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

Abstract

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.

Cocoa-rich diet ameliorates hepatic insulin resistance by modulating insulin signaling and glucose homeostasis in Zucker diabetic fatty rats

“…Accordingly, JNK blockage mediated the inhibition of IRS-1 serine phosphorylation in the liver of ZDF rats [48] and in human hepatic cells [9], which has been related to an improved insulin resistance. Moreover, in the brain of ZDF rats, JNK and p38 were suppressed by a peptide with anti-diabetic properties [47]. Interestingly, in our experimental conditions, p-ERK values remained increased in ZDF rats fed with cocoa, and we have previously shown that a cocoa extract enhanced p-ERK values in hepatic cells, which was associated to a protective effect against an induced oxidative stress [25].…”

“…Indeed, MAPKs induce negative regulators of insulin sensitivity such as protein-tyrosine phosphatase-1B, p-Ser307-IRS-1 and p-(Ser636/ 639)-IRS-1 [10,11]. In concert with this, high phosphorylated levels of ERK, JNK and p38-MAPK have been demonstrated in ZDF rats [47,48]. In the current study, feeding ZDF animals with the cocoa-rich diet abolished the increased p-JNK and p38 values, although not for p-ERK levels.…”

Protein S -Nitrosylation as a Therapeutic Target for Neurodegenerative Diseases

“…For instance, TXMs reversed the inhibitory effects of (S)NO on the Prx-Trx system, suggesting that TXMs may hold potential to improve pathological conditions related to SNO stress. However, TXMs also imitate the oxidoreductase activity of Trx, regulating oxidation (i.e., disulfide formation) of Trx substrate proteins [71,72]. Moreover, similar to NOS inhibitors and antioxidant therapies, TXMs can affect basal SNO (and oxidation) levels.…”

Identification of Methylated Gene Biomarkers in Patients with Alzheimer’s Disease Based on Machine Learning

“…The RF model could effectively predict AD. TXNIP is an early response gene involved in neuronal apoptosis induced by high glucose and oxidative stress [14]. It mediates neuronal repair when transiently expressed [15,16].…”