Synthesis and Evaluation of 1-Substituted-Biguanide Derivatives as Anti-Diabetic Agents for Type II Diabetes Insulin Resistant.

New 1-substituted-biguanide derivatives 1-3 were synthesized by the reaction of 2,4-dimethoxyaniline, hydrazine and methylhydrazine with dicyandiamide in diluted hydrochloric acid. The resulting biguanide salts were fully characterized by spectroscopic methods. The synthesized compounds were screened for their anti-diabetic activity with standard metformin drug. Oral treatment of hyperglycemic rats with the synthesized biguanide derivatives (200 mg/kg/day) for 2 weeks significantly decreased the elevated blood glucose level. Oral administration of biguanide derivative 2 significantly decreased the level of total cholesterol. While, the triglycerides level was little decreased following administration of biguanide 1 as compared to hyperglycemic rats. Additionally, anti-diabetic properties towards liver function enzyme activities (AST and ALT) and kidney functions (urea and critinine) as well as histopathological studies relative to metformin hydrochloride were investigated and discussed.

S100beta protein expression: gender- and age-related daily changes.

S100beta is a soluble protein released by glial cells mainly under the activation of the 5-HT1A receptor. It has been reported as a neuro-trophic and -tropic factor that promotes neurite maturation and outgrowth during development. This protein also plays a role in axonal stability and the plasticity underlying long-term potentiation in adult brains. The ability of S100beta to rapidly regulate neuronal morphology raises the interesting point of whether there are daily rhythm or gender differences in S100beta level in the brain. To answer this question, the S100beta expression in adult female and male rats, as well as in adult female CD-21 and S100beta -/- female mice, were investigated. Scintillation counting and morphometric analysis of the immunoreactivity of S100beta, showed rhythmic daily expression. The female and male rats showed opposite cycles. Females presented the highest value at the beginning of the rest phase (5:00 h), while in males the maximum value appeared in the beginning of the motor activity period (21:00 h). These results confirm previous S100beta evaluations in human serum and cerebrospinal fluid reporting the protein's function as a biomarker for brain damage (Gazzolo et al. in Clin Chem 49:967-970, 2003; Clin Chim Acta 330:131-133, 2003; Pediatr Res 58:1170-1174, 2005), similar behavior was also observed for GFAP in relation to Alzheimer Disease (Fukuyama et al. in Eur Neurol 46:35-38, 2001). The data should be taken into account when considering S100beta as a biomarker of health condition. In addition, the results raise questions on which structure or condition imposes these rhythms as well as on the physiological meaning of the observed gender differences.

Compartmental distribution of hyperpolarization-activated cyclic-nucleotide-gated channel 2 and hyperpolarization-activated cyclic-nucleotide-gated channel 4 in thalamic reticular and thalamocortical relay neurons.

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels conduct a monovalent cationic current, I(h), which contributes to the electrophysiological properties of neurons and regulates thalamic oscillations in circuits containing the glutamatergic ventrobasal complex (VB) and GABAergic reticular thalamic nucleus (RTN). Four distinct HCN channel isoforms (HCN1-4) have been identified, and mRNAs and proteins for HCN channels have been detected in the RTN and VB, with HCN2 and HCN4 being the predominant isoforms. RTN and VB neurons have distinct electrophysiological properties, and those differences may reflect variable compartmental distribution of HCN channels. Whole cell patch clamp recordings from thalamic neurons in brain slices obtained from C57/Bl6 mice demonstrate that I(h) is much smaller in RTN than in VB neurons although the time constants for I(h) current activation are very similar. To study the compartmental distribution of the underlying channels, we performed qualitative and quantitative examination of HCN2 and HCN4 expression using fluorescent immunohistochemistry and confocal microscopy. HCN2-immunoreactivity (IR) on the somata of RTN neurons was approximately 10-fold less than that seen in VB neurons while HCN4-IR was detected on the somata of RTN and VB neurons to an equal degree. HCN2-IR in RTN and VB did not overlap with synaptophysin-IR, but strongly colocalized with cortactin-IR, indicating that HCN2 was not present in axon terminals but was present in dendritic spines. Although HCN2-IR in spines was more pronounced in VB than in RTN, the ratio of spinous to somatic expression in RTN was dramatically higher than that in VB, strongly suggesting that HCN2-IR in RTN is principally located in sites distal to the soma. In contrast, HCN4-IR did not colocalize with either synaptophysin or cortactin. The colocalization of HCN2-IR with HCN4-IR was greater in VB than in RTN. The results suggest that the distinct compartmental distribution of HCN2 channels in RTN and VB neurons contributes to the profound differences in the I(h)-dependent properties of these cells.