Effect of Gabapentin-Fluoxetine Derivative GBP1F in a Murine Model of Depression, Anxiety and Cognition.

Background and Objective: Gabapentin is a commonly prescribed antiepileptic agent for seizures, which is also used for pain and addiction management. Due to growing evidence of its abuse liability, there has been an incentive to synthesise potentially useful gabapentin derivatives devoid of adverse effects. A gabapentin adduct with a fluoxetine moiety, GBP1F, was assessed for any sedative, cognitive, anxiolytic, or antidepressant-like actions in murine behavioral models. Materials and Methods: Selected groups of mice were used for each behavioral paradigm, and the effect of GBP1F (5, 10, and 15 mg/kg) was assessed using spontaneous locomotor activity, the tail suspension test, elevated plus maze test, and the Y maze test models. Immediately following behavioral experiments, postmortem striatal and hippocampal tissues were evaluated for the effect of GBP1F on concentrations of dopamine, DOPAC, HVA, serotonin, 5-HIAA, vitamin C, and noradrenaline using high performance liquid chromatography with electrochemical detection. Results: GBP1F induced a mild suppression of locomotor activity, ameliorated anxiety and depression-like behavior, did not alter cognitive behavior, and raised serotonin and 5-HIAA concentrations in the hippocampus and striatum. GBP1F also positively enhanced dopamine and vitamin C tissue levels in the striatum. Thus, GBP1F represents a compound with anxiolytic- and antidepressant-like effects though further studies are warranted at the molecular level to focus on the precise mechanism(s) of action.

Dapagliflozin inhibits the activity of lateral habenula to alleviate diabetes mellitus-induced depressive-like behavior.

The prevalence of depression in diabetes mellitus (DM) patients is very high, and it severely impacts the prognosis and quality of life of these patients. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, a new type of oral hypoglycemic drugs, have been shown to alleviate depressive symptoms in DM patients; however, the mechanism underlying this effect is not well understood. The lateral habenula (LHb) plays an important role in the pathogenesis of depression expresses SGLT2, suggesting that the LHb may mediate antidepressant effects of SGLT2 inhibitors. The current study aimed to investigate the involvement of the LHb in the antidepressant effects of the SGLT2 inhibitor dapagliflozin. Chemogenetic methods were used to manipulate the activity of LHb neurons. Behavioral tests, Western blotting, immunohistochemistry, and neurotransmitter assays were used to determine the effects of dapagliflozin on the behavior of DM rats, AMP-activated protein kinase (AMPK) pathway and c-Fos expression in the LHb and 5-hydroxyindoleacetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the dorsal raphe nucleus (DRN). We found that DM rats demonstrated depressive-like behavior, increased c-Fos expression, and decreased AMPK pathway activity in the LHb. Inhibition of LHb neurons alleviated the depressive-like behavior of DM rats. Both systemic and local LHb administration of dapagliflozin alleviated the depressive-like behavior and reversed the changes of the AMPK pathway and c-Fos expression in the LHb of DM rats. Dapagliflozin, when microinjected into the LHb, also increased 5-HIAA /5-HT in the DRN. These results suggest that dapagliflozin directly acts on the LHb to alleviate DM-induced depressive-like behavior and that the underlying mechanism involves activating the AMPK signaling pathway, leading to the inhibition of LHb neuronal activity, which in turn increases serotonergic activity in the DRN. These results will help develop new strategies for the treatment of DM-induced depression.

Propofol protects rats against intra-cerebroventricular streptozotocin-induced cognitive dysfunction and neuronal damage.

BACKGROUND: Cognitive dysfunction is a severe issue of Alzheimer's disease. Thus, the present study was conducted to enumerate the protective effect of propofol (PPL) in rats against intra-cerebroventricular streptozotocin (STZ)-induced cognitive dysfunction and neuronal damage. MATERIALS AND METHODS: The effect of PPL was investigated to evaluate behavioural changes in STZ-induced cognitive dysfunction in Wistar rats using Object Recognition Task (ORT) for nonspatial, Morris Water Maze (MWM) for spatial and locomotor activity. The effect of PPL was also investigated on acetylcholine (ACh) esterase (AChE) activity and oxidative stress markers, e.g., nitrite, malonaldehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH). The level of pro-inflammatory cytokines, e.g., tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6, was also studied in the PPL-treated group. The effect of PPL on the level of neurotransmitters, e.g., dopamine (DA), serotonin (5-HT), and norepinephrine (NE) and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), and homovanillic acid (HVA) levels were also estimated in frozen hippocampal tissues by high-performance liquid chromatography. Histopathology analysis of neurons in the hippocampus of rats was performed using haematoxylin and eosin (H&E) staining. RESULTS: Propofol showed significant improvement in the spatial and nonspatial memory deficit of rats in the MWM test and ORT in rats. It also causes improvement in locomotor activity of rats by preserving ACh via inhibition of AChE. It also potentiates the expression of DA, 5-HT, and NE with a simultaneous reduction in the level of metabolites (DOPAC, HVA, and 5-HIAA). PPL showed a reduction of oxidative stress in rats by restoring the level of nitrite, SOD, MDA, and GSH near to normal. In the PPL-treated group, the level of TNF-α, IL-1ß, and IL-6 was found reduced in a dose-dependent manner. In histopathology analysis of neurons in the hippocampus of the STZ rats, PPL causes dose-dependent reduction of pyknosis in the nucleus, which confirmed the protective effect of PPL. CONCLUSIONS: The present study demonstrated that PPL could significantly attenuate cognitive dysfunction and neuronal damage in STZ-induced rats.

Formononetin improves cognitive behavior in aging rats with chronic unpredictable mild in hippocampal tissue stress by blocking the NF-κB pathway and inhibiting the release of inflammatory factors / 细胞与分子免疫学杂志

Objective To investigate the effects of formononetin (FMN) on cognitive behavior and inflammation in aging rats with chronic unpredictable mild stress (CUMS). Methods SD rats aged about 70 weeks were divided into healthy control group, CUMS model group, CUMS combined with 10 mg/kg FMN group, CUMS combined with 20 mg/kg FMN group and CUMS combined with 1.8 mg/kg fluoxetine hydrochloride (Flu) group. Except for healthy control group, other groups were stimulated with CUMS and administered drugs for 28 days. Sugar water preference, forced swimming experiment and open field experiment were used to observe the emotional behavior of rats in each group. HE staining was used to observe the pathological injury degree of brain equine area. The contents of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were detected by the kit. The apoptosis was tested by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) in the brain tissue. The levels of tumor necrosis factor α (TNF-α), inducible nitric oxide synthase (iNOS) and interleukin 6 (IL-6) in peripheral blood were measured by ELISA. Western blot analysis was used to detect Bcl2, Bcl2 associated X protein (BAX), cleaved caspase-9, cleaved caspase-3, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and phosphorylated nuclear factor κB p65 (p-NF-κB p65) in brain tissues. Results Compared with CUMS model group, sugar water consumption, open field activity time, open field travel distance and swimming activity time significantly increased in the CUMS combined with 20 mg/kg FMN group and the CUMS combined with 1.8 mg/kg Flu group. The number of new outarm entry increased significantly, while the number of initial arm entry and other arm entry decreased significantly. The pathological damage of brain equine area was alleviated, and the contents of 5-HT and 5-HIAA were significantly increased. The ratio of BAX/Bcl2 and the expression of cleaved caspase-9 and cleaved caspase-3 protein as well as the number of apoptotic cells were significantly decreased. The contents of TNF-α, iNOS and IL-6 were significantly decreased. The protein levels of TLR4, MyD88 and p-NF-κB p65 were significantly decreased. Conclusion FMN can inhibit the release of inflammatory factors by blocking NF-κB pathway and improve cognitive and behavioral ability of CUMS aged rats.

Anxiolytic, anti-nociceptive and body weight reducing effects of L-lysine in rats: Relationship with brain serotonin an In-Vivo and In-Silico study.

L-lysine (L-lys) had long been comprehended as an essential amino acid for humans. There were reports that the absence or inadequate availability of L-lys in the diet may lead to mental and physical impairments. The present study was designed to explore the effects of L-lys on body weight changes, cumulative food intake, anxiety-like behavior and pain perception in rats. 5-Hydroxytryptamine (5-HT, serotonin) metabolism, and tryptophan (Trp) levels in the midbrain (MB), hippocampus (HP), and prefrontal cortex (PFC) were also determined. Animals were treated with L-lys in doses of 0.5 g/kg and 1 g/kg for 20 days and behavioral studies were performed on day 1st and day 20th. After monitoring behaviors on day 20th, animals were killed to collect the serum and brain regions MB, HP and PFC. 5-HT metabolism and Trp levels were determined by HPLC-EC. The treatment produce no effect on food intakes but body weights were reduced. 20 days administration of L-lys produced an anxiolytic effect and increased exploratory activity on day 1st. Repeated administration of L-lys increased 5-HT levels in the PFC and HP. 5-Hydroxyindoleacetic acid (5-HIAA), the metabolite of 5-HT, decreased in the HP. Trp, the precourser of 5-HT, decreased in the PFC. Results suggested a decrease in 5-HT degredation in enhancing 5-HT levels. Results of in-silico analysis showed that lysine had a potential binding affinity for MAO (monoamine oxidase) A and B with an energy of (-4.8 kcal/mol and -5.3 kcal/mol) respectively. The molecular dynamic simulation study revealed the stability of L-lys after 10 ns for each protein. Conclusively, the present study showed that L-lys produced an anxiolytic effect and reduced body weight. These beneficial effects were associated with an increase in 5-HT levels in the PFC and HP. In-silico analysis suggested that 5-HT increase were due to the binding of L-lys with MAOs resulting in an inhibition of the degradation of monoamine.

Oseltamivir induces favorable response on oxidative damage in the brain of rats treated with Bezafibrate.

AIM: The purpose was to measure the effect of Oseltamivir on oxidative biomarkers and dopaminergic and serotonergic systems in brain of rats with induced hypotriglyceridemia by Bezafibrate.Male young Wistar rats were treated as follows: group 1, NaCl 0.9%, (Controls); group 2, Oseltamivir (100 mg/kg); group 3, single dose of Bezafibrate (150 mg/kg); group 4, four dose of Bezafibrate; group 5, single dose of Bezafibrate + Oseltamivir and group 6, four doses of Bezafibrate + Oseltamivir. Drugs were given orally. Triglycerides, Dopamine, 5-hydroxyindoleacetic acid (5-HIAA), Glutathione (GSH), Hydrogen peroxide (H2O2), lipid peroxidation, as well as total ATPase activity were measured using validated methods. RESULTS: Oseltamivir treated animals showed lower GSH and lipid peroxidation levels and an increment in 5-HIAA in the three evaluated brain regions. Treatment with Oseltamivir also reduces H2O2 in the cortex and cerebellum/medulla oblongata. ATPase enzyme increased in these regions in the groups that were administered with Bezafibrate in repeated doses and in combination with Oseltamivir in single dose. Dopamine concentrations decreased in groups treated with Oseltamivir in the three evaluated regions. Also, there was a decrease in dopamine concentrations in the cerebellum/medulla oblongata of the animals treated with the combination of Oseltamivir and Bezafibrate.Innovation and conclusion: Animals with bezafibrate induced hypo-triglyceridemia that received Oseltamivir, either in single or repeated doses, have a higher improvement of their antioxidant activity and also experienced changes in the dopaminergic and serotonergic system in their brain, intending establish the beneficial of joint administration of both drugs in obese patients.

Antidepressive-Like Effect of Aegle marmelos Leaf Extract in Chronic Unpredictable Mild Stress-Induced Depression-Like Behaviour in Rats.

Background: Depression is a psychiatric disorder leading to anhedonia and lack of interest and motivation. Depressive symptoms are triggered by stressful life events, and patients with major depression are at significantly increased risk of attempting suicide. The crucial concern in depression treatment with antidepressant medications is that few weeks are required to show the therapeutic effect along with moderate side effects. The use of herbal medications is a new strategy for the treatment of depression which is often based on medicinal plants.Aegle marmelos (L.) Corr. (family: Rutaceae) is reported to have several actions on the central nervous system producing beneficial effects in anxiety, Alzheimer's disease, Parkinson's disease, epilepsy, and convulsion. Thus, the current investigation designed to assess the antidepressant activity of the standardized hydroethanolic extract of Aegle marmelos (EAM) leaves in male rats exposed to the chronic unpredictable mild stress (CUMS) paradigm. Methods: Rats were divided in 5 groups. The control group was not subjected to experimental CUMS paradigm, while 4 other groups were subjected to CUMS paradigm to induce depression-like behaviour from day 1 to day 28. Following the CUMS paradigm, 4 groups were divided as CUMS disease control, CUMS+EAM (150 mg/kg, p.o.), CUMS+EAM (300 mg/kg, p.o.), and CUMS+imipramine (15 mg/kg, p.o.), and treatment was given for seven consecutive days to the respective groups (day 29 to day 35). Behavioural parameters such as open field test, forced swim test, sucrose feeding test, and tail suspension test on day 1, day 28, and day 35 were measured, and biochemical parameters such as plasma corticosterone level, serotonergic system (5-HT, 5-HIAA, and 5-HT/5-HIAA), mitochondrial function, and proinflammatory mediators (TNF-α, IL-1ß, and IL-6) were estimated in hippocampus (HIP) and prefrontal cortex (PFC) regions of the brain on day 35, after the behavioural observations. On the other hand, phytochemical profile of Aegle marmelos was done. Results: On day 35, EAM (300 mg/kg) significantly reduced the immobility time during the tail suspension test from 208.66 ± 4.72 s to 108.83 ± 4.81 s and forced swim test from 200.16 ± 4.12 s to 148.5 ± 4.58 s. It also enhanced the behavioural parameters in the open field test such as ambulation from 26.5 ± 2.14 to 56.5 ± 1.80, rearing from 8.33 ± 0.71 to 19 ± 0.57, time spent in centre from 9.16 ± 0.9 to 17.16 ± 0.79 s, total distance travelled from 2.36 ± 0.12 to 4.68 ± 0.10 m, and anhedonia in the sucrose feeding test from 109.33 ± 1.08 to 135.83 ± 3.91 mL. The stimulation of the HPA axis resulting elevated corticosterone level caused by CUMS was reduced by EAM (300 mg/kg) from 80.12 ± 2.020 to 48.25 ± 2.407 µg/dL. Furthermore, EAM (300 mg/kg) increase CUMS-induced changes in serotonin (5-HT) level in HIP and PFC from 3.132 ± 0.09586 to 4.518 ± 0.1812 and 4.308 ± 0.1593 to 5.262 ± 0.1014 ng/mg protein, respectively. EAM (300 mg/kg) significantly attenuated the CUMS-induced changes in proinflammatory cytokine production and mitochondrial function in HIP and PFC. One group used to determine the acute toxicity as per OECD-23 standard protocol which resulted that 300 mg/kg EAM has no significant acute toxicity. Total phenolic content and total flavonoid content of standardized hydroalcoholic extract of AM was found 95.024 ± 2.431 and 36.820 ± 3.41, respectively, and additional identification tests showed the presence of alkaloids, tannins, saponins, cardiac glycosides, flavonoids, and terpenoids. Conclusion: On the basis of findings, EAM can be inferred as a potential antidepressant-like effect of this plan in preclinical research.

Dorsal raphé nucleus glucocorticoid receptors inhibit tph2 gene expression in male C57BL/6J mice.

The serotonergic dorsal raphé nucleus (DRN) expresses glucocorticoid receptors (GR), and systemic glucocorticoids have been shown to regulate expression and activity of tryptophan hydroxylase isoform 2, the rate-limiting enzyme for serotonin synthesis in brain. We have used intra-DRN injection of pseudotyped adeno-associated virus AAV2/9 transducing either green fluorescent protein (GFP control) or Cre recombinase (DRN GR deletion) in floxed GR mice to determine if DRN GR directly regulate DRN mRNA levels of tryptophan hydroxylase 2 (tph2). In a separate set of similarly-treated floxed GR mice, we also measured limbic forebrain region concentrations of serotonin (5-hydroxytryptamine; 5-HT) and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA). DRN GR deletion increased tph2 mRNA levels in the dorsal, lateral wing, and caudal parts of the DRN without altering tissue concentrations of 5-HT, 5-HIAA, or the 5-HIAA/5-HT ratio in limbic forebrain regions. We conclude that DRN GR inhibit DRN tph2 gene expression in mice without marked effects on serotonin metabolism, at least under basal conditions at the circadian nadir. These data provide the first evidence of localized control of DRN tph2 mRNA expression by DRN GR in mice.

5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis.

Using in vivo microdialysis, a comparative study was conducted to examine the effects of amphetamine-related compounds (methamphetamine, MAP; 3,4-methylenedioxymethamphetamine, MDMA; p-methoxyamphetamine, PMA; p-methoxymethamphetamine, PMMA; 4-methylthioamphetamine, 4-MTA; 3,4,5-trimethoxyamphetamine, TMA; 2,5-dimethoxy-4-iodoamphetamine, DOI) on extracellular levels of serotonin (5-HT) and dopamine (DA). Dialysates were assayed using HPLC equipped with electrochemical detector following i.p. administration with each drug at a dose of 5 mg/kg. MAP was found to drastically and rapidly increase 5-HT and DA levels (870% and 1460%, respectively). PMA, PMMA, and 4-MTA slightly increased DA levels (150-290%) but remarkably increased 5-HT levels (540-900%). In contrast, TMA and DOI caused no detectable changes in levels of both monoamines. We observed that the potent DA-releasing action of MAP was remarkably decreased by introduction of methoxy or methylthio group at the para position (MAP vs. PMMA or 4-MTA), but introduction of two additional adjacent methoxy groups into PMA totally abolished its 5-HT-/DA-releasing action (PMA vs. TMA). In addition, para-mono-substituted compounds inhibited both monoamine oxidase (MAO) enzymes more strongly than other compounds; PMA and 4-MTA exhibited submicromolar IC50 values for MAO-A. On the other hand, TMA scarcely affected the activity of both MAO enzymes as well as extracellular levels of 5-HT and DA. In this comparative study, MDMA, PMA, and 4-MTA functioned similar to PMMA, a typical empathogen; these findings therefore could be helpful in clarifying the psychopharmacological properties of amphetamine-related, empathogenic designer drugs.

Anti-oxidative effects of Rooibos tea (Aspalathus linearis) on immobilization-induced oxidative stress in rat brain.

Exposure to chronic psychological stress may be related to increased reactive oxygen species (ROS) or free radicals, and thus, long-term exposure to high levels of oxidative stress may cause the accumulation of oxidative damage and eventually lead to many neurodegenerative diseases. Compared with other organs, the brain appears especially susceptible to excessive oxidative stress due to its high demand for oxygen. In the case of excessive ROS production, endogenous defense mechanisms against ROS may not be sufficient to suppress ROS-associated oxidative damage. Dietary antioxidants have been shown to protect neurons against a variety of experimental neurodegenerative conditions. In particular, Rooibos tea might be a good source of antioxidants due to its larger proportion of polyphenolic compounds. An optimal animal model for stress should show the features of a stress response and should be able to mimic natural stress progression. However, most animal models of stress, such as cold-restraint, electric foot shock, and burn shock, usually involve physical abuse in addition to the psychological aspects of stress. Animals subjected to chronic restraint or immobilization are widely believed to be a convenient and reliable model to mimic psychological stress. Therefore, in the present study, we propose that immobilization-induced oxidative stress was significantly attenuated by treatment with Rooibos tea. This conclusion is demonstrated by Rooibos tea's ability to (i) reverse the increase in stress-related metabolites (5-HIAA and FFA), (ii) prevent lipid peroxidation (LPO), (iii) restore stress-induced protein degradation (PD), (iv) regulate glutathione metabolism (GSH and GSH/GSSG ratio), and (v) modulate changes in the activities of antioxidant enzymes (SOD and CAT).

Description and validation of a dynamical systems model of presynaptic serotonin function: genetic variation, brain activation and impulsivity.

Despite more than a decade of empirical work on the role of genetic polymorphisms in the serotonin system on behavior, the details across levels of analysis are not well understood. We describe a mathematical model of the genetic control of presynaptic serotonergic function that is based on control theory, implemented using systems of differential equations, and focused on better characterizing pathways from genes to behavior. We present the results of model validation tests that include the comparison of simulation outcomes with empirical data on genetic effects on brain response to affective stimuli and on impulsivity. Patterns of simulated neural firing were consistent with recent findings of additive effects of serotonin transporter and tryptophan hydroxylase-2 polymorphisms on brain activation. In addition, simulated levels of cerebral spinal fluid 5-hydroxyindoleacetic acid (CSF 5-HIAA) were negatively correlated with Barratt Impulsiveness Scale (Version 11) Total scores in college students (r = -.22, p = .002, N = 187), which is consistent with the well-established negative correlation between CSF 5-HIAA and impulsivity. The results of the validation tests suggest that the model captures important aspects of the genetic control of presynaptic serotonergic function and behavior via brain activation. The proposed model can be: (1) extended to include other system components, neurotransmitter systems, behaviors and environmental influences; (2) used to generate testable hypotheses.

Stereoselective effect of kynurenine enantiomers on the excretion of serotonin and its metabolite in rat urine.

A solution of optically pure kynurenine (KYN), i.e., D-KYN or L-KYN, was administered intravenously to male Sprague-Dawley rats (10 mg kg(-1) ml(-1)). The time-course of changes in the concentrations of urinary monoamines and their metabolites such as 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine, and 3-methoxytyramine were investigated by reversed-phase high-performance liquid chromatography with electrochemical detection after precolumn derivatization with (2R)-2,5-dioxopyrrolidin-1-yl-2,5,7,8-tetramethyl-6-(tetrahydro-2H-pyran-2-yloxy)chroman-2-carboxylate (NPCA). We observed a stereoselective difference in the effects of the KYN enantiomers. Only D-KYN, not L-KYN, caused a significant increase in urinary 5-HT levels within 30 min after its administration. With regard to the metabolites, urinary 3-MT level was increased by D-KYN administration. On the other hand, no significant change in the DA level was observed after administration of either D-KYN or L-KYN. These results suggest that D-KYN could affect the activity of neuroactive amines, especially 5-HT, in vivo.

Neurochemical and behavioral consequences of striatal injection of 5,7-dihydroxytryptamine.

It is known that central serotonin (5HT) is involved in anxiety, but the behavioral results of many studies have been inconsistent. A prevalent research approach is to destroy 5HT neurotoxically. Such lesions were mostly generated by injecting 5,7-dihydroxytryptamine into ventricles or raphé nuclei, leading to rather global losses of 5HT in the brain. However, there is evidence for differential effects of 5HT in different brain structures regarding anxiety. Therefore, we decided to study the effects of injecting 5,7-dihydroxytryptamine into the forebrain. We chose the ventral striatum as the site of injection, since there is evidence that 5HT may be involved in anxiety there. We administered the neurotoxin bilaterally in adult rats, and analyzed neurochemical and behavioral consequences in three experiments. The first one showed that the toxin dose-dependently (10-50 microg) depleted 5HT in the ventral striatum, neostriatum, frontal cortex, and amygdala. Besides 5HT, dopamine was also partly depleted there. This dopaminergic lesion was prevented in a second experiment, where rats were pre-treated systemically with the dopamine reuptake inhibitor nomifensine. In the final experiment, the functional consequences of such 5HT lesions were tested, which yielded moderate anxiogenic effects in the elevated plus maze and in the open field. Also, there were lesion effects on aversively motivated ultrasonic vocalization during an active avoidance test. In contrast, active avoidance performance itself and general activity in the open field were not affected. Lesion effects became discernible there when challenging rats with MDMA. The psycho-stimulatory effectiveness of this drug, which acts largely via the availability of 5HT in the brain, was reduced to degrees that depended on the size of 5HT lesion. These results are discussed with respect to factors such as severity of lesion, anatomical specificity, and the role of 5HT in anxiety.

Role of hypothalamic alpha-adrenoceptor activity in fructose-induced hypertension.

The aim of the present study was to investigate the effects of the alpha2-adrenoceptor antagonist yohimbine on blood pressure and heart rate (HR) regulation, as well as on adrenergic and serotoninergic neurotransmission, in fructose hypertensive (F) rats. The anterior hypothalamic area of control (C) and F rats was perfused with Ringer's solution containing 10 and 100 microg/mL yohimbine through a microdialysis concentric probe. The effects of yohimbine on mean arterial pressure (MAP) and HR, as well as on hypothalamic dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindole acetic acid (5-HIAA) levels, were measured according to perfusion time. Although intrahypothalamic perfusion of yohimbine increased blood pressure in C rats (DeltaMAP 9 +/- 1 and 11 +/- 2 mmHg for 10 and 100 microg/mL yohimbine, respectively; P < 0.05 vs Ringer's perfusion), the alpha-adrenoceptor antagonist did not modify MAP in F. Intrahypothalamic yohimbine had no effect on HR at either concentration tested. Intrahypothalamic perfusion of 10 and 100 microg/mL yohimbine increased DOPAC levels in C rats (135 +/- 6 and 130 +/- 5% of basal levels, respectively; both n = 6; P < 0.05 vs Ringer's perfusion), but not in F animals (115 +/- 6 and 102 +/- 6% of basal levels, respectively; both n = 6). In both C and F rats, yohimbine administration induced an increase in 5-HIAA dialysate levels. The results of the present study support the notion that alpha2-adrenoceptor tone of the anterior hypothalamus of normotensive rats, which contributes to normal blood pressure regulation, is not involved in the control of HR in either normotensive C or hypertensive F rats. The absence of changes in MAP after yohimbine perfusion in F rats suggests that the alpha2-adrenoceptor tone could be decreased in this group of rats and that this may be responsible for the maintenance of hypertension in this model. Intrahypothalamic perfusion of yohimbine increased DOPAC in the dialysate only in C rats, suggesting changes in presynaptic alpha2-adrenoceptor activity in fructose-overloaded rats. Conversely, increased 5-HIAA levels did not differ between C and F groups.

Protective effects of minocycline on 3,4-methylenedioxymethamphetamine-induced neurotoxicity in serotonergic and dopaminergic neurons of mouse brain.

The repeated administration of 3,4-methylenedioxymethamphetamine (MDMA) produces neurotoxicity in the 5-hydroxytryptamine (5-HT) and dopamine systems of the brain. In this study, we investigated the effects of minocycline, a second-generation tetracycline derivative, on MDMA-induced neurotoxicity in the 5-HT and dopaminergic systems of the mouse brain. The repeated administration of MDMA (10 mg/kg x 3, 3-h intervals, s.c.) significantly decreased the contents of 5-HT and its major metabolite 5-hydroxyindole acetic acid (5-HIAA) in the frontal cortex and hippocampus, and the density of the 5-HT transporter (5-HTT) in the frontal cortex, hippocampus and striatum. The repeated administration of MDMA (10 mg/kg x 3, 3-h intervals, s.c.) significantly decreased the contents of the dopamine and the density of the dopamine transporter (DAT) in the striatum, but not the frontal cortex. Furthermore, pretreatment and the subsequent administration of minocycline (40 mg/kg, i.p.) significantly attenuated the reduction of 5-HT and dopamine as well as the density of 5-HTT and DAT in the mouse brain by the repeated administration of MDMA. Moreover, pretreatment and the subsequent administration of minocycline (40 mg/kg) significantly attenuated the increase of activated microglia in the hippocampus and striatum after the repeated administration of MDMA. Our findings suggest that minocycline protects the neurotoxicity of the 5-HT and dopamine systems in the mouse brain after the administration of MDMA.

Rapid decreases in preoptic aromatase activity and brain monoamine concentrations after engaging in male sexual behavior.

In Japanese quail, as in rats, the expression of male sexual behavior over relatively long time periods (days to weeks) is dependent on the local production of estradiol in the preoptic area via the aromatization of testosterone. On a short-term basis (minutes to hours), central actions of dopamine as well as locally produced estrogens modulate behavioral expression. In rats, a view of and sexual interaction with a female increase dopamine release in the preoptic area. In quail, in vitro brain aromatase activity (AA) is rapidly modulated by calcium-dependent phosphorylations that are likely to occur in vivo as a result of changes in neurotransmitter activity. Furthermore, an acute estradiol injection rapidly stimulates copulation in quail, whereas a single injection of the aromatase inhibitor vorozole rapidly inhibits this behavior. We hypothesized that brain aromatase and dopaminergic activities are regulated in quail in association with the expression of male sexual behavior. Visual access as well as sexual interactions with a female produced a significant decrease in brain AA, which was maximal after 5 min. This expression of sexual behavior also resulted in a significant decrease in dopaminergic as well as serotonergic activity after 1 min, which returned to basal levels after 5 min. These results demonstrate for the first time that AA is rapidly modulated in vivo in parallel with changes in dopamine activity. Sexual interactions with the female decreased aromatase and dopamine activities. These data challenge established views about the causal relationships among dopamine, estrogen action, and male sexual behavior.

Demonstration of antifungal and anti-human immunodeficiency virus reverse transcriptase activities of 6-methoxy-2-benzoxazolinone and antibacterial activity of the pineal indole 5-methoxyindole-3-acetic acid.

6-methoxy-2-benzoxazolinone (6-MBOA), a naturally occurring progonadal compound present in grasses with structural resemblance to melatonin, was tested for antifungal activity against Fusarium oxysporum, Rhizoctonia solani and Coprinus comatus. A variety of pineal products was also examined for the sake of comparison, including 5-methoxytryptamine, melatonin, 5-methoxytryptophol, 5-hydroxytryptamine, 5-methoxyindole-3-acetic acid and 5-hydroxytryptophol. The assay for antifungal activity was carried out in Petri plates containing potato dextrose agar. It was found that 6-MBOA most potently inhibited the growth of C. comatus, R. solani and F. oxysporum. When 6-MBOA and pineal indoles were tested for antibacterial activity against the bacterium Agrobacterium tumefaciens, 5-methoxyindole-3-acetic acid was found to be the most potent. 6-MBOA most potently inhibited human immunodeficiency virus-1 reverse transcriptase.

The effect of serotonin, its precursors and metabolites on brain glutathione-S-transferase.

The isoelectric point and substrate specificity of the main isoform of glutathione-S-transferase (GST, EC 2.5.1.18) isolated from brain stem, hippocampus and parietal cortex of pig brain were determined. The effect of serotonin, its precursors (Try, 5-HTry), physiologically active derivative (melatonin) and final metabolite (5-HIAA) on the activity of this form was examined. Investigation indicated that serotonin did not affect the activity of GST in all studied regions of brain. The inhibitory effect of Try was stronger than that of 5-HTry, but weaker than the one expressed by melatonin and especially by 5-HIAA. Studies on the type of inhibition showed that Try, melatonin and 5-HIAA can compete for the active site with the electrophilic substrate but not with glutathione. Therefore precursors and endogenous derivatives of serotonin but not serotonin itself may affect the detoxification function of brain glutathione-S-transferase and increase the exposure of brain to toxic electrophiles.

Interleukin-6 involvement in antidepressant action of Hypericum perforatum.

Hypericum, a plant widely used as antidepressant has been shown to interact with the immune system. We studied the effects of the administration of the Hypericum perforatum extract Ph-50, a Hypericum extract, standardized to flavonoids (50%) and containing 0.3% of hypericin and 4.5% of hyperforin in a forced swimming test and tryptophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) diencephalic content using a high performance liquid chromatography method in male interleukin-6 (IL-6) knock-out (IL-6(-/-)) and wild type (IL-6(+/+)) mice. Hypericum extract (Ph-50; 500 mg/kg) oral acute administration reduced the immobility time of wild type, but not of knockout mice. Tryptophan content was not modified by Hypericum in all the animal groups. Serotonin and 5-HIAA diencephalic content was increased by Hypericum in both wild type and knockout mice. However, the increase observed in the wild type was greater than in knockout mice. These data indicate that IL-6 could be necessary to the antidepressant action of Hypericum, and that this cytokine (probably) mediates the effects of Hypericum through activation of the serotonin system.

Relative efficacies of indole antioxidants in reducing autoxidation and iron-induced lipid peroxidation in hamster testes.

Increased iron stores are associated with free radical generation and carcinogenesis. Lipid peroxidation is involved in DNA damage, thus indirectly participating in the early steps of tumor initiation. Melatonin and structurally related indoles are effective in protecting against oxidative stress. The aim of the study was to compare the relative efficacies of melatonin, N-acetylserotonin (NAS), indole-3-propionic acid (IPA), and 5-hydroxy-indole-3-acetic acid (5HIAA) in altering basal and iron-induced lipid peroxidation in homogenates of hamster testes. To determine the effect of the indoles on the autoxidation of lipids, homogenates were incubated in the presence of each agent in concentrations of 0.0, 0.01, 0.05, 0.1, 0.25, 0.5, 0.75, 1.0, 2.0, 2.5, or 5.0 mM. To study their effects on induced lipid peroxidation, homogenates were incubated with FeSO(4) (30 microM + H(2)O(2) (0.1 mM) + each of the indoles in the same concentrations as above. The degree of lipid peroxidation was expressed as concentrations of malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA) per mg protein. The indoles decreased both basal and iron-related lipid peroxidation in a concentration-dependent manner. Melatonin reduced basal MDA + 4-HDA levels when used at the concentrations of 0.25 mM or higher, and prevented iron-induced lipid peroxidation at concentrations of 1.0, 2.0, 2.5, or 5.0 mM. The lowest effective concentrations of NAS required to lower basal and iron-related lipid peroxidation were 0.05 mM and 0.25 mM, respectively. IPA, only when used in the highest concentrations of 2.5 mM or 5 mM inhibited basal lipid peroxidation levels and it was ineffective on the levels of MDA + 4-HDA due to iron damage. 5HIAA reduced basal lipid peroxidation when used at concentrations of 0.25 mM or higher, and it prevented iron-induced lipid peroxidation only at the highest applied concentration (5 mM). In conclusion, melatonin and related indoles at pharmacological concentrations protect against both the autoxidation of lipids as well as induced peroxidation of lipids in testes. In doing so, these agents would be expected to reduce testicular cancer that is initiated by products of lipid peroxidation.