Treatment of Streptozotocin-Induced Diabetic Rats with Alogliptin: Effect on Vascular and Neural Complications

We sought to determine the effect of dipeptidyl peptidase IV (DPP-IV) inhibition on streptozotocin diabetes-induced vascular and neural dysfunction. After 4 weeks of untreated diabetes, rats were treated for 12 weeks with Alogliptin (DPP-IV inhibitor). Diabetes caused a slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia, reduction in intraepidermal nerve fiber density in the hindpaw, and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles. Treatment significantly improved motor nerve conduction velocity and thermal response latency. Sensory nerve conduction velocity was marginally improved with treatment of diabetic rats, and treatment did not improve the decrease in intraepidermal nerve fiber density. Vascular relaxation by epineurial arterioles to calcitonin gene-related peptide but not acetylcholine was significantly improved with treatment. These studies suggest that some but not all vascular and neural complications associated with type 1 diabetes can be improved with the inhibition of DPP-IV activity

Slowing of Motor Nerve Conduction Velocity in Streptozotocin-induced Diabetic Rats is Preceded by Impaired Vasodilation in Arterioles that Overlie the Sciatic Nerve

Diabetes mellitus produces marked abnormalities in motor nerve conduction, but the mechanism is not clear. In the present study we hypothesized that in the streptozotocin (STZ)-induced diabetic rat impaired vasodilator function in arterioles that provide circulation to the region of the sciatic nerve is associated with reduced endoneural blood flow (EBF) and that these defects precede slowing of motor nerve conduction velocity, and thereby may contribute to nerve dysfunction. As early as three days after the induction of diabetes endoneural blood flow was reduced in the STZ-induced diabetic rat. Furthermore, after 1 week of diabetes acetylcholine- induced vasodilation was found to be impaired. This was accompanied by an increase in the superoxide level in arterioles that provide circulation to the region of the sciatic nerve as well as changes in the level of other markers of oxidative stress including an increase in serum levels of thiobarbituric acid reactive substances and a decrease in lens glutathione level. In contrast to the vascular related changes that occur within 1 week of diabetes, motor nerve conduction velocity and sciatic nerve Na+/k+ ATPase activity were significantly reduced following 2 and 4 weeks of diabetes, respectively. These studies demonstrate that changes in vascular function in the STZ-induced diabetic rat precede the slowing of motor nerve conduction velocity (MNCV) and are accompanied by an increase in superoxide levels in arterioles that provide circulation to the region of the sciatic nerve

The Roles of Streptozotocin Neurotoxicity and Neutral Endopeptidase in Murine Experimental Diabetic Neuropathy

We demonstrated that inhibition of neutral endopeptidase (NEP), a protease that degrades vaso- and neuroactive peptides, improves vascular and neural function in diabetic animal models. In this study we explored the role of NEP in neuropathy related to either insulin-deficient diabetes or diet-induced obesity using NEP deficient (−/−) mice. Initial studies showed that streptozotocin, in the absence of subsequent hyperglycemia, did not induce nerve conduction slowing or paw thermal hypoalgesia. Glucose disposal was impaired in both C57Bl/6 and NEP −/− mice fed a high fat diet. Thermal hypoalgesia and nerve conduction slowing were present in both streptozotocin-diabetic and high fat fed C57Bl/6 mice but not in NEP −/− mice exposed to either streptozotocin-induced diabetes or a high fat diet. These studies suggest that streptozotocin does not induce neurotoxicity in mice and that NEP plays a role in regulating nerve function in insulin-deficient diabetes and diet-induced obesity

Vascular and Neural Dysfunctions in Obese Zucker Rats: Effect of AVE7688

The purpose of this study was to determine whether AVE7688 a drug that inhibits both angiotensin converting enzyme and neutral endopeptidase activity protects vascular and nerve functions in an animal model of metabolic syndrome. Obese Zucker rats at 20 weeks of age were treated for 12 weeks with AVE7688. Vasodilation in epineurial arterioles was measured by videomicroscopy and nerve conduction velocity was measured following electrical stimulation. Treatment with AVE7688 improved vascular relaxation in response to acetylcholine and motor and sensory nerve conduction velocity. In obese Zucker rats superoxide levels and nitrotyrosine staining were elevated in the aorta and treatment corrected both conditions. Obese Zucker rats were hypoalgesic in response to a thermal stimulus and demonstrated signs of impaired tactile response and both conditions were significantly improved with treatment. Even though obese Zucker rats are normoglycemic vascular and neural dysfunctions develop with age and can be improved by treatment with AVE7688

Kinetics of diffusion-limited catalytically-activated reactions: An extension of the Wilemski-Fixman approach

We study kinetics of diffusion-limited catalytically-activated $A + B \to B$ reactions taking place in three dimensional systems, in which an annihilation of diffusive $A$ particles by diffusive traps $B$ may happen only if the encounter of an $A$ with any of the $B$s happens within a special catalytic subvolumen, these subvolumens being immobile and uniformly distributed within the reaction bath. Suitably extending the classical approach of Wilemski and Fixman (G. Wilemski and M. Fixman, J. Chem. Phys. \textbf{58}:4009, 1973) to such three-molecular diffusion-limited reactions, we calculate analytically an effective reaction constant and show that it comprises several terms associated with the residence and joint residence times of Brownian paths in finite domains. The effective reaction constant exhibits a non-trivial dependence on the reaction radii, the mean density of catalytic subvolumens and particles' diffusion coefficients. Finally, we discuss the fluctuation-induced kinetic behavior in such systems.Comment: To appear in J. Chem. Phy

The Role of Regulated mRNA Stability in Establishing Bicoid Morphogen Gradient in Drosophila Embryonic Development

The Bicoid morphogen is amongst the earliest triggers of differential spatial pattern of gene expression and subsequent cell fate determination in the embryonic development of Drosophila. This maternally deposited morphogen is thought to diffuse in the embryo, establishing a concentration gradient which is sensed by downstream genes. In most model based analyses of this process, the translation of the bicoid mRNA is thought to take place at a fixed rate from the anterior pole of the embryo and a supply of the resulting protein at a constant rate is assumed. Is this process of morphogen generation a passive one as assumed in the modelling literature so far, or would available data support an alternate hypothesis that the stability of the mRNA is regulated by active processes? We introduce a model in which the stability of the maternal mRNA is regulated by being held constant for a length of time, followed by rapid degradation. With this more realistic model of the source, we have analysed three computational models of spatial morphogen propagation along the anterior-posterior axis: (a) passive diffusion modelled as a deterministic differential equation, (b) diffusion enhanced by a cytoplasmic flow term; and (c) diffusion modelled by stochastic simulation of the corresponding chemical reactions. Parameter estimation on these models by matching to publicly available data on spatio-temporal Bicoid profiles suggests strong support for regulated stability over either a constant supply rate or one where the maternal mRNA is permitted to degrade in a passive manner

How do proteins search for their specific sites on coiled or globular DNA

It is known since the early days of molecular biology that proteins locate their specific targets on DNA up to two orders of magnitude faster than the Smoluchowski 3D diffusion rate. It was the idea due to Delbruck that they are non-specifically adsorbed on DNA, and sliding along DNA provides for the faster 1D search. Surprisingly, the role of DNA conformation was never considered in this context. In this article, we explicitly address the relative role of 3D diffusion and 1D sliding along coiled or globular DNA and the possibility of correlated re-adsorbtion of desorbed proteins. We have identified a wealth of new different scaling regimes. We also found the maximal possible acceleration of the reaction due to sliding, we found that the maximum on the rate-versus-ionic strength curve is asymmetric, and that sliding can lead not only to acceleration, but in some regimes to dramatic deceleration of the reaction.Comment: 16 pages, 5 figure

Pascal Principle for Diffusion-Controlled Trapping Reactions

"All misfortune of man comes from the fact that he does not stay peacefully in his room", has once asserted Blaise Pascal. In the present paper we evoke this statement as the "Pascal principle" in regard to the problem of survival of an "A" particle, which performs a lattice random walk in presence of a concentration of randomly moving traps "B", and gets annihilated upon encounters with any of them. We prove here that at sufficiently large times for both perfect and imperfect trapping reactions, for arbitrary spatial dimension "d" and for a rather general class of random walks, the "A" particle survival probability is less than or equal to the survival probability of an immobile target in the presence of randomly moving traps.Comment: 4 pages, RevTex, appearing in PR

On the joint residence time of N independent two-dimensional Brownian motions

We study the behavior of several joint residence times of N independent Brownian particles in a disc of radius $R$ in two dimensions. We consider: (i) the time T_N(t) spent by all N particles simultaneously in the disc within the time interval [0,t]; (ii) the time T_N^{(m)}(t) which at least m out of N particles spend together in the disc within the time interval [0,t]; and (iii) the time {\tilde T}_N^{(m)}(t) which exactly m out of N particles spend together in the disc within the time interval [0,t]. We obtain very simple exact expressions for the expectations of these three residence times in the limit t\to\infty.Comment: 8 page