Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease.

Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease.

Publication date: Jun 05, 2019

Huntington disease is a neurodegenerative condition for which there is no cure to date. Activation of AMP-activated protein kinase has previously been shown to be beneficial in in vitro and in vivo models of Huntington’s disease. Moreover, a recent cross-sectional study demonstrated that treatment with metformin, a well-known activator of this enzyme, is associated with better cognitive scores in patients with this disease. We performed a preclinical study using metformin to treat phenotypes of the zQ175 mouse model of Huntington disease. We evaluated behavior (motor and neuropsychiatric function) and molecular phenotypes (aggregation of mutant huntingtin, levels of brain-derived neurotrophic factor, neuronal inflammation, etc.). We also used two models of polyglutamine toxicity in Caenorhabditis elegans to further explore potential mechanisms of metformin action. Our results provide strong evidence that metformin alleviates motor and neuropsychiatric phenotypes in zQ175 mice. Moreover, metformin intake reduces the number of nuclear aggregates of mutant huntingtin in the striatum. The expression of brain-derived neurotrophic factor, which is reduced in mutant animals, is partially restored in metformin-treated mice, and glial activation in mutant mice is reduced in metformin-treated animals. In addition, using worm models of polyglutamine toxicity, we demonstrate that metformin reduces polyglutamine aggregates and restores neuronal function through mechanisms involving AMP-activated protein kinase and lysosomal function. Our data indicate that metformin alleviates the progression of the disease and further supports AMP-activated protein kinase as a druggable target against Huntington’s disease.

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Sanchis, A., Garc’ia-Gimeno, M.A., Ca~nada-Mart’inez, A.J., Sequedo, M.D., Mill’an, J.M., Sanz, P., and V’azquez-Manrique, R.P. Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease. 06516. 2019 Exp Mol Med (51):6.

Concepts Keywords
AMP Neurodegeneration
Caenorhabditis Elegans MTOR
Cognitive Metformin
Cross Huntingtin
Enzyme Huntington’s disease
Glial Guanidines
Huntingtin Nervous system
Huntington Biguanides
Inflammation Organ systems
Kinase Branches of biology
Lysosomal RTT
Metformin Neuronal inflammation
Mice
Mutant
Neurodegenerative Condition
Neuropsychiatric
Phenotypes
Striatum
Toxicity
Vivo
Worm

Semantics

Type Source Name
drug DRUGBANK D-glucose
drug DRUGBANK Dextrose unspecified form
gene UNIPROT MARS
gene UNIPROT SAMD11
gene UNIPROT CYREN
gene UNIPROT MBNL1
drug DRUGBANK Flurbiprofen
gene UNIPROT FXYD1
drug DRUGBANK Hexadecanal
drug DRUGBANK Inositol
disease MESH diabetic kidney disease
pathway BSID Glucose Homeostasis
gene UNIPROT PROC
gene UNIPROT ELP1
gene UNIPROT BRD2
pathway BSID Apoptosis
gene UNIPROT STK11
gene UNIPROT TNFSF10
gene UNIPROT MAP3K7
gene UNIPROT NR2C2
gene UNIPROT DUOXA1
pathway BSID Proteasome
pathway BSID Insulin signaling pathway
gene UNIPROT INTU
gene UNIPROT SERPINI2
gene UNIPROT LANCL1
gene UNIPROT ARHGEF2
gene UNIPROT RPSA
gene UNIPROT IL9
gene UNIPROT PSMD7
gene UNIPROT RABEPK
gene UNIPROT TP63
gene UNIPROT EBNA1BP2
gene UNIPROT ARMH1
gene UNIPROT WLS
gene UNIPROT MAGEE1
pathway BSID Immune System
disease MESH infection
gene UNIPROT REST
gene UNIPROT MTOR
drug DRUGBANK Sirolimus
pathway BSID Aging
disease MESH aging
gene UNIPROT NR1H4
gene UNIPROT ADRB2
gene UNIPROT BFAR
gene UNIPROT MENT
drug DRUGBANK Trestolone
gene UNIPROT EPHB2
gene UNIPROT MAPK1
gene UNIPROT SGSM3
gene UNIPROT EIF2AK3
gene UNIPROT OPRM1
gene UNIPROT TNF
disease MESH dif
gene UNIPROT CTBP1
gene UNIPROT DYRK3
gene UNIPROT IK
drug DRUGBANK Coenzyme M
gene UNIPROT RXFP2
disease MESH depression
drug DRUGBANK Hyaluronic acid
gene UNIPROT DNMT1
gene UNIPROT CD69
gene UNIPROT CD5L
pathway BSID Lysosome
gene UNIPROT ARSA
drug DRUGBANK Acetylsalicylic acid
gene UNIPROT APP
drug DRUGBANK Esomeprazole
gene UNIPROT CCL21
gene UNIPROT AIF1
gene UNIPROT CXCL8
gene UNIPROT SDS
gene UNIPROT SBDS
drug DRUGBANK Sodium lauryl sulfate
drug DRUGBANK Edetic Acid
drug DRUGBANK Tromethamine
gene UNIPROT TNFSF14
gene UNIPROT LIF
gene UNIPROT DIAPH2
gene UNIPROT ABCB6
drug DRUGBANK Abacavir
drug DRUGBANK Biotin
drug DRUGBANK Coenzyme A
gene UNIPROT KHDRBS1
gene UNIPROT DCTN4
gene UNIPROT GTF2H1
disease MESH separated
gene UNIPROT SCGB1D4
gene UNIPROT SP5
gene UNIPROT TCOF1
drug DRUGBANK Chloroquine
drug DRUGBANK Nystatin
gene UNIPROT MIXL1
gene UNIPROT DEPP1
gene UNIPROT CCL28
gene UNIPROT GOPC
disease DOID mec
gene UNIPROT BDNF
pathway BSID Brain derived neurotrophic factor
gene UNIPROT ERBB2
disease MESH defects
gene UNIPROT NEU1
gene UNIPROT NEURL1
disease DOID ers
disease MESH suffering
gene UNIPROT HDAC9
pathway BSID Metabolism
disease MESH death
drug DRUGBANK ATP
gene UNIPROT ATP8A2
gene UNIPROT REG1A
gene UNIPROT PRKAB1
gene UNIPROT PRKAA2
gene UNIPROT PRKAA1
gene UNIPROT HTT
drug DRUGBANK L-Glutamine
disease DOID chorea
gene UNIPROT ATXN3
disease MESH chorea
disease MESH inflammation
drug DRUGBANK Tropicamide
disease DOID Huntington disease
disease MESH Huntington disease
drug DRUGBANK Metformin
gene UNIPROT SLC6A4
gene UNIPROT TNMD
gene UNIPROT CYLD
drug DRUGBANK Tretamine
drug DRUGBANK Water
gene UNIPROT DDX53
gene UNIPROT CHRM3
gene UNIPROT TSPO
gene UNIPROT SQSTM1
gene UNIPROT NUP62
drug DRUGBANK Calcium
gene UNIPROT ALYREF
gene UNIPROT GFAP
drug DRUGBANK Tricyclazole
drug DRUGBANK Isoxaflutole
gene UNIPROT SLC35G1
drug DRUGBANK Ademetionine
gene UNIPROT PRDM6
gene UNIPROT USP9X
gene UNIPROT TBX1
gene UNIPROT GGCT
gene UNIPROT MPG
gene UNIPROT ACACA
gene UNIPROT GAA
gene UNIPROT BMS1
gene UNIPROT GCG
gene UNIPROT KIT
gene UNIPROT LARGE1
gene UNIPROT RNMT
gene UNIPROT MET
gene UNIPROT SLTM
drug DRUGBANK Methionine

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