Effects of endurance cycling training on neuromuscular fatigue in healthy active men. Part II: Corticospinal excitability and voluntary activation.

This study investigated the effects of 9-week endurance cycling training on central fatigability and corticomotor excitability of the locomotor muscles. Fourteen healthy participants undertook three incremental fatiguing cycling tests to volitional exhaustion (EXH): (i) before training (PRE), (ii) after training at the same absolute power output as PRE (POSTABS) and (iii) after training at the same percentage of V̇O2max as PRE (POSTREL). At baseline (i.e. before cycling), every 5 min during cycling and immediately at EXH, a neuromuscular evaluation including a series of 5-s knee extensions at 100, 75 and 50% of maximal voluntary knee extension (MVC) was performed. During each contraction, transcranial magnetic and peripheral nerve stimuli were elicited to obtain motor evoked potential (MEP), silent period (SP) and compound muscle action potential (Mmax) and to calculate voluntary activation (VA). The MEP·Mmax-1 ratio recorded from vastus lateralis at 100 and 50% MVC did not show any difference between conditions. At 75% MVC, MEP exhibited significantly lower values in POSTABS and POSTREL compared to PRE at baseline (P = 0.022 and P = 0.011, respectively) as well as at 25% of time to EXH of PRE (P = 0.022) for POSTREL. No adaptations, either at baseline or during cycling, were observed for VA and SPs. In conclusion, endurance training may result in some adaptations in the corticomotor responses when measured at rest or with low level of fatigue, yet these adaptations do not translate into attenuation of central fatigue at a similar cycling workload or at exhaustion.

Effects of endurance training on neuromuscular fatigue in healthy active men. Part I: Strength loss and muscle fatigue.

PURPOSE: The adaptations induced by endurance training on the neuromuscular function remain under investigation and, for methodological reasons, unclear. This study investigates the effects of cycling training on neuromuscular fatigue and its peripheral contribution measured during and immediately after cycling exercise. METHODS: Fourteen healthy men performed a fatigue test before a 9-week cycling program (PRE) and two tests after training: at the same absolute power output as PRE (POSTABS) and based on the post-training maximal aerobic power (POSTREL). Throughout the tests and at exhaustion (EXH), maximal voluntary contraction (MVC) and peripheral fatigue were assessed in the quadriceps muscle by electrical nerve stimulation [single twitch (Pt); high-frequency doublet (Db100) and low-to-high-frequency ratio (Db10:100)]. RESULTS: Time to EXH was longer in POSTABS than PRE (34 ± 5 vs. 27 ± 4 min, P < 0.001), and POSTREL tended to be longer than PRE (30 ± 6 min, P = 0.053). MVC and peripheral fatigue were overall less depressed in POSTABS than PRE at isotime. At EXH, MVC and Db10:100 were similarly reduced in all sessions (-37 to - 42% and - 30 to - 37%, respectively). Db100 tended to be less depressed in POSTABS than PRE (-40 ± 9 vs. - 48 ± 16%, P = 0.050) and in POSTREL than PRE (-39 ± 9%, P = 0.071). Pt decreased similarly in POSTABS and PRE (-52 ± 16 vs. - 54 ± 16%), but POSTREL tended to be less depressed than PRE (-48 ± 14%, P = 0.075). CONCLUSIONS: This study confirms fatigue attenuation at isotime after training. Yet lower or similar fatigue at EXH indicates that, unlike previously suggested, fatigue tolerance may not be upregulated after 9 weeks of cycling training.

RESULTS FROM A NEW METHOD TO ASSESS THE OCCUPATIONAL LENS DOSE IN INTERVENTIONAL RADIOLOGY.

Interventional radiology procedures have always been of particular concern because of the potential high dose to the workers. Special attention has recently been given to the lens dose: in 2011 the ICRP issued the recommendation 'Statement on Tissue Reactions' where a new limit of 20 mSv in a year, averaged over defined periods of 5 years, is given. Due to the impossibility of measuring the dose directly on the eye, there is not still a general consensus on a standardized methodology to assess the lens dose, which should be at the same time reliable, robust and simple to implement in practice. The procedure described here aims to assess the lens dose using the Hp(0.07) equivalent dose measured with a dosimeter worn at chest level above the lead apron, through a correlation with the total KAP per procedure and considering the type of the protection tools used during each procedure: glasses (with lateral shields), ceiling screen, both or neither of them and the frequency of their use.

Radiation doses in cerebral perfusion computed tomography: patient and phantom study.

The purpose of this study was to investigate radiation doses in cerebral perfusion computed tomography (CT) examination. As a part of routine patient monitoring, data were collected on patients in terms of the skin dose and CT dose index (CTDIvol) and dose-length product (DLP) values. For the estimation of the dose to the lens a phantom study was performed. Dose values for skin and lens were below the threshold for deterministic effects. The results were also compared with already published data. For better comparison, the effective dose was also estimated. The values collected on patients were in the ranges 230-680 mGy for CTDI and 2120-2740 mGy cm for DLP, while the skin dose and estimated effective dose were 340-800 mGy and 4.9-6.3 mSv, respectively. These values measured in the phantom study were similar, while the doses estimated to the lens were 53 and 51 mGy for the right and left lens, respectively.

Sonographic characteristics of carotid artery plaques: Implications for follow-up planning?

UNLABELLED: The aim of our study was to analyze the ultrasound characteristics of carotid plaques in an outpatient population and to determine their implications for planning the ultrasound follow-up. MATERIALS AND METHODS: We studied 747 consecutive outpatients (397 [53%] of whom were women) who underwent color Doppler sonography of the carotid arteries. Most of the patients presented multiple cardiovascular risk factors or were being followed-up for carotid artery stenosis. RESULTS: Stenosis ranging from 1% to 69% was observed at the level of the right internal carotid arteries (ICA) in 419 (56.1%) of the 747 patients and in the left ICA in 408 of 747 (54.5%). One hundred twenty-four (29.5%) of the 419 RICA plaques and 77 (18.8%) of the 408 LICA plaques were classified as type 1 or type 2 according to the modified Gray-Weale classification. CONCLUSIONS: Type 1 and type 2 plaques, which are referred to as "vulnerable plaques," were found in 160 (21.4%) of the 747 patients we examined. These patients should be subjected to closer ultrasound follow-up, even if they have only moderate carotid artery stenosis.

Count-rate analysis from clinical scans in PET with LSO detectors.

The purpose of optimising the acquisition parameters in positron emission tomography is to improve the quality of the diagnostic images. Optimisation can be done by maximising the noise equivalent count rate (NECR) that in turn depends on the coincidence rate. For each bed position the scanner records coincidences and singles rates. For each patient, the true, random and scattered coincidences as functions of the single count rate(s) are determined by fitting the NEMA (National Electrical Manufacturers Association) 70 cm phantom count rate curves to measured clinical points. This enables analytical calculation of the personalised PNECR [pseudo NECR(s)] curve, linked to the NECR curve. For central bed positions, missing activity of approximately 70% is estimated to get maximum PNECR (PNECR(max)), but the improvement in terms of signal-toz-noise ratio would be approximately 15%. The correlation between patient weight and PNECR(max) is also estimated to determine the optimal scan duration of a single bed position as a function of patient weight at the same PNEC. Normalising the counts at PNECR(max) for the 70 kg patient, the bed duration for a 90 kg patient should be 230 s, which is approximately 30% longer. Although the analysis indicates that the fast scanner electronics allow using higher administered activities, this would involve poor improvement in terms of NECR. Instead, attending to higher bed duration for heavier patients may be more useful.

[Peripheral arterial disease in a population of type 2 diabetic patients: its correlation with diabetic microangiopathy and laboratory parameters]. / L'arteriopatia obliterante periferica in una popolazione di diabetici di tipo 2: correlazione con la microangiopatia diabetica e parametri laboratoristici.

BACKGROUND: The aim of this study was to evaluate the incidence of peripheral arterial disease (PAD) in a population of type 2 diabetic patients (NIDDM) and its possible correlation with diabetic nephropathy (DN), diabetic retinopathy (DR) and also with some biochemical parameters of glomerular and tubular renal function. METHODS: The study included a total of 150 NIDDM patients, randomly selected, who have been followed-up at the Metabolic Center of our Division. All patients underwent assessment of the ankle/brachial pressure index (ABI) and Doppler ultrasound of the lower extremities. They were then divided into 2 groups: Group 0 without PAD and Group 1 with PAD. They also underwent a echo color-Doppler study of the renal interlobar arteries in order to evaluate the resistive index (RI), while the retinal vessels were assessed by biomicroscopy and fluorangiography. RESULTS: The incidence of PAD in this study was 30.6%, occurring on average 14 years from the onset of diabetes, and affecting particularly patients with nephropathy. The presence of both albuminuria and retinopathy in the same patient increases by 8.9 times the risk of cardiovascular disease. CONCLUSIONS: The RI, measured at the level of the intrarenal arteries, is of great interest as a marker not only of renal vascular damage in NIDDM patients, but also of a generalized vascular involvement.

New milrinone analogues: in vitro study of structure-activity relationships for positive inotropic effect, antagonism towards endogenous adenosine, and inhibition of cardiac type III phosphodiesterase.

Two mechanisms are responsible for the positive inotropic effect of the cardiotonic drug milrinone, i.e., inhibition of type III cAMP phosphodiesterase (PDE III), and displacement of endogenous adenosine from A(1) inhibitory receptor. Since PDE III inhibition may increase the likelihood of cardiac arrhythmias by increasing cAMP content, our attention focused on the synthesis of new compounds with more pronounced characteristics as adenosine antagonists. In this work, four new milrinone analogues were studied, in comparison with the parent drug, for their effects on the contractility of guinea pig isolated atrial preparations, their ability to antagonize endogenous adenosine at the level of A(1) receptor, and to inhibit the activity of PDE III partially purified from guinea pig heart. The new compounds present various chemical substitutions with respect to the parent drug: in compounds SF397 (methyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate) and SF399 (benzyl 5-cyano-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate), the 4-pyridil moiety of milrinone was replaced with a methoxycarbonyl and a benzyloxycarbonyl group, respectively; the same structural modifications were also associated with the replacement of the cyano-group in 5-position with an acetyl group in compounds SF416 (methyl 5-acetyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate) and SF419 (benzyl 5-acetyl-2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate). All the new compounds had a marked positive inotropic effect, most of them also being more active and more potent than milrinone. When their affinity for A(1) receptor was assessed as the displacement of [(3)H] 8-cyclopentyl-1,3-dipropylxanthine ([(3)H]DPCPX) from cardiac membranes, SF397 and SF399 showed affinity (K(i) of about 600 nM) similar to that of milrinone (K(i) 550 nM). By contrast, SF416 and SF419 had very low (K(i) of about 10000 nM) or scarce (K(i) of about 2000 nM) anti-adenosine component, respectively. All the new compounds inhibited PDE III activity, their K(i) values proceeding in the following order: milrinone (3.80 microM)

Callipeltin A, a cyclic depsipeptide inhibitor of the cardiac sodium-calcium exchanger and positive inotropic agent.

Callipeltin A, a cyclic depsipeptide from the New Caledonian Lithistida sponge Callipelta sp., is a macrocyclic lactone containing four amino acids in the L configuration, Ala, Leu, Thr (2 residues); one (Arg) in the D configuration; two N-methyl amino acids, N-MeAla and N-MeGln; a methoxy tyrosine, a 3, 4-dimethyl-l-glutamine; and a 4-amino-7-guanidino-2,3 dihydroxypentanoic acid (AGDHE), formally derived from L-Arg. In cardiac sarcolemmal vesicles Callipeltin A induces a powerful (IC(50) = 0.85 microM) and selective inhibition of the Na(+)/Ca(2+) exchanger. In electrically driven guinea-pig atria, at concentrations ranging between 0.7 and 2.5 microM, Callipeltin A induces a positive inotropic effect, which at the highest concentrations is accompanied by a rise in resting tension. It is suggested that the positive inotropic effect is linked to the inhibition of the Na(+)/Ca(2+) exchanger and that Callipeltin A may be an useful tool to study the role of the cardiac Na(+)/Ca(2+) exchanger in physiological and pathological conditions.

Pharmacological characterization of a new Ca(2+) sensitizer.

The benzimidazole molecule was modified to synthesize a Ca(2+) sensitizer devoid of additional effects associated with Ca(2+) overload. Newly synthesized compounds, termed 1, 2, 3, 4, and 5, were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Compound 3 resulted as the most effective positive inotropic agent, and experiments were performed to study its mechanism of action. In spontaneously beating atria, the inotropic effect of 3 was concentration-dependent (3.0 microM-0.3 mM). Compound 3 was more potent and more active than the structurally related Ca(2+) sensitizers sulmazole and caffeine, but unlike them it did not increase the heart rate. In electrically driven atria, the inotropic activity of 3 was well preserved and it was not inhibited by propranolol, prazosin, ranitidine, pyrilamine, carbachol, adenosine deaminase, or ruthenium red. At high concentrations (0.1-1.0 mM) 3 inhibited phosphodiesterase-III, whereas it did not affect Na(+)/K(+)-ATPase, sarcolemmal Ca(2+)-ATPase, Na(+)/Ca(2+) exchange carrier, or sarcoplasmic reticulum Ca(2+) pump activities of guinea pig heart. In skinned fibers obtained from guinea pig papillary muscle and skeletal soleus muscle, compound 3 (0.1 mM, 1 mM) shifted the pCa/tension relation curve to the left, with no effect on maximal tension and no signs of toxicity. Compound 3 did not influence the basal or raised tone of guinea pig isolated aorta rings, whose cells do not contain the contractile protein troponin. The present results indicate that the inotropic effect of compound 3 seems to be primarily sustained by sensitization of the contractile proteins to Ca(2+).

In vivo antitumor activity and host toxicity of methoxymorpholinyl doxorubicin: role of cytochrome P450 3A.

Methoxymorpholinyl doxorubicin (MMDX; PNU 152243) is a promising doxorubicin derivative currently undergoing clinical evaluation. Previous in vitro studies suggested that the compound undergoes hepatic biotransformation by cytochrome P450 (CYP) 3A into a more cytotoxic metabolite(s). The present study examined the role of CYP3A-mediated metabolism in the in vivo antitumor activity and host toxicity of MMDX in the mouse model and investigated the potential for increasing the therapeutic effectiveness of the drug by inducing its hepatic CYP-catalyzed activation. We found that MMDX cytotoxicity for cultured M5076 tumor cells was potentiated 22-fold by preincubating the drug with NADPH-supplemented liver microsomes from untreated C57BL/6 female mice. A greater (50-fold) potentiation of MMDX cytotoxicity was observed after its preincubation with liver microsomes isolated from animals pretreated with the prototypical CYP3A inducer pregnenolone-16alpha-carbonitrile. In contrast, in vivo administration of the selective CYP3A inhibitor troleandomycin (TAO) reduced both potentiation of MMDX cytotoxicity and the rate of CYP3A-catalyzed N-demethylation of erythromycin by isolated liver microsomes (55.5 and 49% reduction, respectively). In vivo antitumor activity experiments revealed that TAO completely suppressed the ability of 90 microg/kg MMDX i.v., a dose close to the LD10, to delay growth of s.c. M5076 tumors in C57BL/6 mice and to prolong survival of DBA/2 mice with disseminated L1210 leukemia. Moreover, TAO administration markedly inhibited the therapeutic efficacy of 90 microg/kg MMDX i.v. in mice bearing experimental M5076 liver metastases; a complete loss of MMDX activity was observed in liver metastases-bearing animals receiving 40 microg/kg MMDX i.v. plus TAO. However, pregnenolone-16alpha-carbonitrile pretreatment failed to enhance MMDX activity in mice bearing either s.c. M5076 tumors or experimental M5076 liver metastases. Additional experiments carried out in healthy C57BL/6 mice showed that TAO markedly inhibited MMDX-induced myelosuppression and protected the animals against lethal doses of MMDX. Taken together, these findings demonstrate that an active metabolite(s) of MMDX synthesized via CYP3A contributes significantly to its in vivo antitumor activity and host toxicity.

Protective action of cardiac DT-diaphorase against menadione toxicity in guinea pig isolated atria.

In myocardial preparations isolated from guinea pigs, 2-methyl-1, 4-naphthoquinone (menadione) causes an increase in contractility that is strictly related to the generation of reactive oxygen species (ROS) as a consequence of quinone metabolism. In heart, menadione undergoes one-electron reduction to semiquinone, a reaction mainly catalysed by mitochondrial NADH: ubiquinone oxidoreductase. It is also converted to hydroquinone by the soluble two-electron reductase, DT-diaphorase, and is conjugated with GSH by glutathione S-transferase. In order to assess the role of DT-diaphorase in cardiac responses to menadione, we examined the effects of both a specific inhibitor (dicoumarol) and an inducer (beta-naphthoflavone) of the enzyme on the inotropic action of the quinone. In electrically driven left atria of guinea pig, 4 microM dicoumarol significantly enhanced the positive inotropic effect of menadione, especially at the lower concentrations of the quinone. In myocardial preparations isolated from guinea pigs treated with beta-naphthoflavone (80 mg/kg i.p.for 2 days), DT-diaphorase activity was enhanced (+36% with respect to control animals, P < 0. 01), whereas the activities of the other enzymes involved in menadione metabolism were not modified. In these preparations, menadione caused a significantly lower increase in the force of contraction than in atria from untreated animals; moreover, pretreatment with beta-naphthoflavone caused a significant decrease in the menadione-induced oxidative stress, as evaluated from the GSH redox index. Taken together, these results demonstrate that cardiac DT-diaphorase does not contribute to ROS generation, but represents a detoxification system.

Intracellular glutathione levels determine cerebellar granule neuron sensitivity to excitotoxic injury by kainic acid.

Glutathione (GSH) is a key component of the cellular defence cascade against injury caused by reactive oxygen species. Kainic acid (KA) is a potent central nervous system excitotoxin. KA-elicited neuronal death may result from the generation of ROS. The present study was undertaken to characterize the role of GSH in KA-induced neurotoxicity. Cultures of cerebellar granule neurons were prepared from 8-day-old rats, and used at 8, 14 and 20 days in vitro (DIV). Granule neurons displayed a developmental increase in their sensitivity to KA injury, as quantified by an ELISA-based assay with the tetrazolium salt MTT. At DIV 14 and 20, a 30-min challenge with KA (500 microM) reduced cell viability by 45% after 24 h, significantly greater (P<0.01) than the 22% cell loss with DIV 8 cultures. Moreover acute (30 min) KA exposure concentration-dependently reduced intracellular GSH and enhanced reactive oxygen species generation (evaluated by 2', 7'-dichlorofluorescein diacetate). In comparison to control, KA (500 microM) lowered GSH levels in DIV 8 granule neurons by 16% (P=0. 0388), and by 36% (P=0.0001) in both DIV 14 and DIV 20 neurons, after 30 min. Preincubation of granule neurons with the membrane permeant GSH delivery agent, GSH ethyl ester (5 mM), for 30 min significantly increased intracellular GSH content. Importantly, GSH ethyl ester reduced the toxic effects of KA, becoming significant at 1 mM (P=0.007 vs. KA-treated group), and was maximal at >/=2.5 mM (P<0.0001). GSH ethyl ester displayed a similar dose-dependence in its ability to counteract KA-induced depletion of cellular GSH. The data strengthen the notion that cellular GSH levels have a fundamental role in KA-induced neurotoxicity.

Renal clearance of N(1)-methylnicotinamide: a sensitive marker of the severity of liver dysfunction in cirrhosis.

BACKGROUND/AIMS: Data have appeared suggesting that an impairment of renal tubular secretion is present in liver cirrhosis, even in the absence of a clinically evident renal dysfunction. To address this question, we evaluated the renal clearance of N(1)-methylnicotinamide (NMN), a marker of the renal secretory function, in healthy subjects and patients with liver cirrhosis of increasing severity, but with a normal glomerular filtration rate. METHODS: The renal clearances of endogenous NMN, inulin, and creatinine were measured in 14 normal subjects and in two groups of age-matched cirrhotic patients (10 Child A and 10 Child C). In 6 subjects, 2 per group, the concentration dependence of the NMN clearance was also studied, following an oral nicotinamide load. RESULTS: Contrary to expectations, the renal NMN clearance increased in cirrhotic patients, in relation to the severity of liver disease (r = 0.83 with Pugh's score; p < 0.001). The NMN-to-inulin clearance ratio increased from a control value of 2.2 +/- (SD) 0.4 to 3.1 +/- 0.2 and 5.2 +/- 0.9 in Child A and Child C cirrhotics, respectively (p < 0.001 for all comparisons), indicating that NMN was completely cleared from plasma in the latter patients. Consistently, the analysis of the concentration dependence of the renal NMN clearance revealed the presence of a carrier-mediated reabsorption which apparently was no longer operating in the decompensated patients. Discriminant analysis showed that renal NMN clearance, and NMN-to-creatinine and NMN-to-inulin clearance ratios could all distinguish between the three study groups, with sensitivities and specificities equal or greater than 90%. CONCLUSIONS: Contrary to previous proposals, NMN is not a probe of general validity for renal tubular secretion. In particular, due to an imbalance between secretion and reabsorption, its renal clearance in liver cirrhosis cannot be used to determine the degree of tubular secretion of which an individual is capable. However, renal NMN clearance appears to be a very sensitive marker of the severity of liver dysfunction in cirrhosis. The potentialities of this renal parameter as a diagnostic and prognostic test in liver cirrhosis deserve further study.

[Renal Doppler color ultrasonography in the study of diabetic nephropathy]. / Eco-color Doppler renale nello studio della nefropatia diabetica.

The traditional ultrasound approach in the field of diabetic nephropathy provides only partial clinical information; moreover, the data obtained are merely descriptive, in particular regarding the involvement of the intrarenal arteries, which is however the area mainly involved. The aim of our study was to assess the data provided by Doppler ultrasound and in particular the role of the Resistive Index (RI) in a population of 160 type 2 diabetics (NIDDM), divided into 4 groups according to the severity of diabetic nephropathy. The assessment of RI has enabled us to detect among patients in the early stages of diabetic nephropathy (64 patients of group 1), a subgroup of 28 subjects (43.8%) showing RI values equal to or above the threshold value of 0.7. The determination of renal size and of renal parenchyma echogenicity proved to be of little value. The most relevant clinical information is provided by the RI, a parameter that will allow the early detection of patients affected by NIDDM, who show renal vascular involvement without however any other alterations of the traditional ultrasound parameters.

Evaluation of measured and calculated creatinine clearances as glomerular filtration markers in different stages of liver cirrhosis.

BACKGROUND: Discrepant results have been published regarding the suitability of creatinine clearance (C(Cr)) as a measure of glomerular filtration rate (GFR) in cirrhotic patients with normal renal function. SUBJECTS AND METHODS: In this study we evaluated the accuracy and precision of measured and calculated C(Cr) as indexes of GFR by comparing their values to those of inulin clearance (C(In)) in 10 healthy subjects and 20 patients with either Child's class A or Child's class C liver cirrhosis. RESULTS: The accuracy and precision of GFR estimates obtained by measuring C(Cr) were good in all three study groups. The mean values of the C(Cr)/C(In) ratio were 1.05, 1.03 and 1.04, respectively, and the corresponding coefficients of variations were 2.9, 2.9 and 3.8%. A close correlation between C(Cr) and C(In) was also found in each study group (r = 0.98, 0.99 and 0.97, respectively, with p < 0.001 in each case). C(Cr) calculated from serum creatinine by means of the Cockcroft-Gault formula (predicted GFR) proved to be a suitable measure of GFR in normal subjects and patients with Child's class A cirrhosis: the predicted-to-true GFR ratios were 0.93 and 0.94, respectively, CV was 12% in both cases. Moreover, a significant correlation between predicted and true GFR was observed in both groups (r = 0.73, p < 0.02 and r = 0.69, p < 0.025, respectively). On the contrary, in Child's class C cirrhotics, calculated C(Cr) significantly overestimated GFR (predicted-to-true GFR ratio 1.23, CV 20%) and no significant correlation was found between predicted and true GFR (r = 0.58, p > 0.05). CONCLUSION: In conclusion, this study shows that measured C(Cr) is a reliable index of GFR in cirrhotic patients, irrespective of the degree of liver dysfunction. Calculated C(Cr) is still an adequate marker of GFR in patients with compensated liver cirrhosis, whereas it overestimates GFR in patients with decompensated cirrhosis. A lower muscle mass, a reduced ability to convert creatine to creatinine, and the presence of ascites are most likely responsible for the overestimation of GFR by the Cockcroft-Gault formula in the latter patients.

Further evidences for neuroprotective effects of melatonin.

The physiological roles of the pineal hormone melatonin are still not completely clarified. Recently it has been shown that melatonin is a potent, endogenous scavenger of reactive oxygen species suggesting that it might interfere with neurodegenerative processing involving free-radical formation and excitatory aminoacid release. These neuroprotective effects of melatonin may result, at least in part, from a sparing of glutathione reductase, which is decreased following administration of the neurotoxic agent kainate (KA) in rats. Moreover, KA causes a rapid decrease in glutathione (GSH) content of cultured cerebellar granule neurons but not in astrocytes. These cell types both express functional KA receptors, but only the former is sensitive to reactive oxygen species-dependent KA injury. Melatonin counteracts the changes in GSH, induced by KA, in cultured cerebellar granule neurons.

Excitotoxicity, oxidative stress, and the neuroprotective potential of melatonin.

The brain consumes large quantities of oxygen relative to its contribution to total body mass. This, together with its paucity of oxidative defense mechanisms, places this organ at risk for damage mediated by reactive oxygen species. The pineal secretory product melatonin possesses broad-spectrum free radical scavenging and antioxidant activities, and prevents kainic acid-induced neuronal lesions, glutathione depletion, and reactive oxygen species-mediated apoptotic nerve cell death. Melatonin's action is thought to involve electron donation to directly detoxify free radicals such as the highly toxic hydroxyl radical, which is a probable end-product of the reaction between NO. and peroxynitrite. Moreover, melatonin limits NO.-induced lipid peroxidation, inhibits cerebellar NO. synthase, scavenges peroxynitrite, and alters the activities of enzymes that improve the total antioxidative defense capacity of the organism. Melatonin function as a free radical scavenger and antioxidant is likely facilitated by the ease with which it crosses morphophysiological barriers, e.g., the blood-brain barrier, and enters cells and subcellular compartments. Pinealectomy, which eliminates the nighttime rise in circulating and tissue melatonin levels, worsens both reactive oxygen species-mediated tissue damage and brain damage after focal cerebral ischemia and excitotoxic seizures. That melatonin protects against hippocampal neurodegeneration linked to excitatory synaptic transmission is fully consistent with the last study. Conceivably, the decreased melatonin secretion that is documented to accompany the aging process may be exaggerated in populations with dementia.