PMID- 35970890
OWN - NLM
STAT- MEDLINE
DCOM- 20220817
LR  - 20221024
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 12
IP  - 1
DP  - 2022 Aug 15
TI  - A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse 
      model of infantile neurometabolic disease.
PG  - 13825
LID - 10.1038/s41598-022-17338-1 [doi]
LID - 13825
AB  - Infantile neuroaxonal dystrophy (INAD) is a rare paediatric neurodegenerative 
      condition caused by mutations in the PLA2G6 gene, which is also the causative 
      gene for PARK14-linked young adult-onset dystonia parkinsonism. INAD patients 
      usually die within their first decade of life, and there are currently no 
      effective treatments available. GLP1 receptor (GLP-1R) agonists are licensed for 
      treating type 2 diabetes mellitus but have also demonstrated neuroprotective 
      properties in a clinical trial for Parkinson's disease. Therefore, we evaluated 
      the therapeutic efficacy of a new recently licensed GLP-1R agonist diabetes drug 
      in a mouse model of INAD. Systemically administered high-dose semaglutide 
      delivered weekly to juvenile INAD mice improved locomotor function and extended 
      the lifespan. An investigation into the mechanisms underlying these therapeutic 
      effects revealed that semaglutide significantly increased levels of key 
      neuroprotective molecules while decreasing those involved in 
      pro-neurodegenerative pathways. The expression of mediators in both the apoptotic 
      and necroptotic pathways were also significantly reduced in semaglutide treated 
      mice. A reduction of neuronal loss and neuroinflammation was observed. Finally, 
      there was no obvious inflammatory response in wild-type mice associated with the 
      repeated high doses of semaglutide used in this study.
CI  - (c) 2022. The Author(s).
FAU - Poupon-Bejuit, L
AU  - Poupon-Bejuit L
AD  - UCL School of Pharmacy, University College London, London, UK.
FAU - Hughes, M P
AU  - Hughes MP
AD  - UCL School of Pharmacy, University College London, London, UK.
FAU - Liu, W
AU  - Liu W
AD  - UCL School of Pharmacy, University College London, London, UK.
FAU - Geard, A
AU  - Geard A
AD  - UCL School of Pharmacy, University College London, London, UK.
FAU - Faour-Slika, N
AU  - Faour-Slika N
AD  - UCL School of Pharmacy, University College London, London, UK.
FAU - Whaler, S
AU  - Whaler S
AD  - UCL School of Pharmacy, University College London, London, UK.
FAU - Massaro, G
AU  - Massaro G
AD  - UCL School of Pharmacy, University College London, London, UK. 
      giulia.massaro.13@ucl.ac.uk.
FAU - Rahim, A A
AU  - Rahim AA
AD  - UCL School of Pharmacy, University College London, London, UK. a.rahim@ucl.ac.uk.
LA  - eng
GR  - MR/S036784/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/N026101/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/R025134/1/MRC_/Medical Research Council/United Kingdom
GR  - 562868/DH_/Department of Health/United Kingdom
GR  - MR/T044853/1/MRC_/Medical Research Council/United Kingdom
GR  - 562646/WT_/Wellcome Trust/United Kingdom
GR  - MR/R015325/1/MRC_/Medical Research Council/United Kingdom
GR  - MR/S009434/1/MRC_/Medical Research Council/United Kingdom
GR  - 204841/Z/16/Z/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220815
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - EC 3.1.1.4 (Group VI Phospholipases A2)
RN  - EC 3.1.1.4 (Pla2g6 protein, mouse)
RN  - Dystonia-Parkinsonism, Adult-Onset
SB  - IM
MH  - Animals
MH  - *Diabetes Mellitus, Type 2
MH  - Disease Models, Animal
MH  - Dystonic Disorders
MH  - Group VI Phospholipases A2/deficiency
MH  - Mice
MH  - *Neuroaxonal Dystrophies/genetics
MH  - *Parkinsonian Disorders/genetics
PMC - PMC9378686
COIS- The authors declare no competing interests.
EDAT- 2022/08/16 06:00
MHDA- 2022/08/18 06:00
PMCR- 2022/08/15
CRDT- 2022/08/15 23:19
PHST- 2021/10/28 00:00 [received]
PHST- 2022/07/25 00:00 [accepted]
PHST- 2022/08/15 23:19 [entrez]
PHST- 2022/08/16 06:00 [pubmed]
PHST- 2022/08/18 06:00 [medline]
PHST- 2022/08/15 00:00 [pmc-release]
AID - 10.1038/s41598-022-17338-1 [pii]
AID - 17338 [pii]
AID - 10.1038/s41598-022-17338-1 [doi]
PST - epublish
SO  - Sci Rep. 2022 Aug 15;12(1):13825. doi: 10.1038/s41598-022-17338-1.