T-type Ca2+ channel activity increases in rat hippocampal CA1 region during kindling epileptogenesis.

Epileptogenesis is a dynamical process that involves synaptic plasticity changes such as synaptic reorganization of excitatory and inhibitory systems and axonal sprouting in the hippocampus, which is one of the most studied epileptogenic regions in the brain. However, the early events that trigger these changes are not understood well. We investigated short-term and long-term synaptic plasticity parameters and T-type Ca2+ channel activity changes in the early phase of a rat kindling model. Chronic pentylenetetrazole (PTZ) application was used in order to induce the kindling process in rats. The recordings were obtained from hippocampal slices in the CA1 region at 25th day of PTZ application. Tetraethylammonium was used in order to induce long-term potentiation and T-type Ca2+ channel activity was assessed in the presence of mibefradil. We found that tetraethylammonium-induced long-term potentiation was not prevented by mibefradil in the kindling group in contrast to control group. We also found an increase in paired-pulse ratios in the PTZ-applied group. Our findings indicate an increase in the "T-type Ca2+ channel component of LTP" in the kindling group, which may be an early mechanism in epileptogenesis.

Vital Role of Monoamine Oxidases and Cholinesterases in Central Nervous System Drug Research: A Sharp Dissection of the Pathophysiology.

BACKGROUND: Monoamine oxidase and cholinesterase enzymes are very critical enzymes that regulate the level of neurotransmitters such as acetylcholine and monoamines. Monoamine neurotransmitters and acetylcholine play a very important role in many physiological events. An increase or decrease in the amount of these neurotransmitters is observed in a wide range of central nervous system pathologies. Balancing the amount of these neurotransmitters is important in improving the progression of these diseases. Inhibitors of monoamine oxidase and cholinesterase enzymes are important in symptomatic therapy and delaying progression of a group of central nervous system disease manifested with memory loss, cognitive decline and psychiatric disturbances like depression. OBJECTIVE: In this article, the relationship between central nervous system diseases and the vital role of the enzymes, monoamine oxidase and cholinesterase, is discussed on the pathophysiologic basis, focusing on drug research. CONCLUSION: Monoamine oxidase and cholinesterase enzymes are still a good target for the development of novel drug active substances with optimized pharmacokinetic and pharmacodynamic properties, which can maximize the benefits of current therapy modalities.

New Human Monoamine Oxidase A Inhibitors with Potential Anti- Depressant Activity: Design, Synthesis, Biological Screening and Evaluation of Pharmacological Activity.

AIM AND OBJECTIVE: Depression is a momentous disease that can greatly reduce the quality of life and cause death. In depression, neurotransmitter levels such as serotonine, dopamine and noradrenaline are impaired. Monoamine oxidases (MAO) are responsible for oxidative catalysis of these monoamine neurotransmitters. Because of this relation, MAO-A inhibitors show antidepressant activity by regulating neurotransmitter levels. This study was carried out to investigate the design, synthesis and activity of new antidepressant compounds in pyrazoline and hydrazone structure. MATERIAL AND METHOD: Chalcones and hydrazides were heated under reflux to give new pyrazoline and hydrazone derivatives. Docking simulations were performed using AutoDock4.2. hMAO activities were determined by a fluorimetric method. To determine cell viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used. Behavioral activities of the three compounds were determined by using Forced Swim Test, Step-Through Passive Avoidance Test, Elevated Plus Maze and Open Field Arena Tests. RESULTS: According to in vitro tests, all of the synthesized compounds were found more potent than moclobemide and six of the synthesized compounds were found more selective than moclobemide. Three of the synthesized compounds were investigated for their behavioral activities comparing with moclobemide after 7 days of i.p. treatment at 30 mg/kg. One of the three compounds elicited significant antidepressant properties. CONCLUSION: All of the synthesized compounds were found potent hMAO-A inhibitors in in vitro screening tests. Only one of the in vivo tested three compounds, (3-(2-hydroxy-5-methylphenyl)-5- p-tolyl-4,5-dihydropyrazol-1-yl)(pyridin-4-yl) methanone indicated significant antidepressant activity. This article opens a window for further development of new pyrazoline and hydrazone derivatives as antidepressant agents.

Increased maternal intraabdominal pressure alters the contractile properties of fetal rabbit bladder.

BACKGROUND/PURPOSE: Increased intraabdominal pressure (IAP) causes impairment of urine flow by compressing the urine-transporting structures and leads to development of various types of anatomical and functional abnormalities in the urinary system. An intrauterine experiment was conducted to determine the relationship between IAP and intraamniotic pressure (IAMNP) and the effects of increased IAMNP on the contractile properties of fetal bladder in the rabbit model. MATERIALS AND METHODS: Fourteen time-mated pregnant rabbits were used. A preliminary study (n = 5, 20-day gestation) was performed to determine the relation between IAP and IAMNP. Intraabdominal pressure and IAMNP were recorded through an intraperitoneal catheter and 2 intraamniotic transducers, respectively. Basal IAP and IAMNP were recorded. Then, IAP was increased for 4 cm H(2)O in each subsequent 30-minute period until reaching 20 cm H(2)O. Control (n = 5) and experiment (n = 4) group animals underwent intraperitoneal catheter placement in the 15th day of gestation. Intraabdominal pressure was increased by intraperitoneal air insufflations from 20th day to term in the experiment group. At term, the fetal bladders were excised and the contractile activity was then recorded isometrically. Electrical field stimulation was applied, and contractile responses to carbachol and high potassium (20 mmol/L KCl) were also evaluated. RESULTS: A strong relationship was found between IAMNP and IAP and defined as IAMNP = IAP x 0.8 + 2.0 (R(2) = 0.816, P = .000). Increased IAP did not change basal rhythmic activity but resulted in frequency-related electrical field stimulation responses being higher contractility responses for frequencies below 10 Hz (P < .05) and similar responses at and above 10 Hz. Bladders imposed to elevated IAP displayed greater sensitivity to carbachol with a shift to the left in the concentration-response curve. High potassium-induced contractions had a shorter rise time (P < .05) but similar contraction amplitudes and half decay times in bladders imposed to increased IAP. CONCLUSION: Intraamniotic pressure is affected by IAP in pregnant rabbits in accordance with an equation (IAMNP = IAP x 0.8 + 2.0). Increased IAMNP changes contractile properties of the fetal rabbit bladder without affecting spontaneous activity and shortens the rise time of high potassium-induced contractions. Increased IAMNP also results in cholinergic hypersensitivity in fetal bladders. These results may explain the mechanism of dysfunctional voiding and abnormal bladder function observed in conditions in which IAP and/or IAMNP are elevated.