Seckin Tuncer

Comparative Effects of Alpha Lipoic Acid and Melatonin on Cisplatin-Induced Neurotoxicity

ABSTRACT Cisplatin is a carcinogenic agent having important cytotoxic effects. Cisplatin treatment increases the levels of free oxygen radicals in neurologic tissues. We investigated the effects of alpha lipoic acid (ALA) and melatonin (MEL) on the electrophysiological parameters and on activities of nerve fibers having different conduction properties on cisplatin neurotoxicity. Neurotoxicity was induced by a single injection of 10 mg/kg intraperitoneal (ip) cisplatin. Supplementation was started 1 day before cisplatin injection with either 100 mg/kg/day ip ALA or 4 mg/kg/day ip MEL for 7 days. Compound action potentials were recorded from isolated sciatic nerves in vitro, and numerical analyses were conducted. Cisplatin-induced neurotoxicity resulted in a significant decrease (p <.05) in maximum depolarization (mV), areas (mV·ms), and maximum and minimum upstroke velocity values (mV/ms). Although these decrements were restored by ALA and MEL, ALA was found to be more effective. Conventional conduction velocity measurements and conduction velocity distribution histograms have shown that ALA supplementation can recover the effects of cisplatin while MEL cannot. The conduction velocity distribution histograms have shown that antioxidant supplementation results in a restoration on contribution of fast-conducting fibers (51.8–77.7 m/s), which is deteriorated by cisplatin. Consequently, ALA has more potential to make up for the deleterious effects of cisplatin-induced neurotoxicity.

Selenium-Induced Changes on Rat Sciatic Nerve Fibers : Compound Action Potentials

The nervous system, through its important role as a communication network, governs reactions to stimuli, processes information and generates elaborate patterns of signals to control complex behaviors. Although selenium (Se) was shown to have some beneficial effects in pathological conditions, it is still a toxic element with a fairly small therapeutic window. In this study, the direct effects of Se ranging from 10(-8) to 10(-4) M were tested on rat sciatic nerve preparations. The toxicity started at 10(-8) M and the degree of alterations was found to be dose-dependent. In between the measured parameters, total compound action potential area (Astart = 3.70 +/- 0.16 ms x mV and A(-8) M = 3.04 +/- 0.14 ms x mV) and maximum depolarization points (MDstart = 6.70 +/- 0.22 mV and MD(-8) M = 6.04 +/- 0.18 mV) were the first to be affected from 10(-8) M. Latencies and conduction velocity distribution measurements have shown that nerve fibers having intermediate conduction velocities (20-35 m/s) are the first to be affected from this toxicity. Despite the fact that the new claims concluded the positive effects of the administrations, it is evident that the dose of supplementation must be fine-tuned to avoid possible side effects.

Coenzyme Q(10) and alpha-lipoic acid supplementation in diabetic rats: conduction velocity distributions.

Diabetic neuropathies are a family of nerve disorders caused by diabetes. Patients with diabetes can develop nerve problems at any time, but the longer a person has diabetes the greater the risk. This study aims to investigate diabetes- and coenzyme Q(10) (CoQ(10)) or alpha-lipoic acid (ALA) supplementation-induced changes in the conduction velocity (CV) distributions of rat sciatic nerve fibers. Sciatic nerve compound action potentials (CAPs) were recorded by suction electrode and CV distributions by the collision technique. Diabetes resulted in a significant increase in time to peak, rheobase and chronaxie values of these CAP waveforms, whereas the maximum depolarization, area, kinetics and CVs of both fast and slow nerve fiber groups were found to be decreased. Coenzyme Q(10) (CoQ(10)) supplementation was found to have some positive effect on the diabetes-induced alterations. CoQ(10) supplementation induced positive changes mainly in the area and fall-down phase of the kinetics of CAP waveforms, as well as rheobase, chronaxie and speed of the intermediately conducting groups ( approximately or equal to 40 m/s). alpha-Lipoic acid (ALA) supplementation did not produce statistically significant effects. This study has shown for the first time that diabetes induces a shift of actively contributing nerve fibers toward slower CVs, and supplementation with CoQ(10) not only stopped this shift but also tended to restore velocities toward those of the age-matched control group. In addition to its effects on mitochondrial alterations, these positive effects of CoQ10 on diabetic neuropathy can be attributed to its antioxidant activity.

An early diagnostic tool for diabetic neuropathy: conduction velocity distribution.

Diabetes is a metabolic disorder that affects much of the human population. As a secondary complication, diabetic neuropathy causes time‐dependent damage to peripheral nerves. In this study, experimental diabetes was induced by streptozotocin (STZ; 50 mg/kg intraperitoneally) in rats. Diabetic animals were grouped into those with 2 or 4 weeks of diabetes, whereas a control group received only the STZ vehicle (0.1 M citrate). Sciatic nerves were dissected, and compound action potentials (CAPs) were recorded. Results deduced by conventional calculation carried less information when compared with conduction velocity distribution (CVD) obtained by a computer‐based mathematical model. Using the conventional approach, statistically significant changes were first seen in the fourth week of diabetes, whereas results deduced by CVD measurement could be seen in the second week. Consequently, the CVD calculation provides more information for the early diagnosis of neuropathies compared with classical conduction velocity measurements. Muscle Nerve 43: 237–244, 2011

Gender-dependent effects of selenite on the perfused rat heart: a toxicological study.

Gender differences are related to the manner in which the heart responds to chronic and acute stress conditions of physiological and pathological nature. Depending on dose, sodium selenite acts as an antioxidant proven to have beneficial effects in several pathological conditions G. Drasch, J. Schopfer, and G. N. Schrauzer, Selenium/cadmium ratios in human prostates: indicators of prostate cancer risk of smokers and non-smokers, and relevance to the cancer protective effects of selenium,Biol. Trace Element Res.103(2), 103–107 (2005); R. G. Kasseroller and G. N. Schrauzer, Treatment of secondary lymphedema of the arm with physical decongestive therapy and sodium selenite: a review,Am. J. Ther.7(4), 273–279 (2000); G. N. Schrauzer, Anticarcinogenic effects of selenium,Cell. Mol. Life Sci.57(13–14), 1864–1873 (2000); I. S. Palmer and O. E. Olson, Relative toxicities of selenite and selenate in the drinking water of rats,J. Nutr.104(3), 306–314 (1974). To date, little is known about the gender-dependent direct effects of toxic doses of selenite on electrophysiology of the cardiovascular system H. A. Schroeder and M. Mitchener, Selenium and tellurium in rats: effect on growth, survival and tumors,J. Nutr.101(11), 1531–1540 (1971); G. N. Schrauzer, The nutritional significance, metabolism and toxicology of selenomethionine,Adv. Food Nutr. Res.47, 73–112 (2003). In the present study, the effects of in vitro toxic concentrations of sodium selenite ranging from 10-6 M to 10-3 M were tested on both male and female rat heart preparations. The toxic effects seen in an electrocardiogram and left ventricular pressure were dose and sex dependent at most of the tested concentrations. The present study clearly shows that at toxic doses, stress conditions are induced by selenite, resulting in gender-dependent modifications of the heart function. This modification is more pronounced in the contraction cascade of female rats. Males, on the other hand, had been much more affected in excitation-related parameters.

Electrophysiological alterations in diaphragm muscle caused by abdominal ischemia-reperfusion.

Ischemia-reperfusion injury is the major complication of abdominal aortic surgery, and it mainly affects the lower extremities and remote organs. In the present study, the electrophysiological alterations in diaphragm that underlie the post-operative respiratory dysfunction were investigated. Wistar Albino rats were randomly divided into two groups: SHAM (only laparotomy was performed) and IR (abdominal aorta was clamped for 30min and reperfused for 2h). Following the operational period diaphragm muscles were isolated and electrophysiological experiments were carried out in-vitro. 3nM Ryanodine application, Na+ and K+ current blockage (0.3mM 4-Aminopyridine and 127mM N-methyl-d-glukamine) experiments were also conducted to further reveal any alterations. Twitch and tetanic force were decreased significantly. Action potential overshoot, amplitude and area were increased while diaphragm muscle cells were found to be hyperpolarized significantly. Mechanical alterations were shown to be caused by deterioration of Ca++ homeostasis. At resting state, a decrease in persistent Na+ current was found. The reshaping of action potential, on the other hand, was shown to be due to altered kinetics of Na+ channels and delayed activation of voltage dependent K+ channels.

Axonal excitability and conduction alterations caused by levobupivacaine in rat

Abstract In this study, effects of the long-acting amide-type local anesthetic levobupivacaine on axonal conduction and excitability parameters of the rat sciatic nerve were thoroughly examined both in vitro and in vivo. In order to deduce its effects on isolated nerve conduction, compound nerve action potential (CNAP) recordings were performed using the suction method over sciatic nerves of Wistar rats before and after administration of 0.05 % (1.7 mmol L−1) levobupivacaine. Levobupivacaine caused complete CNAP area and amplitude depression by blocking conduction in a time-dependent manner. To assess the influence of levobupivacaine on in vivo excitability properties, threshold-tracking (TT) protocols were performed at sciatic nerves of rats injected with perineural 0.05 % (1.7 mmol L−1) levobupivacaine or vehicle alone. Charge-duration TT results revealed that levobupivacaine increases the rheobase and decreases the strength-duration time constant, suggesting interference of the anesthetic with the opening of Na+ channels. Twenty and 40 % threshold electrotonus curves were found for both groups to follow the same paths, suggesting no significant effect of levobupivacaine on K+ channels for either the fastest or relatively slow conducting fibers. Current-threshold relationship results revealed no significant effect on axonal rectifying channels. However, according to the results of the recovery cycle protocol yielding the pattern of excitability changes following the impulse, potential deviation was found in the recovery characteristics of Na+ channels from the absolute refractory period. Consequently, conduction blockage caused by levobupivacaine may not be due to the passive (capacitive) properties of axon or the conductance of potassium channels but to the decrease in sodium channel conductance.

SEXUAL DEPENDENCY OF RAT SCIATIC NERVE FIBER CONDUCTION VELOCITY DISTRIBUTIONS

Gender differences, either with the structural or through with hormones, dictate how the corresponding organ or organ system responses to physiological signals. Current study aims to investigate gender dependent differences in conduction related parameters of rat sciatic nerve. Compound action potentials (CAP) were recorded via suction electrode whereas the conduction velocity distributions (CVD) were performed using the method known as collision technique in the literature. Studied CAP parameters, namely conduction velocities (CV), area of the CAPs and time required to reach the maximum depolarization (TP) have been found significantly different for female and male rats. Detailed analyses have shown that sex dependent differences were more remarkable in the right leg responses of female and male rats. Additionally, CVDs indicate that the number of fibers having CVs between 5–30 m/s is much more in male right sciatic nerve trunk when compared to age matched female rats. The present study, for the first time clearly shows that shift in the contribution of nerve fibers to lower CVs is the main causal of the sex dependent differences seen in rat sciatic nerve fibers.