The effect of constant light and chemical sympathectomy on the development of serotonin, n-acetyltransferase and monoamine oxidase activities in the rat epiphyses.

The daytime activity of N-acetyltransferase per mg epiphysis decreased to 1/10 the newborn level by the age of 13 days, and subsequently remained unchanged. The night activity was equal to the day activity at the age of 3 days, was higher at the age of 6 days and was 20 X that of the day level at the age of 40 days. Keeping animals in constant light after birth depressed the development of these diurnal differences in N-acetyltransferase activity and slowed down the decrease in enzyme activity after birth. Sympathectomy with 6-hydroxydopamine after birth abolished the development of the diurnal rhythm in N-acetyltransferase in 12-day-old rats in two experiments out of five and only decreased the night activity without abolishing the rhythm in three experiments. Monoamine oxidase activity (MAO) per mg epiphysis, which is the same in newly born and in adult animals, decreased to half the original value for 6 days after birth and then increased again. Constant light after birth did not influence MAO activity, but sympathectomy with 6-hydroxydopamine decreased activity in the epiphysis in 12-day-old animals.     

Effects of acute ethanol administration on nocturnal pineal serotonin N-acetyltransferase activity

The effect of acute ethanol administration on pineal serotonin N-acetyltransferase (NAT) activity, norepinephrine and indoleamine content was examined in male rats. When ethanol was administered in two equal doses (2 g/kg body weight) over a 4 hour period during the light phase, the nocturnal rise in NAT activity was delayed by seven hours. The nocturnal pineal norepinephrine content was not altered by ethanol except for a delay in the reduction of NE with the onset of the following light phase. Although ethanol treatment led to a significant reduction in nocturnal levels of pineal serotonin content, there was no significant effect upon pineal content of 5-hydroxyindoleacetic acid (5-HIAA). The data indicate that ethanol delays the onset of the rise of nocturnal pineal NAT activity.     

Pharmacological profile of the "triple" monoamine neurotransmitter uptake inhibitor, DOV 102,677

1. The molecular and behavioral pharmacology of DOV 102,677 is characterized. 2. This characterization was performed using radioligand binding and neurotransmitter uptake assays targeting the monoamine neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, "triple" uptake inhibitor that suppresses [(3)H]dopamine (DA), [(3)H]norepinephrine (NE) and [(3)H]serotonin (5-HT) uptake by recombinant human transporters with IC(50) values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k (i) values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of beta-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days). 4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity. 5. In summary, DOV 102,677 is an orally active, "balanced" inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.     

Entrainment of the circadian rhythm in the rat pineal N-acetyltransferase activity by prolonged periods of light

Summary Entrainment of the circadian rhythm in the pineal N-acetyltranferase activity by prolonged periods of light was studied in rats synchronized with a light:dark regime of 1212 h by observing phase-shifts in rhythm after delays in switching off the light in the evening or after bringing forward of the morning onset of light. When rats were subjected to delays in switching off the light of up to 10 h and then were released into darkness, phase-delays of the evening N-acetyltransferase rise during the same night corresponded roughly to delays in the light switch off. However, phasedelays of the morning decline were much smaller. After a delay in the evening switch off of 11 h, no N-acetyltransferase rhythm was found in the subsequent darkness. The evening N-acetyltransferase rise was phase-delayed by 6.2 h at most 1 day after delays. Phase-delays of the morning Nacetyltransferase decline were shorter than phasedelays of the N-acetyltransferase rise by only 0.7 h to 0.9 h at most. Hence, 1 day after delays in the evening switch off, the period of the high night N-acetyltransferase activity may be shortened only slightly. The N-acetyltransferase rhythm was abolished only after a 12 h delay in switching off the light.Rats were subjected to a bringing forward of the morning light onset and then were released into darkness 4 h before the usual switch off of light. In the following night, the morning N-acetyltransferase decline, but not the evening rise, was phase advanced considerably. Moreover, when the onset of light was brought forward to before midnight, the N-acetyltransferase rise was even phase-delayed. Hence, 1 day after bringing forward the morning onset of light, the period of the high night N-acetyltransferase activity may be drastically reduced. When rats were subjected to a 4 h light pulse around midnight and then released into darkness, the N-acetyltransferase rhythm in the next night was abolished.The data are discussed in terms of a two-component pacemaker controlling the N-acetyltransferase rhythm. It is suggested that delays in the evening switch off of light may disturb the N-acetyltransferase rhythm the next day only a little, as the morning component may adjust to phasedelays of the evening component almost within one cycle. On the other hand, bringing forward the morning onset of light may disturb the N-acetyltransferase rhythm heavily the next day, as the evening component not only does not adjust to phase-advances of the morning component, but it may even be phase-delayed when the light onset occurs before midnight.Abbreviations NAT N-acetyltransferase - PRC phase response curve - E evening component of the N-acetyltransferase rhythm or of its pacemaker - M morning component of the N-acetyltransferase rhythm or of its pacemaker - LD xy light dark cycle comprising x h of light and y h of darkness     

Cold prevents the light induced inactivation of pineal N-acetyltransferase in the Djungarian hamster,Phodopus sungorus

Summary In the Djungarian hamster seasonal acclimatization is primarily controlled by photoperiod, but exposure to low ambient temperature amplifies the intensity and duration of short day-induced winter adaptations. The aim of this study was to test, whether the pineal gland is involved in integrating both environmental cues. Exposure of hamsters to cold (0 °C) reduces the sensitivity of the pineal gland to light at night and prevents inactivation of N-acetyltransferase (NAT). The parallel time course of NAT activity and plasma norepinephrine content suggests that circulating catecholamines may stimulate melatonin synthesis under cold load.Abbreviations NAT N-acetyltransferase - NE norepinephrine - T _a ambient temperature     

Darkness-induced changes in noradrenergic input determine the 24 hour variation in beta-adrenergic receptor density in the rat pineal gland: in vivo physiological and pharmacological evidence

In male rats housed under a 14:10 LD cycle (lights on at 0600 h), pineal beta-adrenergic receptors, assessed as 125Iodopindolol (IPIN) binding to membrane preparations, showed a 24 hour variation characterized by a nocturnal increase that peaked around middark (2300 h-0200 h) and a decrease during the latter half of the dark period. Animals exposed to light for 3 hours into the normal dark period showed a similar increase in IPIN binding that was prevented by a single sc injection (0.5 mg/kg) of isoproterenol (ISO). The decrease in IPIN binding observed after middark was prevented both by moving the animals to light at 0200 h and by propranolol administration (20 mg/kg). Likewise, the reduction in IPIN binding was induced in light exposed animals both by ISO administration (in a dose dependent manner) and by injection of norepinephrine (NE) plus the catecholamine uptake blocker desmethylimipramine (DMI). DMI alone was without effect. Chronic denervation of the pineal gland by superior cervical ganglionectomy (SCGx) increased IPIN binding to levels not higher than those observed at middark. The results suggest that rat pineal beta-adrenergic receptors are regulated in a rhythmic 24 hour pattern. A decrease in density (downregulation) induced by a darkness-associated increase in NE release, occurs late in the night before lights on; recovery from the down regulated state (upregulation) occurs during the light and early dark phase, reaching a maximum density of beta-adrenergic receptors at middark not different from that observed in chronically denervated pineal glands.     

Hemodynamic and cardiac actions of trazodone and imipramine in the anesthetized dog.

The relative cardiovascular effects of trazodone and imipramine were compared in two open-chest, anesthetized dog models. Trazodone lowered arterial blood pressure (0.3 mg/kg), slowed heart rate (3 mg/kg) and reduced myocardial contractile force (3–10 mg/kg) following i.v. administration. Low i.v. doses (0.05–0.15 mg/kg) of imipramine increased arterial blood pressure and heart rate, presumably as a consequence of its known anticholinergic properties and/or effects on neuronal catecholamine re-uptake mechanisms. Subsequent to administration of 1.5 and 5 mg/kg, however, the vascular and myocardial depressant effects of imipramine were evident. Trazodone (1–10 mg/kg, i.v.), unlike imipramine, effected a substantial level of $\text{alpha}$-adrenergic blockade $\text{vs.}$ a fixed challenge dose of norepinephrine, although less than that associated with phentolamine. Both trazodone and imipramine reduced aortic flow although $\text{via}$ different mechanisms. The reduction following administration of trazodone resulted from a decrease in heart rate whereas imipramine depressed aortic flow by lowering stroke volume.     

Delta-Sleep-Inducing Peptide and Two of Its Analogs Reduce Nocturnal Increase of N-Acetyltransferase Activity in Rat Pineal Gland

Serotonin N-acetyltransferase, an enzyme of the pineal gland, converts serotonin to N-acetylserotonin. The activity of this enzyme is induced by norepinephrine in the evening to reach high levels during the dark phase. Delta-sleep-inducing peptide, a humoral sleep factor, also seems to affect circadian rhythms. Intravenous injection of this peptide or either of two of its analogs in the evening significantly reduced the increase of N-acetyltransferase 4 h later. The dose-response relationship of the peptides showed an inverted U-shaped pattern with the active dose about 30 nmol/kg. The effect appears to be dependent on the time of day of administration, as injections in the morning did not change the enzymatic activity. These findings indicate that delta-sleep-inducing peptide (and two of its analogs) can affect enzymatic activities and that these influences probably vary throughout a time period of 24 h.     

Are spontaneous activity and supraspinal control co-responsible for functional development of the generator of embryonic motility?

The effect of chronic administration of phenobarbital (from the 4th to the 16th day of incubation) combined with chronic spinal decentralization (decapitation at stage 11-13) on the development of spontaneous motor activity (recorded on the 17th day of incubation) was studied in 4 to 17-day-old chick embryos. 1. Combination of the two experimental treatments led to summation of their negative effect on development; spontaneous motor activity fell to 15.2% of the control value (to 26.9% after the isolated administration of phenobarbital and to 30.5% after isolated decapitation). 2. Metrazol activation of motor activity (100 mg/kg egg weight) after combination of the two factors was relatively no different from the results after their isolated use. 3. The acute administration of GABA (100 mg/kg e.w.) likewise induced relatively the same depression of spontaneous motility as after isolated chronic decapitation and the isolated chronic administration of phenobarbital. The results confirm the hypothesis of the significance of spontaneous activity of the spinal motoneurones for their survival and their actual functional development during the embryonic period.     

Interactions of nimodipine and cocaine on endogenous catecholamines in the squirrel monkey

The effects of nimodipine on the cocaine-induced alterations in blood pressure, heart rate, and plasma catecholamines were studied in the squirrel monkey. Cocaine in intravenously administered doses of 0.5, 1, and 2 mg/kg produced significant increases in blood pressure and significant decreases in heart rate. These cardiovascular changes were associated with transient episodes of arrhythmias and with significant increases in plasma concentrations of dopamine, epinephrine, and norepinephrine. Nimodipine, 1 micrograms/kg/min for 5 min administered intravenously 5 min after cocaine, corrects the cardiovascular and plasma catecholamine concentration changes induced by this alkaloid. The same dose of nimodipine administered 5 min before cocaine prevents elevations of blood pressure. Plasma catecholamine increments are also prevented except for the highest dose of cocaine. Cardiovascular changes induced by cocaine administration in the squirrel monkey are temporally associated with significant increments in plasma catecholamines. Administration of nimodipine prevents or minimizes these endocrine and physiologic changes.     

Pharmacological Profile of the “Triple” Monoamine Neurotransmitter Uptake Inhibitor, DOV 102,677

Summary 1. The molecular and behavioral pharmacology of DOV 102,677 is characterized.2. This characterization was performed using radioligand binding and neurotransmitter uptake assays targeting the monoamine neurotransmitter receptors. In addition, the effects of DOV 102,677 on extracellular neurotransmitter levels were investigated using in vivo microdialysis. Finally, the effects of DOV 102,677 in the forced swim test, locomotor function, and response to prepulse inhibition was investigated.3. DOV 102,677 is a novel, “triple” uptake inhibitor that suppresses [³H]dopamine (DA), [³H]norepinephrine (NE) and [³H]serotonin (5-HT) uptake by recombinant human transporters with IC₅₀ values of 129, 103 and 133 nM, respectively. Radioligand binding to the dopamine (DAT), norepinephrine (NET), and serotonin (SERT) transporters is inhibited with k _i values of 222, 1030, and 740 nM, respectively. DOV 102,677 (20 mg/kg IP) increased extracellular levels of DA and 5-HT in the prefrontal cortex to 320 and 280% above baseline 100 min after administration. DA levels were stably increased for the duration (240 min) of the study, but serotonin levels declined to baseline by 200 min after administration. NE levels increased linearly to a maximum of 348% at 240 min post-dosing. Consistent with these increases in NE levels, the density of β-adrenoceptors was selectively decreased in the cortex of rats treated with DOV 102,677 (20 mg/kg per day, PO, 35 days).4. DOV 102,677 dose-dependently reduced the amount of time spent immobile by rats in the forced swim test, a model predictive of antidepressant activity, with a minimum effective dose (MED) of 20 mg/kg and a maximal efficacy comparable to imipramine. This decrease in immobility time did not appear to result from increased motor activity. Further, DOV 102,677 was as effective as methylphenidate in reducing the amplitude of the startle response in juvenile mice, without notably altering motor activity.5. In summary, DOV 102,677 is an orally active, “balanced” inhibitor of DAT, NET and SERT with therapeutic versatility in treating neuropsychiatric disorders beyond depression.     

Near-ultraviolet radiation suppresses melatonin synthesis in the chicken retina: a role of dopamine

Effects of near-ultraviolet radiation (UV-A; 325-390 nm, peak at 365 nm) on melatonin content and activity of serotonin N-acetyltransferase (AA-NAT; a key regulatory enzyme in melatonin biosynthesis) were examined in the retina of chickens. Acute exposure of dark-adapted animals to UV-A light produced a marked decline in melatonin content and AA-NAT activity of the retina. The magnitude of the observed changes was dependent upon duration of the light pulse and age of chickens, with 1-2-week old birds being more sensitive to UV-A action than 6-7-week old ones. The decrease in the nocturnal AA-NAT activity evoked by a 5-min UV-A pulse gradually deepened during the first 30 min after the return of chickens to constant darkness, then the enzyme activity began to rise, reaching nearly complete restoration within 2.5 hr. Systemic administration to chickens of alpha-methyl-p-tyrosine (an inhibitor of catecholamine synthesis; 0.3 g/kg) blocked the suppressive effect of UV-A light on retinal AA-NAT activity. Haloperidol, sulpiride (blockers of D2-family of dopamine (DA) receptors) and 2-chloro-11-(4-methylpiperazino)dibenz[b,f]oxepin (an antagonist of D4-DA receptors), given intraocularly (1-100 nmol/eye) prevented the UV-A light-evoked decrease in AA-NAT activity in the chicken retina in a dose-dependent manner, while raclopride (300 nmol/eye), an antagonist of D2/D3-DA receptors, was ineffective. In dark-adapted chickens exposure to UV-A light increased the DA content of the retina. It is concluded that UV-A radiation, similar to visible light, potently suppresses melatonin biosynthesis in the retina of chicken, with a D4-dopaminergic signal playing the role of an intermediate in this action.     

Serotonin phase-shifts the circadian rhythm of locomotor activity in the cockroach

Serotonin, a putative neurotransmitter in insects, was found to cause consistent phase shifts of the circadian rhythm of locomotor activity of the cockroach Leucophaea maderae when administered during the early subjective night as a series of 4-microliters pulses (one every 15 min) for either 3 or 6 hr. Six-hour treatments with dopamine also caused significant phase shifts during the early subjective night, but 3-hr treatments with dopamine had no phase-shifting effect. Other substances tested in early subjective night (norepinephrine, octopamine, gamma-aminobutyric acid, glutamate, carbachol, histamine, tryptophan, tryptamine, N-acetyl serotonin, or 5-hydroxyindole-3-acetic acid) did not consistently cause phase shifts. The phase-shifting effect of serotonin was found to be phase-dependent. The phase response curve (PRC) for serotonin treatments was different from the PRC for light. Like light, serotonin caused phase delays in the late subjective day and early subjective night, but serotonin did not phase-shift rhythms when tested at phases where light causes phase advances.     

Photoperiod modifies daily maps of light and dark sensitivity for N-acetyltransferase activity in pineal glands of 3-week oldGallus domesticus

Summary N-acetyltransferase (NAT) activity in pineal glands exhibits a circadian rhythm with peak activity occurring in the dark-time. We previously showed that inGallus domesticus chicks pretreated with LD12:12, NAT activity was increased by dark exposure (peak dark sensitivity occurred during the expected dark-time) or decreased by light at night (peak light sensitivity occurred early in the night during the time of dark sensitivity). In this study we mapped dark sensitivity vs time (for NAT activity increase in response to 2 h dark pulses), and light sensitivity vs time (for NAT activity decrease in response to 10 min or 30 min light pulses) over a cycle for 3-week old chicks,Gallus domesticus, pretreated with long (LD16:8) or short photoperiod (LD8:16). Sensitivity to light was increased in the second 8 h after L/D by LD8:16. Sensitivity to dark was increased in the first 8 h after L/D by LD16:8.Abbreviations LD16:8 a light-dark cycle consisting of 16 h of light alternating with 8 h of dark - LD8:16 a light-dark cycle consisting of 8 h of light alternating with 16 h of dark - DD constant dark - LL constant light - L/D lights-off - D/L lights-on - NAT pineal serotonin N-acetyltransferase - NAT activity is given in nmoles/pineal gland/h - chick used here to denote a young bird of either sex of the speciesGallus domesticus from hatching to three weeks of age     

Chick pineal melatonin synthesis: light and cyclic AMP control abundance of serotonin N-acetyltransferase protein

Melatonin production in the pineal gland is high at night and low during the day. This rhythm reflects circadian changes in the activity of serotonin N-acetyltransferase [arylalkylamine N-acetyltransferase (AA-NAT); EC 2.3.1.87], the penultimate enzyme in melatonin synthesis. The rhythm is generated by an endogenous circadian clock. In the chick, a clock is located in the pinealocyte, which also contains two phototransduction systems. One controls melatonin production by adjusting the clock and the other acts distal to the clock, via cyclic AMP mechanisms, to switch melatonin synthesis on and off. Unlike the clock in these cells, cyclic AMP does not appear to regulate activity by altering AA-NAT mRNA levels. The major changes in AA-NAT mRNA levels induced by the clock seemed likely (but not certain) to generate comparable changes in AA-NAT protein levels and AA-NAT activity. Cyclic AMP might also regulate AA-NAT activity via changes in protein levels, or it might act via other mechanisms, including posttranslational changes affecting activity. We measured AA-NAT protein levels and enzyme activity in cultured chick pineal cells and found that they correlated well under all conditions. They rose and fell spontaneously with a circadian rhythm. They also rose in response to agents that increase cyclic AMP. They were raised by agents that increase cyclic AMP, such as forskolin, and lowered by agents that decrease cyclic AMP, such as light and norepinephrine. Thus, both the clock and cyclic AMP can control AA-NAT activity by altering the total amount of AA-NAT protein. Effects of proteosomal proteolysis inhibitors suggest that changes in AA-NAT protein levels, in turn, reflect changes in the rate at which the protein is destroyed by proteosomal proteolysis. It is likely that cyclic AMP-induced changes in AA-NAT protein levels mediate rapid changes in chick pineal AA-NAT activity. Our results indicate that light can rapidly regulate the abundance of a specific protein (AA-NAT) within a photoreceptive cell.     

Differential regulation of the brain and gut immunoreactive dynorphin by the serotonin system

Administration of drugs such as fenfluramine, 20-40 mg/kg, and m-chlorophenylpiperazine (m-CPP), 2.5-5 mg/kg, which release serotonin or activate postsynaptic serotonin receptors, respectively, induced a dramatic decrease in the duodenal content of immunoreactive dynorphin (ir-DYN). The effect was antagonized by cyproheptadine, 1 mg/kg. Similarly, acute administration of the specific serotonin reuptake blockers fluvoxamine, 15 mg/kg, or femoxetine, 10 mg/kg, and 5-hydroxytryptophan (5-HTP), 40-160 mg/kg, evoked a marked decrease in the duodenal content of ir-DYN. A combined administration of fluvoxamine or femoxetine and 5-HTP failed to potentiate the effect of individual treatment. Only a higher dose of fenfluramine, 40 mg/kg, increased the ir-DYN content in the hypothalamus. These results suggest that the brain and gut ir-DYN is independently regulated by the serotonin system and that a serotonin mechanism might stimulate release of the gut dynorphin content.     

EFFECT OF γ-AMINOBUTYRIC ACID ON BRAIN SEROTONIN AND CATECHOLAMINES

—Intraperitoneal injections of GABA (5 mg/kg) to rats lowered the level of norepinephrine in brain, heart and spleen but not suprarenals and raised that of serotonin in brain. Changes of these monoamines were most pronounced in the hypothalamic region after 20min. A reduction of hypothalamic norepinephrine was also observed 15min following the intracarotid administration of 0·5 mg/kg of GABA. In these experiments there was a concomitant increase in the level of free GABA in the anterior portion of the ventral hypothalamus. Brain dopamine level and 5-hydroxytryptophan decarboxylase, dihydroxyphenylalanine decarboxylase and monoamine oxidase activities were not affected. The 20 per cent increase of endogenous GABA observed in the midbrain 30 min following the administration of amino-oxyacetic acid was accompanied by a sharp fall in norepinephrine level (39 per cent) and an increase in serotonin (20 per cent). In in vitro studies 10–300 μg/ml of GABA were shown to release norepinephrine from cortical and hypothalamic slices, and to inhibit serotonin release without affecting 5-hydroxytryptophan uptake and to have no effect on the release of dopamine from slices of the region of the corpus striatum nor on the activity of the enzymes mentioned. Subcellular studies showed that the particulate:supernatant ratio for norepinephrine was reduced from a control value of 2·04 to 1·75 and that of serotonin was raised from 2·8 to 3·5. Following pretreatment with iproniazid, GABA reduced the raised level of brain norepinephrine to a greater extent than reserpine but not as intensively as amphetamine. The results obtained suggest that these monoamines may be involved in the mechanisms underlying the action of GABA in brain and that the effect of GABA on brain monoamines may be of certain significance in synaptic events.     

Mechanism of prolactin release by 5-hydroxytryptophan

Male Wistar rats were intraperitoneally administered 300 mg/kg b.w. of α-methyl-p-tyrosine methyl ester(α-MT). These α-MT pretreated rats were anesthetized with urethane and then 5% glucose or dopamine (1 μg/kg b.w./min) was infused for 45 min. At 1 min before or 15 min after dopamine infusion, 10 or 50 mg/kg of 5-hydroxytryptophan (5-HTP) was injected intraperitoneally, and blood samples were taken from the jugular vein for prolactin determination. In rats treated with α-MT, the administration of 5-HTP increases the serum prolactin level in a dose-related manner. Dopamine infusion caused a marked decrease in serum prolactin level. The concomitant administration of dopamine and 5-HTP prevented the dopamine-induced decrease of serum prolactin in α-MT treated rats. These results indicate that the serotonergic stimulus enhanced prolactin release, not by inhibiting the dopaminergic activity, but by stimulating a prolactin-releasing factor or by activating other neurotransmitter systems.     

Effect of melatonin on hyperlipidemic nephropathy under constant light exposure

Studies have shown anti-hyperlipidemic actions of melatonin, with pharmacological doses inducing changes in cholesterol levels. This study was designed to evaluate the effect of melatonin on adriamycin-induced (25mg/kg b.w., i.p.) hyperlipidemia under constant light exposure. Melatonin was injected i.p. (1,000 microg/kg b.w./day). Triglycerides, total cholesterol, high-density lipoprotein cholesterol, light-density lipoprotein cholesterol, non-proteic nitrogen compounds (urea and creatinine levels), total protein in serum, proteins eliminated in the urine and melatonin levels in serum and kidney were determined. Results show a decrease in melatonin levels induced by both adriamycin and constant light. Likewise, adriamycin induced significant increases in triglycerides, total cholesterol and light-density lipoprotein cholesterol, and lowered high-density lipoprotein cholesterol levels. Constant light exposure also prompted an increase in LDL-c levels and a decrease in HDL-c values, and intensified the effects of adriamycin on these two lipoproteins. All changes induced by adriamycin and constant light were reverted toward normality by melatonin administration.     

Protective effect of curcumin nanoparticles against cardiotoxicity induced by doxorubicin in rat

The present study designed to investigate the protective effect of curcumin nanoparticles (CUR-NPs) on the cardiotoxicity induced by doxorubicin. Rats were divided into four groups; control, rats treated daily with CUR-NPs (50 mg/kg) for 14 days, rats treated with an acute dose of doxorubicin (20 mg/kg) and rats treated daily with CUR-NPs for 14 days injected with doxorubicin on the 10th day. After electrocardiogram (ECG) recording from rats at different groups, rat decapitation was carried out and the heart of each rat was excised out to measure the oxidative stress parameters; lipid peroxidation (MDA), nitric oxide (NO) and reduced glutathione (GSH) and the activities of Na,K,ATPase and acetylcholinesterase (AchE). In addition, the levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) were determined in the cardiac tissues. Lactate dehydrogenase (LDH) activity was measured in the serum. The ECG recordings indicated that daily pretreatment with CUR- NPs has prevented the tachycardia (i.e. increase in heart rate) and ameliorated the changes in ST wave and QRS complex induced by doxorubicin. In addition, CUR-NPs prevented doxorubicin induced significant increase in MDA, NO, DA, AchE and LDH and doxorubicin induced significant decrease in GSH, NE, 5-HT and Na,K,ATPase. According to the present findings, it could be concluded that CUR-NPs have a protective effect against cardiotoxicity induced by doxorubicin. This may shed more light on the importance of CUR-NPs pretreatment before the application of doxorubicin therapy.