Administration Of 5-hydroxytryptophan Research Articles

The States of Different 5-HT Receptors Located in the Dorsal Raphe Nucleus Are Crucial for Regulating the Awakening During General Anesthesia.

General anesthesia is widely used in various clinical practices due to its ability to cause loss of consciousness. However, the exact mechanism of anesthesia-induced unconsciousness remains unclear. It is generally thought that arousal-related brain nuclei are involved. 5-Hydroxytryptamine (5-HT) is closely associated with sleep arousal. Here, we explore the role of the 5-HT system in anesthetic awakening through pharmacological interventions and optogenetic techniques. Our data showed that exogenous administration of 5-hydroxytryptophan (5-HTP) and optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DR) could significantly shorten the emergence time of sevoflurane anesthesia in mice, suggesting that regulation of the 5-HT system using both endogenous and exogenous approaches could mediate delayed emergence. In addition, we first discovered that the different 5-HT receptors located in the DR, known as 5-HT autoreceptors, are essential for the regulation of general anesthetic awakening, with 5-HT1A and 5-HT2A/C receptors playing a regulatory role. These results can provide a reliable theoretical basis as well as potential targets for clinical intervention to prevent delayed emergence and some postoperative risks.

A diabetes-like biochemical and behavioural phenotype of Drosophila induced by predator stress.

Predation can have both lethal and non-lethal effects on prey. The non-lethal effects of predation can instil changes in prey life history, behaviour, morphology and physiology, causing adaptive evolution. The chronic stress caused by sustained predation on prey is comparable to chronic stress conditions in humans. Conditions like anxiety, depression, and post-traumatic stress syndrome have also been implicated in the development of metabolic disorders such as obesity and diabetes. In this study, we found that predator stress induced during larval development in fruit flies Drosophila melanogaster impairs carbohydrate metabolism by systemic inhibition of Akt protein kinase, which is a central regulator of glucose uptake. However, Drosophila grown with predators survived better under direct spider predation in the adult phase. Administration of metformin and 5-hydroxytryptophan (5-HTP), a precursor of the neurotransmitter serotonin, reversed these effects. Our results demonstrate a direct link between predator stress and metabolic impairment, suggesting that a diabetes-like biochemical phenotype may be adaptive in terms of survival and reproductive success. We provide a novel animal model to explore the mechanisms responsible for the onset of these metabolic disorders, which are highly prevalent in human populations.

Oral Administration of 5-Hydroxytryptophan Restores Gut Microbiota Dysbiosis in a Mouse Model of Depression.

5-Hydroxytryptophan (5-HTP) has positive clinical effects on various neuropsychiatric and metabiotic disorders, especially depression. Although it increases serotonin levels in the brain and gastrointestinal tract, its pharmacology remains largely unknown. Our goal was to determine the effects of 5-HTP on the mouse gut microbiome, which has a close relationship with depression through the “microbiota-gut-brain axis.” We confirmed that depressive disorder restructures the gut microbial community, and 5-HTP efficiently improves depressive symptoms in mice. Oral administration of 5-HTP significantly restored gut microbiota dysbiosis in mice with depression-like behaviors. The diversity and richness of gut microbial communities and relative abundance of specific microbial taxa at both phylum and genus levels were partially recovered. 5-HTP exhibited some positive effects on restoring the alterations in the concentrations of short-chain fatty acids and brain-derived neurotrophic factors caused by depression in mice. Our results may provide new insights into the pharmacology of 5-HTP in treating depression and other disorders.

Residual effects of abomasal 5-hydroxytryptophan administration on serotonin metabolism in cattle

Studies of serotonin in animal husbandry has received growing interest. However, there is limited information about serotonin manipulation using 5-HTP administered postruminally and its residual effects in cattle. The objective of this study was to evaluate the effectiveness of 5-HTP infused into the abomasum for enhancing circulating serotonin in cattle. Four Holstein steers (487 ± 7.6 kg) fitted with ruminal cannulas were used in a 4 × 4 Latin Square design experiment. The treatments were intra-abomasal infusion of 5-HTP at 0, 0.25, 0.5, and 1 mg/kg BW. Blood was collected from the jugular vein of each steer at -60, -30, 0, 30, 60, 120, 240, and 480 min from 5-HTP infusion for basal and short term evaluation and, at 1, 2, 4, and 7 d after 5-HTP infusion for long term evaluation. Dry matter intake was not affected (P > 0.05) by intra-abomasal infusions. The half-life of 5-HTP was dose-independent (128 min). The serum 5-HTP, serotonin, and 5-hydroxyindoleacetic acid area under the curve increased (P < 0.05) linearly with an increased dose of 5-HTP. Serum 5-HTP reached peak concentration in approximately 30 min after dosing while serum and plasma serotonin peaked after 240 min postinfusion. Serotonin was greater than control for all 5-HTP doses 1 d and 2 d after infusion in serum and plasma, respectively. Intra-abomasal infusion of 5-HTP at doses up to 1 mg/ kg BW increases circulating serotonin for up 2 days.

The Effects of 5-Hydroxytryptophan on Pain Following Formalin Administration

The aim of the study was to investigate the effect of repeated administration of 5-Hydroxytryptophan (5-HTP) on pain sensation. The quantity of 5-HTP reaching the Central Nervous System (CNS) is affected by the extent to which 5-HTP is converted to serotonin in the periphery. The formalin test was used to access pain perception using two groups of mice weighing 22g-32g (n=10 each). The control group received (15g) normal rodent chow, while the test group received (15g w/w) 5-HTP diet. Daily food intake, water intake and body weight change were measured. The results in the formalin test, showed that the frequency and duration of paw attention and paw lick in both phases of the test was significantly lower (P< 0.05) in the 5-Hydroxytryptophan group (5-HTP) compared to the control. Therefore, repeated administration of 5-Hydroxytryptophan diet decreases pain perception in mice.

Improved strength on 5-hydroxytryptophan and carbidopa in spinal cord atrophy

There is ample evidence of an important role of descending serotonergic projections in modulating spinal motor neuron activation and firing, and experimental studies suggest that 5-HT receptor stimulation can improve motor function after spinal cord injury; however, relevant clinical data is sorely lacking. We describe two sisters with hemiplegic migraine, low CSF and platelet serotonin levels, and progressive spastic paraparesis associated with profound spinal cord atrophy whose lower extremity strength and ambulation responded to a precursor replacement strategy (5-hydroxytryptophan and carbidopa administration), an approach that may have broader applicability in myelopathies of diverse etiology where descending serotonergic projections are compromised.

Action of naftopidil on spinal serotonergic neurotransmission for inhibition of the micturition reflex in rats.

We examined the mechanism of action of naftopidil, an α1D/A blocker, on spinal descending serotonergic neurotransmission for the micturition reflex. We examined (1) urinary 5-hydroxyindole acetic acid (5-HIAA) after intraperitoneal administration of saline, para-chlorophenylalanine (PCPA; a serotonin synthetic enzyme inhibitor), and/or 5-hydroxytryptophan (5-HTP; a serotonin precursor); (2) isovolumetric cystometry after intraperitoneal administration of saline, PCPA, and/or 5-HTP and intravenous injection of naftopidil; and (3) isovolumetric cystometry before and after intrathecal administration of serotonin (5-HT) receptor antagonists and intravenous injection of naftopidil. PCPA decreased and 5-HTP increased urinary 5-HIAA/creatinine. Intraperitoneal injection of PCPA did not influence cystometric parameters. Intraperitoneal injection of 5-HTP significantly shortened the interval between bladder contractions. Intravenous injection of naftopidil transiently abolished bladder contractions. However, the duration of abolishment of bladder contractions after injection of naftopidil in rats given PCPA was significantly shorter than that in rats given vehicle, but significantly longer than that in rats given PCPA and 5-HTP. Intrathecal injection of 5-HT1B, 5-HT3, or 5-HT7 receptor antagonists significantly prolonged the interval between bladder contractions. Intrathecal injection of 5-HT1D or 5-HT2B receptor antagonists significantly shortened the interval between bladder contractions. Combined administration of the maximum non-effective dose of 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, or 5-HT3 receptor antagonists and intravenous injection of naftopidil significantly shortened the duration of abolishment of bladder contraction compared to intravenous injection of naftopidil alone. Naftopidil may inhibit the micturition reflex via 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT3 receptors in the spinal cord. Neurourol. Urodynam. 36:604-609, 2017. © 2016 Wiley Periodicals, Inc.

Activation of brain serotonergic system by repeated intracerebral administration of 5-hydroxytryptophan (5-HTP) decreases the expression and activity of liver cytochrome P450

Our recent studies suggest that brain serotonergic system may be involved in the neuroendocrine regulation of cytochrome P450 expression. Intracerebral injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine affected serum hormone concentration and increased the expression and activity of the hormone-dependent isoforms CYP1A1/2, CYP2C11 and CYP3A1. Therefore, the aim of the present study was to investigate the effect of stimulation of brain serotonergic system on cytochrome P450 expression in the liver. The serotonin precursor 5-hydroxytryptophan (5-HTP) was injected for 5 days to the lateral ventricles of rat brain. Afterwards, the brain concentrations of serotonin and its metabolite 5-hydroxyindoleacetic acid 5-HIAA, serum hormone levels and liver cytochrome P450 expression and activity were measured. 5-HTP potently increased the concentration of serotonin and its metabolite 5-HIAA in all the brain structures studied including the hypothalamus. The brain concentrations of noradrenaline or dopamine and its metabolites were not changed in that structure. At the same time, a significant decrease in the serum concentration of the growth hormone and an increase in that of thyroxine were observed. In the liver, the activity of CYP1A, CYP2A, CYP2B, CYP2C11 and CYP3A was diminished, which positively correlated with a decrease in the respective CYP protein levels and a reduction in the mRNA levels of CYP1A2, CYP2A2, CYP2C11, CYP3A1 and CYP3A2. The obtained results provide evidence to prove that brain serotonergic system negatively regulates liver cytochrome P450 expression via endocrine system and suggest mechanisms by which this enzyme may be regulated by drugs with a serotonergic profile such as antidepressants.

Flos Albiziae aqueous extract and its active constituent quercetin potentiate the hypnotic effect of pentobarbital via the serotonergic system.

Flos albiziae (FA) is reportedly used for treatment of insomnia and anxiety in traditional medicine. The hypnotic effect of an extract of FA (FAE) and its constituent quercetin [2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one, QR] was examined in mice. QR is a widely distributed natural flavonoid abundant in FA flowers and other tissues. The possible mechanisms underlying the hypnotic effects of FAE and QR were investigated using behavioral pharmacology. FAE and QR significantly potentiated pentobarbital-induced [50 mg/kg, intraperitoneal (ip)] sleep (prolonged sleeping time; shortened sleep latency) in a dose-dependent manner, and these effects were augmented by administration of 5-hydroxytryptophan (5-HTP), a precursor of 5-hydroxytryptamine. With a sub-hypnotic dose of pentobarbital (28 mg/kg, ip), FAE and QR significantly increased the rate of sleep onset and were synergistic with 5-HTP (2.5 mg/kg, ip). Pretreatment with p-chlorophenylalanine, an inhibitor of tryptophan hydroxylase, significantly decreased sleeping time and prolonged sleep latency in pentobarbital-treated mice, whereas FAE and QR significantly reversed this effect. Data show that FAE and QR have hypnotic activity, possibly mediated by the serotonergic system. The present study offers a rationale for the use of FA in treating sleep disorders associated with serotonin system dysfunction.

The Effect Of 5-hydroxytryptophan (5-htp) And Intense Exercise On Plasma And Salivary Cortisol

Background: Oral administration of 5-hydroxytryptophan (5-HTP), the precursor of serotonin, has been reported to stimulate the Hypothalamic-Adrenal Axis resulting in increased cortisol in healthy volunteers and clinical populations. Exercise is known to stimulate the cortisol secretion, whether pre-exercise 5-HTP enhances the cortisol response to intense exercise is not yet known. PURPOSE: The purpose of this study was to examine the effect of 5-HTP and a graded exercise test to maximal effort (EX) on plasma (PL) and salivary(SA) cortisol in 9 healthy young volunteers (7M/2F). METHODS: Each subject completed an EX trial in the evening spaced at least 5 days apart, one under placebo and another under 5-HTP (200mg capsule 90-120 min prior to testing). The study was randomized double-blinded trial. Capillary and SA samples were obtained at rest before exercise (EX0), at 5 (Post-EX5) and at 20 (Post-EX20) minutes post-exercise. An ANOVA for crossover experimental design and t-tests were used to determine differences in PL and SA cortisol concentrations between placebo vs 5-HTP trials, and to determine if plasma and salivary cortisol increased over time, respectively. Cortisol was analyzed by enzyme immunoassays. RESULTS: There was a significant increase in plasma cortisol in the placebo (EX0: 265 ± 67 nM vs Post-EX20: 664 ± 78 nM; p<0.001) and in the 5-HTP trial (EX0: 349 ± 58 nM vs Post-EX20: 567 ± 81 nM, p< 0.001). Similarly, there was a significant increase in SA cortisol in the placebo (EX0: 1.26 ± 0.20 nM, Post-EX20: 8.63 ± 1.96 nM; p<0.01) and in the 5-HTP trial (EX0: 3.96 ± 1.73 nM vs Post-EX20: 9.57 ± 2.96 nM, p< 0.01). However, there was no treatment effect for cortisol in either media nor was there a treatment effect at baseline (p>0.05). CONCLUSIONS: Under the present experimental conditions, there was no difference between placebo and 5-HTP. There was an increase from EX0 to Post-EX20 for both placebo and 5-HTP. Increasing sample size, and examining higher 5-HTP dosage regimen are warranted.

Oral administration of 5-hydroxytryptophan aggravated periodontitis-induced alveolar bone loss in rats

Objective5-Hydroxytryptophan (5-HTP) is the precursor of serotonin and 5-HTP has been widely used as a dietary supplement to raise serotonin level. Serotonin has recently been discovered to be a novel and important player in bone metabolism. As peripheral serotonin negatively regulates bone, the regular take of 5-HTP may affect the alveolar bone metabolism and therefore influence the alveolar bone loss induced by periodontitis. The aim of this study was to investigate the effect of 5-HTP on alveolar bone destruction in periodontitis. DesignMale Sprague-Dawley rats were randomly divided into the following four groups: (1) the control group (without ligature); (2) the 5-HTP group (5-HTP at 25mg/kg/day without ligature); (3) the L group (ligature+saline placebo); and (4) the L+5-HTP group (ligature+5-HTP at 25mg/kg/day). Serum serotonin levels were determined by ELISA. The alveolar bones were evaluated with micro-computed tomography and histology. Tartrate-resistant acid phosphatase staining was used to assess osteoclastogenesis. The receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG) expression in the periodontium as well as the interleukin-6 positive osteocytes were analysed immunohistochemically. Results5-HTP significantly increased serum serotonin levels. In rats with experimental periodontitis, 5-HTP increased alveolar bone resorption and worsened the micro-structural destruction of the alveolar bone. 5-HTP also stimulated osteoclastogenesis and increased RANKL/OPG ratio and the number of IL-6 positive osteocytes. However, 5-HTP treatment alone did not cause alveolar bone loss in healthy rats. ConclusionThe present study showed that 5-HTP aggravated alveolar bone loss, deteriorated alveolar bone micro-structure in the presence of periodontitis, which suggests 5-HTP administration may increase the severity of periodontitis.

Short prolactin profile for monitoring treatment in BH4 deficiency

Tetrahydrobiopterin (BH4) deficiency causes hyperphenylalaninemia and impaired synthesis of serotonin and dopamine, leading to brain degeneration and early death if left untreated. Replacement therapy with neurotransmitters precursors is the cornerstone of treatment, relying on 5-hydroxytryptophan and l-dopa administration. Effective restoration of dopaminergic activity is thickened, like in Parkinson's disease, by the pulsatile pharmacokinetic profile of l-dopa. Monitoring of l-dopa therapy in BH4 deficiency is generally based upon clinical observation and periodical measurement of homovanillic acid (HVA) concentration in the cerebrospinal fluid (CSF). According to the finding that dopamine is the natural inhibitor of prolactin (PRL) incretion, we introduced the use of peripheral PRL measurement as an index of dopaminergic homeostasis, so avoiding the need of repeated lumbar punctures in patients with BH4 deficiency. As a single PRL evaluation can be misleading, due to the dependency of PRL fluctuations on l-dopa administration schedule, here we show that a short PRL profile is suitable for monitoring these patients. Together with the assessment of patients' clinical symptoms, this standardized tool will ensure an objective non-invasive reference to the management of dopaminergic replacement therapy in BH4 deficiency, even in patients treated with dopamine agonists.

Ferulic acid potentiates pentobarbital-induced sleep via the serotonergic system

Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA) is a widely distributed natural phenolic compound that is abundant in many plant tissues and foods. This study investigated possible mechanisms underlying the sedative–hypnotic effect of FA through behavioral pharmacology methods. FA showed dose-dependent sedative effects on locomotion activity in normal mice. FA also significantly potentiated pentobarbital-induced (45mg/kg, i.p.) sleep by prolonging sleeping time and shortening sleep latency in a dose-dependent manner. These effects were augmented by the administration of 5-hydroxytryptophan (5-HTP), a precursor of 5-hydroxytryptamine (5-HT). With a sub-hypnotic dose of pentobarbital (25mg/kg, i.p.), FA significantly increased the rate of sleep onset and exhibited a synergistic effect with 5-HTP (2.5mg/kg, i.p.). Pretreatment with p-chlorophenylalanine (PCPA, an inhibitor of tryptophan hydroxylase) significantly decreased the duration of pentobarbital-induced sleep, whereas FA significantly reversed this effect. These results suggest that FA has sedative–hypnotic activity, possibly mediated by the serotonergic system.

Effects of two N-arylpiperazinylmethylpyrazolo [1,5-d][1,2,4]triazine derivatives in pain and antidepressant tests in mice.

The antinociceptive and antidepressant effects of two pyrazolotriazine derivatives, 2-phenyl-3,3a-dihydro-4-oxo-5-(4-phenylpiperazin-1-yl) methyl-pyrazolo[1,5-d][1,2,4]-triazine (SM1) and 2-phenyl-3,3a-dihydro-4-oxo-5-[4-(4-fluorophenyl)piperazin-1-yl] methylpyrazolo[1,5-d][1,2,4] triazine (SM3) have been investigated in mice using classical pharmacological tests. The intraperitoneal LD50 values of SM1 and SM3 were 253.4 and 218.8 mg kg-1 respectively. SM1 and SM3 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (ED50 approximately 10-15 mg kg-1, i.p.) and in the hot-plate test. The antinociceptive effects of the triazines were significantly reduced by administration of naloxone (1 and 3.2 mg kg-1, s.c.) and yohimbine (1 mg kg-1, p.o.). Acute intraperitoneal administration of both compounds (1 mg kg-1 SM1 or 1.5 mg kg-1 SM3) potentiated morphine (0.15 mg kg-1, s.c.) analgesia in the phenylbenzoquinone test. Although this synergistic activity was not reversed by methysergide (0.5 mg kg-1, i.p.), the analgesic activity of both compounds was enhanced by administration of 5-hydroxytryptophan (50 mg kg-1, i.p.) in conjunction with carbidopa (25 mg kg-1, i.p.). Furthermore, neither compound (at 100 mg kg-1, i.p.) significantly reduced the duration of immobility of mice in the forced swimming test, and both (at 75 mg kg-1, i.p.) were ineffective at enhancing the toxic effects of yohimbine (30 mg kg-1, s.c.). Only SM3 (ED50 = 74.5 mg kg-1, i.p.) significantly antagonized reserpine (2.5 mg kg-1, i.p.)-induced ptosis. Thus, the results suggest that SM1 and SM3 have antinociceptive properties related to co-involvement of opioidergic and alpha 2-adrenoceptor mechanism without associated antidepressant properties.

Oral administration of 5‐hydroxytryptophan (5‐HTP) impairs decision making under ambiguity but not under risk: evidence from the Iowa Gambling Task

Although the serotonin precursor 5-hydroxytryptophan (5-HTP) is marketed as a psychoactive nutritional supplement, knowledge is limited regarding the effects of exogenous 5-HTP on brain activity. This study examined if oral administration of 5-HTP to healthy adults impacted: (1) mood states, as measured by the Profile of Mood States (POMS); and (2) performance on the Iowa Gambling Task (IGT), a measure sensitive to alterations in frontocortical serotonin levels. A sample of 46 undergraduates participated, and each received either two 50 mg 5-HTP capsules or placebos, and completed the IGT and POMS following an absorption period. 5-HTP did not significantly alter mood states, but did impair performance on the IGT. Specifically, the 5-HTP group performed more poorly than the placebo group during the first 20 trials of the IGT but did not differ from the placebo group on trials 21-100. This suggests that oral 5-HTP specifically impaired decision making under ambiguity but not under risk. Males also performed more poorly on the first 20 trials of the IGT, regardless of treatment group. Oral 5-HTP is psychoactive at low doses. Decisions made under ambiguity may be differentially sensitive to increased serotonin release or associated reductions in frontocortical dopamine activity.

5-Hydroxytryptophan rescues serotonin response to stress in prefrontal cortex of hyperphenylalaninaemic mice

Adult early treated hyperphenylalaninaemic patients can show specific deficits of prefrontal cortical functions. The development of additional therapeutic strategies for these patients requires the understanding of the mechanisms involved in phenylalanine-dependent impairment of fronto-cortical functions. We tested the hypothesis of phenylalanine interference with aminergic neurotransmission in the prefrontal cortex by evaluating, in vivo, amine release in adult Pah(enu2) mice, the genetic model of phenylketonuria. Mice of healthy background responded to a psychogenic stressor with the classic time-dependent increase of norepinephrine, dopamine and serotonin release from prefrontal cortical terminals. Neither the dopaminergic nor the serotoninergic responses were observable in the Pah(enu2) mice. Temporary reduction of circulating phenylalanine, by phenylalanine-free diet without amino- acid supplement, promoted recovery of the serotonin response only, demonstrating direct interference with serotonin synthesis in the mature brain. Evaluation of different steps of serotonin synthesis in the prefrontal cortex of hyperphenylalaninaemic mice demonstrated inhibition of cortical tryptophan hydroxylase activity. Finally, systemic administration of 5-hydroxytryptophan, the product of tryptophan hydroxylase activity, allowed frontal cortical serotonin response to stress in hyperphenylalaninaemic mice. Collectively, these results demonstrate that hyperphenylalaninaemia interferes with the ability of the mature prefrontal cortex to respond to psychological challenges, point to serotonin synthesis as the target of phenylalanine interference, and support the use of 5-hydroxytryptophan in lifelong treatment of hyperphenylalaninaemic subjects.

Role of atypical opiates in OCD. Experimental approach through the study of 5-HT2A/C receptor-mediated behavior

The selective serotonin (5-HT) reuptake inhibitors (SSRIs) represent the first-line pharmacotherapy for obsessive-compulsive disorder (OCD), and atypical antipsychotic drugs, which block 5-HT2A receptors, are used in augmentation strategies. Opiate drugs are also effective in treatment-refractory OCD and Tourette syndrome. The 5-HT2A-related behavior (i.e., head twitch) has been related with tics, stereotypes, and compulsive symptoms observed in Tourette syndrome and OCD. The aim of this study was to explore whether 5-HT2A-related behavior is affected by atypical opiate drugs. Head-twitch response was induced in mice by administration of either 5-hydroxytryptophan (5-HTP) or the 5-HT2A/C agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). Dose-effect curves of atypical opiate drugs [(+/-)-tramadol, (-)-methadone and levorphanol], morphine, and other psychoactive drugs (fluvoxamine, desipramine, nefazodone, and clozapine) were performed. Opioid mechanisms were investigated by administration of naloxone. All the opiates tested reduced both 5-HTP and DOI-induced behavior in a naloxone-reversible fashion, atypical opiates being more effective. The effects of the other drugs depended on the protocol, clozapine being the most effective. Combined 5-HT and opioid properties result in a greater efficacy in antagonizing 5-HT2A-related behavior. These results provide behavioral evidence to support convergent effects of the 5-HT and opioid systems in discrete brain areas, offering the potential for therapeutic advances in the management of refractory stereotypes and compulsive behaviors.

Role of serotonin in cerebral oxidative stress in rat

Terotonin or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter synthesized by the aromatic amino acid decarboxylase using 5-hydroxytryptophan (5-HTP) as a substrate. It was recently shown that serotonin and its precursor have powerful antioxidant properties. The aim of this study was to evaluate the effect of reduction in 5-HT levels by parachlorophenylalanine (pCPA) and their restoration by 5-HTP administration on lipid peroxidation and antioxidant status in rat brain. Serotonin levels were decreased by p-chlorophenylalanine administration. The effect of pchlorophenylalanine was counteracted by the intraperitoneal administration of 5-hydroxytryptophan. We evaluated the concentration of serotonin, malonyl dialdehyde and the status of antioxidants (GSH, catalase and superoxide dismutase) in brain. The results showed that p-chlorophenylalanine (300 mg/kg) induced a depletion of serotonin concentration and antioxidant status, as well as enhancing malonyl dialdehyde concentration in brain. The exogenous administration of 5-hydroxytryptophan prevented all effects induced by pchlorophenylalanine in brain tissue. The recovery of the neurotransmitter concentration in brain was related to the reduction of lipid peroxide generation and improved antioxidant status. In conclusion, our study supports the view that the antioxidant properties of serotonin protect against basal oxidative stress in brain.

Antinociceptive Activity of New Imidazolidine Carbonyl Derivatives. Part 4. Synthesis and Pharmacological Activity of 8‐Aryl‐3,4‐dioxo‐2H,8H‐6,7‐dihydroimidazo[2,1‐c][1,2,4]triazines.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Antinociceptive activity of new imidazolidine carbonyl derivatives.: Part 4. Synthesis and pharmacological activity of 8-aryl-3,4-dioxo-2 H,8 H-6,7-dihydroimidazo[2,1- c] [1,2,4]triazines

Synthesis and pharmacological activity of 8-aryl-3,4-dioxo-2 H,8 H-6,7-dihydroimidazo[2,1- c] [1,2,4]triazines ( A) are presented. The title compounds were obtained from 1-aryl-2-hydrazinoimidazolines ( 1) by cyclization reaction with ethyl oxalate ( 2). They were tested for pharmacological activity in behavioral animal tests ( A1, A3, A5, A6, A8, A9). With relatively low acute toxicity (LD 50 in range from 1100 to over 2000 mg kg –1, intraperitoneally, i.p.), some of them exhibited significant antinociceptive activity as the result of the ‘writhing’ test indicated. Especially strong antinociception for compound A8 and significant for A6 was observed in doses of 12.5–200 mg (0.00625–0.1 LD 50) and 37.5–150 mg (0.025–0.1 LD 50), respectively. Reversion of the antinociception for A1 and A8 produced in the ‘writhing’ test by 5 mg kg –1 dose of naloxon can suggest an opioid-like mechanism of their analgesic activity. Additionally, compound A9 reduced number of the “head twitch” episodes after 5-hydroxytryptophan (5-HTP) administration with no antinociceptive effect at all and compound A3 showed significant protection in the pentylentetrazol-induced seizure model. Differences observed in the activity spectrum between A8 and A9 derivatives can be explained on the base of difference in the amido-imido tautomeric equilibrium observed between these two compounds.