Dynamics of neuronal oscillations underlying nociceptive response in the mouse primary somatosensory cortex.

Pain is caused by tissue injury, inflammatory disease, pathogen invasion, or neuropathy. The perception of pain is attributed to the neuronal activity in the brain. However, the dynamics of neuronal activity underlying pain perception are not fully known. Herein, we examined theta-oscillation dynamics of local field potentials in the primary somatosensory cortex of a mouse model of formalin-induced pain, which usually shows a bimodal behavioral response interposed between pain-free periods. We found that formalin injection exerted a reversible shift in the theta-peak frequency toward a slower frequency. This shift was observed during nociceptive phases but not during the pain-free period and was inversely correlated with instantaneous pain intensity. Furthermore, instantaneous oscillatory analysis indicated that the probability of slow theta oscillations increased during nociceptive phases with an association of augmented slow theta power. Finally, cross-frequency coupling between theta and gamma oscillations indicated that the coupling peak frequency of theta oscillations was also shifted toward slower oscillations without affecting coupling strength or gamma power. Together, these results suggest that the dynamic changes in theta oscillations in the mouse primary somatosensory cortex represent the ongoing status of pain sensation.

Design, synthesis, and pharmacological evaluation of 2-(4-sulfonylphenyl)-2-[(E)-pyrrolidin-1-ylimino]-N-thiazoleacetamides as glucokinase activators.

This paper presents the synthesis and glucokinase activity of novel hydrazone derivatives. The 2-(4-cyclopropylsulfonylphenyl)-2-[(E)-pyrrolidin-1-ylimino]-acetamide derivatives 5a-5h presented the in vitro glucokinase activities and in vivo blood glucose-lowering effects in mice. Particularly, 5h showed an oral hypoglycemic effect in rats at 1 mg/kg. These hydrazone derivatives are a potential new class of glucokinase activators for the treatment of type 2 diabetes.

SAR, pharmacokinetics, safety, and efficacy of glucokinase activating 2-(4-sulfonylphenyl)-N-thiazol-2-ylacetamides: discovery of PSN-GK1.

Allosteric activators of the glucose-sensing enzyme glucokinase (GK) are currently attracting much interest as potential antidiabetic therapies because they can achieve powerful blood glucose lowering through actions in multiple organs. Here, the optimization of a weakly active high-throughput screening hit to (2 R)-2-(4-cyclopropanesulfonylphenyl)- N-(5-fluorothiazol-2-yl)-3-(tetrahydropyran-4-yl)propionamide (PSN-GK1), a potent GK activator with an improved pharmacokinetic and safety profile, is described. Following oral administration, this compound elicited robust glucose lowering in rats.

Long-term treatment with the Na+-glucose cotransporter inhibitor T-1095 causes sustained improvement in hyperglycemia and prevents diabetic neuropathy in Goto-Kakizaki Rats.

We examined the effects of T-1095, an orally active inhibitor of Na(+)-glucose cotransporter (SGLT), on the development and severity of diabetes in Goto-Kakizaki (GK) rat, a spontaneous, non-obese model of type 2 diabetes. T-1095 was administered as dietary admixture (0.1% w/w) beginning at 7 weeks of age for 32 weeks. Untreated male GK rats were hyperglycemic compared with Wistar rats. Throughout the study, T-1095 treatment significantly decreased both blood glucose and hemoglobin A(1C) levels in the GK rats. The concomitant increase of urinary glucose excretion indicated that the hypoglycemic action of T-1095 is derived from the enhancement of urinary glucose disposal. Although food intake was not changed in the T-1095-treated rats, the body weight gain was retarded. T-1095 treatment partially ameliorated oral glucose tolerance but not the impaired glucose-induced insulin secretion. Homeostasis model assessment (HOMA) indicated the existence of insulin resistance in GK rats and a significant restoration by T-1095-treatment. There was a reduction of the thermal response in tail-flick testing following long-term hyperglycemia (diabetic neuropathy). Treatment of T-1095 significantly prevented the development of diabetic neuropathy in male GK rats. Sustained improvement of hyperglycemia and prevention of diabetic neuropathy by the T-1095-treatment provide further support the use of SGLT inhibitors for the treatment of diabetes.

Glucokinase-activating ureas.

The synthesis, SAR and biological evaluation of a series of ureas that activate glucokinase, a target for diabetes therapy as a result of its critical role in the regulation of whole-body glucose homeostasis, are described. Some of the urea-containing glucokinase activators lowered blood glucose levels in vivo following oral dosing to C57BL/6J mice.

Epigallocatechin gallate, a constituent of green tea, represses hepatic glucose production.

Herbs have been used for medicinal purposes, including the treatment of diabetes, for centuries. Plants containing flavonoids are used to treat diabetes in Indian medicine and the green tea flavonoid, epigallocatechin gallate (EGCG), is reported to have glucose-lowering effects in animals. We show here that the regulation of hepatic glucose production is decreased by EGCG. Furthermore, like insulin, EGCG increases tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 (IRS-1), and it reduces phosphoenolpyruvate carboxykinase gene expression in a phosphoinositide 3-kinase-dependent manner. EGCG also mimics insulin by increasing phosphoinositide 3-kinase, mitogen-activated protein kinase, and p70(s6k) activity. EGCG differs from insulin, however, in that it affects several insulin-activated kinases with slower kinetics. Furthermore, EGCG regulates genes that encode gluconeogenic enzymes and protein-tyrosine phosphorylation by modulating the redox state of the cell. These results demonstrate that changes in the redox state may have beneficial effects for the treatment of diabetes and suggest a potential role for EGCG, or derivatives, as an antidiabetic agent.