Thioredoxin-mimetic peptide CB3 lowers MAPKinase activity in the Zucker rat brain

Autor: Michael Trus, James M. Lenhard, Moshe Cohen-Kutner, Lena Khomsky, Tonya Martin, Hila Ben-Yehuda, Daphne Atlas, Yin Liang
Rok vydání: 2014
Předmět:
AMPK
Blood Glucose
Male
Thioredoxin reductase
Clinical Biochemistry
ZDF rat-model
medicine.disease_cause
Biochemistry
Diabetes type 2
Insulin
Thioredoxin mimetics
Phosphorylation
lcsh:QH301-705.5
lcsh:R5-920
Kinase
AICAR
5-amino-4-imidazole carboxamide riboside
Ad-AMPK-CA
AMPK-constitutively active AMP-activated protein kinase mutants
Brain
CB3
TXNIP/TBP-2
TXNIP/TBP-2
thioredoxin-interacting protein
Thioredoxin
lcsh:Medicine (General)
Oligopeptides
TXNIP
Research Paper
medicine.medical_specialty
MAP Kinase Signaling System
p38 mitogen-activated protein kinases
Caspase 3
Biology
CB3
NAc-Cys-Pro Cys-amide
TXM-CB3
Redox
Internal medicine
Cell Line
Tumor
medicine
Animals
Humans
Obesity
Sulfhydryl Compounds
Inflammation
Organic Chemistry
MAPK
Rats
Rats
Zucker
AMPK
AMP-activated protein kinase
Disease Models
Animal
Oxidative Stress
Endocrinology
lcsh:Biology (General)
Diabetes Mellitus
Type 2
Peptidomimetics
Oxidative stress
Zdroj: Redox Biology
Redox Biology, Vol 2, Iss C, Pp 447-456 (2014)
ISSN: 2213-2317
DOI: 10.1016/j.redox.2013.12.018
Popis: Diabetes is a high risk factor for dementia. High glucose may be a risk factor for dementia even among persons without diabetes, and in transgenic animals it has been shown to cause a potentiation of indices that are pre-symptomatic of Alzheimer's disease. To further elucidate the underlying mechanisms linking inflammatory events elicited in the brain during oxidative stress and diabetes, we monitored the activation of mitogen-activated kinsase (MAPKs), c-jun NH2-terminal kinase (JNK), p38 MAP kinases (p38MAPK), and extracellular activating kinsae1/2 (ERK1/2) and the anti-inflammatory effects of the thioredoxin mimetic (TxM) peptides, Ac-Cys-Pro-Cys-amide (CB3) and Ac-Cys-Gly-Pro-Cys-amide (CB4) in the brain of male leptin-receptor-deficient Zucker diabetic fatty (ZDF) rats and human neuroblastoma SH-SY5Y cells. Daily i.p. injection of CB3 to ZDF rats inhibited the phosphorylation of JNK and p38MAPK, and prevented the expression of thioredoxin-interacting-protein (TXNIP/TBP-2) in ZDF rat brain. Although plasma glucose/insulin remained high, CB3 also increased the phosphorylation of AMP-ribose activating kinase (AMPK) and inhibited p70S6K kinase in the brain. Both CB3 and CB4 reversed apoptosis induced by inhibiting thioredoxin reductase as monitored by decreasing caspase 3 cleavage and PARP dissociation in SH-SY5Y cells. The decrease in JNK and p38MAPK activity in the absence of a change in plasma glucose implies a decrease in oxidative or neuroinflammatory stress in the ZDF rat brain. CB3 not only attenuated MAPK phosphorylation and activated AMPK in the brain, but it also diminished apoptotic markers, most likely acting via the MAPK–AMPK–mTOR pathway. These results were correlated with CB3 and CB4 inhibiting inflammation progression and protection from oxidative stress induced apoptosis in human neuronal cells. We suggest that by attenuating neuro-inflammatory processes in the brain Trx1 mimetic peptides could become beneficial for preventing neurological disorders associated with diabetes.
Graphical abstract
Highlights • Thioredoxin mimeitics peptides (TXM) lower apoptosis in the brain of ZDF rat. • TxM peptides prevent TXNIP/TBP-2 expression in the brain of ZDF rat. • TxM peptides could become beneficial for preventing diabetes associated neurological disorders.
Databáze: OpenAIRE
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