Nika Roa
AU - Tassone, Flora
AU - Rogawski, Michael A
AU - Hagerman, Randi J
AU - Giulivi, Cecilia R
PY - 2018/1/1
Y1 - 2018/1/1
N2 - Currently, there is no effective treatment for the fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. In this pilot study, we evaluated whether allopregnanolone, a natural neurosteroid that exerts beneficial effects in neurodegenerative diseases, nervous system injury, and peripheral neuropathies, could improve lymphocytic bioenergetics and plasma pharmacometabolomics in six males with FXTAS (68 ± 3 years old; FMR1 CGG repeats 94 ± 4; FXTAS stages ranging from 3 to 5) enrolled in a 12-week open-label intervention study conducted at the University of California Davis from December 2015 through July 2016. Plasma pharmacometabolomics and lymphocytic mitochondria function were assessed at baseline (on the day of the first infusion) and at follow-up (within 48 h from the last infusion). In parallel, quantitative measurements of tremor and ataxia and neuropsychological evaluations of mental state, executive function, learning, memory, and psychological symptoms were assessed at the same time points. Allopregnanolone treatment impacted significantly GABA metabolism, oxidative stress, and some of the mitochondria-related outcomes. Notably, the magnitude of the individual metabolic response, as well as the correlation with some of the behavioral tests, was overwhelmingly carrier-specific. Based on this pilot study, allopregnanolone treatment has the potential for improving cognitive and GABA metabolism in FXTAS aligned with the concept of precision medicine.
AB - Currently, there is no effective treatment for the fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. In this pilot study, we evaluated whether allopregnanolone, a natural neurosteroid that exerts beneficial effects in neurodegenerative diseases, nervous system injury, and peripheral neuropathies, could improve lymphocytic bioenergetics and plasma pharmacometabolomics in six males with FXTAS (68 ± 3 years old; FMR1 CGG repeats 94 ± 4; FXTAS stages ranging from 3 to 5) enrolled in a 12-week open-label intervention study conducted at the University of California Davis from December 2015 through July 2016. Plasma pharmacometabolomics and lymphocytic mitochondria function were assessed at baseline (on the day of the first infusion) and at follow-up (within 48 h from the last infusion). In parallel, quantitative measurements of tremor and ataxia and neuropsychological evaluations of mental state, executive function, learning, memory, and psychological symptoms were assessed at the same time points. Allopregnanolone treatment impacted significantly GABA metabolism, oxidative stress, and some of the mitochondria-related outcomes. Notably, the magnitude of the individual metabolic response, as well as the correlation with some of the behavioral tests, was overwhelmingly carrier-specific. Based on this pilot study, allopregnanolone treatment has the potential for improving cognitive and GABA metabolism in FXTAS aligned with the concept of precision medicine.
KW - Allopregnanolone
KW - Bioenergetics
KW - FXTAS
KW - GABA
KW - Lymphocytes
KW - Pharmacometabolomics
UR - http://www.scopus.com/inward/record.url?scp=85053454892&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053454892&partnerID=8YFLogxK
U2 - 10.1007/s12035-018-1330-3
DO - 10.1007/s12035-018-1330-3
M3 - Article
C2 - 30187385
AN - SCOPUS:85053454892
JO - Molecular Neurobiology
JF - Molecular Neurobiology
SN - 0893-7648
ER -