Increase In Monoamine Oxidase Activity Research Articles

Rauvolfia vomitoria phenol extract relieves pentylenetetrazol-induced seizures in Swiss mice and protects some temporal lobe structures

BackgroundRauvolfia vomitoria (R. vomitoria) is a plant of economic importance due to its diverse ethnomedicinal properties, including the anticonvulsant effect. In this study, we studied the antiseizure and neuroprotective potentials of R. vomitoria extracts against pentylenetetrazol (PTZ)-induced kindling.MethodsTwenty-five adult Swiss mice (25–30 g) were assigned to five groups (n = 5): control group, PTZ treatment group, and PTZ treatment after receiving oral R. vomitoria crude extract (100 mg/kg), R. vomitoria phenol extract (50 mg/kg) or sodium valproate (15 mg/kg) every 48 h for 28 days. Seizure scores, cognitive behavioral tests including novel object test, Y-maze test, and the elevated plus maze test, as well as brain neurochemicals and histomorphology studies, were performed.ResultsCompared with the control group, the PTZ group showed comparable body weight and durations in closed and open arms (P > 0.05), but preference for familiar objects, significant (P < 0.05) spontaneous alternation, increased monoamine oxidase activity and nitric oxide level, and Nissl chromatolysis in the temporal lobe structures including the cortex, hippocampus, and amygdala. R. vomitoria phenol extract pretreatment significantly (P < 0.05) reduced seizures, prevented adverse cognitive behaviors, decreased the nitric oxide level, and reduced the temporal lobe Nissl chromatolysis compared with the R. vomitoria crude extract pretreatment group and the sodium valproate pretreatment groups.ConclusionsThus, R. vomitoria phenol extract showed promising results against seizures and potential for general brain protection, suggesting that the anticonvulsant property of R. vomitoria may be attributed to its phenol constituent. More studies are needed to delineate the mechanisms of its action.

Microdialysis perfusion of COA-Cl enhances dopamine metabolism in the dorsal striatum of freely moving mice.

We performed a microdialysis study to examine the effects of local perfusion of COA‑Cl on the extracellular levels of dopamine (DA) and its metabolites in the dorsal striatum of mice in vivo. The mice were perfused with Ringer's solution (control) and COA‑Cl (0.05, 0.1, or 0.5 mM) into the dorsal striatum. Dialysate samples were collected every 30 min and then analyzed using high‑performance liquid chromatography coupled with an electrochemical detector. We found that local perfusion of COA‑Cl (0.1 or 0.5 mM) into the dorsal striatum of living mice produced a significant and dose‑dependent increase in extracellular levels of DA, 3‑methoxytyramine (3‑MT), and homovanillic acid (HVA), where only 0.5 mM COA‑Cl increased dihydroxyphenylacetic acid (DOPAC) levels. However, 0.05 mM of COA‑Cl did not significantly affect either DA levels or its metabolites. Then, we administered the monoamine oxidase (MAO) inhibitor clorgyline alone or in combination with COA‑Cl (0.1 mM) to test whether COA‑Cl‑induced increases in DOPAC and HVA are mediated by increased MAO activity. Clorgyline alone increased 3‑MT levels and decreased DOPAC and HVA levels but not DA levels. When combined with COA‑Cl, clorgyline increased 3‑MT levels and reversed the decrease in DOPAC and HVA levels caused by clorgyline. The increase in DA metabolism induced by COA‑Cl suggests that some DA was further metabolized into DOPAC, 3‑MT, and HVA. This indicates that COA‑Cl plays a role in DA metabolism via increased DA release and/or activation of MAO, offering new insights into the effects of COA‑Cl on DA metabolism in the brain.

Cyperus esculentus extract mitigates sertraline-induced behavioral and histopathological changes in the brain of rats

ABSTRACT Chronic use of sertraline (SRT) for depression treatment can elevate oxidative stress, potentially leading to neuropathy. Cyperus esculentus extract (CEE) has demonstrated neuroprotective properties against oxidative imbalance, memory impairment, and neural degeneration. Adult male albino rats (40 rats) were placed into four groups: control (GI), CEE (200 mg/kg/day, orally) (GII), SRT (20 mg/kg/day, intraperitoneal) (GIII), and SRT+CEE (GIV). The rats’ spatial learning was assessed using a multiple T-maze after four weeks. Subsequently, rats were euthanized, and brain tissue samples were collected to assess oxidative stress indicators, monoamine oxidase, and dopamine. Brain tissue samples were also examined histologically and immunohistochemically for synaptophysin. SRT significantly increased monoamine oxidase activity, leading to oxidative stress, reduced dopamine levels, and neuronal degeneration in the brain. Treatment with SRT resulted in a decrease in the expression of synaptophysin in the cerebral cortex, dentate gyrus of the hippocampus, and cornu ammonis. These changes, in turn, led to impaired spatial learning. Co-treatment with CEE ameliorated changes in the levels of monoamine oxidase, dopamine, and synaptophysin, restored the redox balance, and improved spatial learning. CEE demonstrated a protective effect against sertraline-induced oxidative damage, preserving neurons, synaptogenesis, and spatial learning. These findings suggest CEE’s potential positive impact on sertraline-related neurodegeneration.

Lactobacillus brevis-Fermented Gamma-Aminobutyric Acid Ameliorates Depression- and Anxiety-Like Behaviors by Activating the Brain-Derived Neurotrophic Factor-Tropomyosin Receptor Kinase B Signaling Pathway in BALB/C Mice.

This study investigated the effects of Lactobacillus brevis-fermented gamma-aminobutyric acid (LB-GABA) on depressive and anxiety-like behaviors with the underlying molecular mechanism in a chronic stress model of BALB/c mice. LB-GABA attenuates both neuronal cell death and the increase of monoamine oxidase activity induced by hydrogen peroxide. Behavioral tests revealed that GABA significantly increased sucrose preference and reduced immobility time in both tail suspension and forced swimming tests. LB-GABA increased exploration of the open arms in the elevated plus maze and restored activity in the open field. Moreover, LB-GABA lowered stress hormone and inflammatory mediator levels. Mechanistically, LB-GABA increased protein levels of BDNF and TrkB, activating downstream targets (AKT, ERK, and CREB), crucial for neuronal survival and plasticity. Furthermore, LB-GABA protected hippocampal neurons from stress-induced cell death and increased serotonin and dopamine levels. Overall, LB-GABA has the potential to alleviate stress-induced depression and anxiety-like symptoms and neuroinflammation by activating the BDNF-TrkB signaling pathway.

Assessment of the neuroprotective effect of green synthesized iron oxide nanoparticles capped with curcumin against a rat model of Parkinson's disease.

The current study aims to investigate the protective effect of iron oxide nanoparticles capped with curcumin (FeONPs-Cur) against motor impairment and neurochemical changes in a rat model of Parkinson's disease (PD) induced by reserpine. Rats were grouped into control, PD model induced by reserpine, and PD model treated with FeONPs-Cur (8 rats/group). The open field test was used to assess motor activity. The concentration of dopamine (DA), norepinephrine (NE), serotonin (5-HT), lipid peroxidation (MDA), reduced glutathione (GSH), and nitric oxide (NO), and the activities of Na+,K+,ATPase, acetylcholinesterase (AchE), and monoamine oxidase (MAO) were determined in the midbrain and striatum. Data were analyzed by ANOVA at P-value<0.05. The PD model exhibited a decrease in motor activity. In the midbrain and striatum of the PD model, DA, NE, and 5-HT levels decreased significantly (P-value<0.05). However, an increase in MAO, NO, and MDA was observed. GSH, AchE and Na+,K+,ATPase decreased significantly in the two brain areas. FeONPs-Cur prevented the decline of dopamine and norepinephrine and reduced oxidative stress in both areas. It also prevented the increased MAO activity in the two areas and the inhibited activity of AchE and Na+,K+,ATPase in the midbrain. These changes were associated with improvements in motor activity. The present data indicate that FeONPs-Cur could prevent the motor deficits induced in the PD rat model by restoring dopamine and norepinephrine in the midbrain and striatum. The antioxidant activity of FeONPs-Cur contributed to its protective effect. These effects nominate FeONPs-Cur as an antiparkinsonian candidate.

Sex differences of cerebrospinal fluid biomarkers in Alzheimer’s disease

AbstractBackgroundAlzheimer’s disease (AD) is more common in women than in men. Thus, to investigate the sex‐specific mechanism is important to understand the pathogenesis of AD. We examined the sex differences in levels of CSF biomarkers (tau, ptau‐181, Aβ42, HVA and 5HIAA) in AD.MethodThe subjects of this study consisted of clinically diagnosed 386 patients with AD (age 75.9±8.4 years, 237 women and 149 men). The clinical diagnosis was made based on the AD diagnostic criteria (NIA/AA, McKhann GM, et al., Alzheimers Dement 2011; 7: 263‐269). The CSF samples were obtained by lumbar puncture after informed consent was obtained. The levels of CSF tau, ptau‐181 and Aβ42 were measured by ELISA (Fujirebio, Belgium) according to the manufacturer’s protocol. The levels of CSF HVA and 5HIAA were measured by HPLC. We compared the levels of CSF biomarkers between women and men.ResultAge, the levels of CSF tau, ptau‐181 and Aβ42 showed no sex differences. The levels of CSF HVA (ng/ml) were 32.6±19.3 in women and 25.9±14.4 in men. The levels of 5HIAA were 19.1±11.7 in women and 14.8±7.7 in men. The levels of CSF HVA and 5HIAA were significantly higher in women than those in men (t‐test, HVA: p&lt;0.001, 5HIAA: p&lt;0.001).It has been reported that women have higher values of HVA and 5HIAA among normal subjects, due to higher monoamine oxidase (MAO) activity in women. The MAO‐A and MAO‐B genes are located on the X chromosome, and are controlled by XCI (X‐chromosome inactivation). However, the MAO genes may escape XCL MAO‐B has also been reported to be γ‐secretase associated protein and regulate neuronal amyloid β‐peptide levels. Thus, increased MAO‐B activity may be one of the reasons why AD is more common in women.ConclusionBoth CSF levels of HVA and 5HIAA were significantly higher in women in AD, presumably due to increased MAO activity.

Chronic environmental inorganic arsenic exposure causes social behavioral changes in juvenile zebrafish (Danio rerio)

Arsenic (As) is a metalloid commonly found worldwide. Environmental As exposure may cause potential health hazards and behavioral changes in humans and animals. However, the effects of environmental As concentrations on social behavior, especially during the juvenile stage, are unclear. In this study, we observed behavioral changes in juvenile zebrafish after 28 days of exposure to inorganic As (NaAsO2 100 and 500 ppb) in water, especially anxiety and social deficits. Additionally, the level of oxidative stress in the zebrafish brain after As treatment increased, the content of dopamine (DA) decreased, and the transcription level of genes involved in DA metabolism with the activity of monoamine oxidase (MAO) increased. Oxidative stress is a recognized mechanism of nerve damage induced by As exposure. The zebrafish were exposed to N-acetylcysteine (NAC) to reduce As exposure-induced oxidative stress. The results showed improvements in social behavior, DA content, MAO activity, and gene transcription in zebrafish. In conclusion, environmental As exposure can induce behavioral abnormalities, such as anxiety and social deficits in zebrafish, which may be caused by As-induced oxidative stress altering gene transcription levels, causing an increase in MAO activity and a decrease in DA.

Suppression of Chronic Unpredictable Stress-Persuaded Increased Monoamine Oxidase Activity by Taurine Promotes Significant Neuroprotection in Zebrafish Brain.

Neuropsychiatric upshots following chronic exposure to unpredictable adverse stressors have been well documented in the literature. Considering the significant impact of chronic unpredictable stress (CUS), the literature is elusive regarding the neuroprotective efficacy of taurine against CUS-induced oxidative stress and chromatin condensation in the zebrafish brain. In this study, to ameliorate CUS-persuaded neurological outcomes, waterborne treatment of taurine as a prophylactic intervention was undertaken. Further, our approach also focused on the gross neurobehavioral response of zebrafish, oxidative stress indices and neuromorphology of the zebrafish brain following CUS exposure with taurine treatment. Because taurine provides significant neuroprotection against oxidative insult, the cytosolic level of monoamine oxidase (MAO) in the zebrafish brain following CUS exposure is worth investigating. Further, as heightened MAO activity is associated with augmented oxidative and chromatin condensation, the focus of this study was on whether taurine provides neuroprotection by downregulating MAO levels in the brain. Our findings show that CUS-persuaded altered neurobehavioral response was significantly rescued by taurine. Moreover, our findings firmly support the hypothesis that taurine acts as a radical neuroprotector by restoring glutathione biosynthesis in the zebrafish brain subsequent to CUS exposure. Additionally, the rising level of brain MAO following chronic exposure to CUS is ameliorated by taurine treatment. These findings strongly advocate the role of taurine as a natural MAO inhibitor through the neuroprotection it provides against CUS-instigated oxidative stress in zebrafish. However, the fundamental neuroprotective mechanism of such natural compounds needs to be elucidated to determine their neuroprotective efficacy against stress regimens.

Increased monoamine oxidase activity and imidazoline binding sites in insulin-resistant adipocytes from obese Zucker rats.

BACKGROUNDDespite overt insulin resistance, adipocytes of genetically obese Zucker rats accumulate the excess of calorie intake in the form of lipids.AIMTo investigate whether factors can replace or reinforce insulin lipogenic action by exploring glucose uptake activation by hydrogen peroxide, since it is produced by monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) in adipocytes.METHODS 3H-2-deoxyglucose uptake (2-DG) was determined in adipocytes from obese and lean rats in response to insulin or MAO and SSAO substrates such as tyramine and benzylamine. 14C-tyramine oxidation and binding of imidazolinic radioligands [3H-Idazoxan, 3H-(2-benzofuranyl)-2-imidazoline] were studied in adipocytes, the liver, and muscle. The influence of in vivo administration of tyramine + vanadium on glucose handling was assessed in lean and obese rats.RESULTS2-DG uptake and lipogenesis stimulation by insulin were dampened in adipocytes from obese rats, when compared to their lean littermates. Tyramine and benzylamine activation of hexose uptake was vanadate-dependent and was also limited, while MAO was increased and SSAO decreased. These changes were adipocyte-specific and accompanied by a greater number of imidazoline I2 binding sites in the obese rat, when compared to the lean. In vitro, tyramine precluded the binding to I2 sites, while in vivo, its administration together with vanadium lowered fasting plasma levels of glucose and triacylglycerols in obese rats. CONCLUSIONThe adipocytes from obese Zucker rats exhibit increased MAO activity and imidazoline binding site number. However, probably as a consequence of SSAO down-regulation, the glucose transport stimulation by tyramine is decreased as much as that of insulin in these insulin-resistant adipocytes. The adipocyte amine oxidases deserve more studies with respect to their putative contribution to the management of glucose and lipid handling.

Characterization of Catecholaldehyde Adducts with Carnosine and l-Cysteine Reveals Their Potential as Biomarkers of Catecholaminergic Stress.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of dopamine and norepinephrine to produce 3,4-dihydroxyphenylacetaldehyde (DOPAL) and 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), respectively. Both of these aldehydes are potently cytotoxic and have been implicated in pathogenesis of neurodegenerative and cardiometabolic disorders. Previous work has demonstrated that both the catechol and aldehyde moieties of DOPAL are reactive and cytotoxic via their propensity to cause macromolecular cross-linking. With certain amines, DOPAL likely reacts via a Schiff base before oxidative activation of the catechol and rearrangement to a stable indole product. Our current work expands on this reactivity and includes the less-studied DOPEGAL. Although we confirmed that antioxidants mediated DOPAL’s reactivity with carnosine and N-acetyl-l-lysine, antioxidants had no effect on reactivity with l-cysteine. Therefore, we propose a non-oxidative mechanism where, following Schiff base formation, the thiol of l-cysteine reacts to form a thiazolidine. Similarly, we demonstrate that DOPEGAL forms a putative thiazolidine conjugate with l-cysteine. We identified and characterized both l-cysteine conjugates via HPLC-MS and additionally identified a DOPEGAL adduct with carnosine, which is likely an Amadori product. Furthermore, we were able to demonstrate that these conjugates are produced in biological systems via MAO after treatment of the cell lysate with norepinephrine or dopamine along with the corresponding nucleophiles (i.e., l-cysteine and carnosine). As it has been established that metabolic and oxidative stress leads to increased MAO activity and accumulation of DOPAL and DOPEGAL, it is conceivable that conjugation of these aldehydes to carnosine or l-cysteine is a newly identified detoxification pathway. Furthermore, the ability to characterize these adducts via analytical techniques reveals their potential for use as biomarkers of dopamine or norepinephrine metabolic disruption.

Inhibition of histone deacetylase promotes a neuroprotective mechanism in an experimental model of Parkinson's disease.

Therapies targeting histone deacetylase (HDAC) have gained wider attention in the treatment of various clinical conditions. However, the use of HDAC inhibitors in pre-clinical trials in the case of Parkinson's disease (PD) is very limited. In the present study, the HDAC inhibitor, entinostat, was tested in animals induced with Parkinson's disease experimentally. Wistar male rats (150 ±10 g) were administered with rotenone (2 mg/kg/day, s.c.) for 21 days to induce PD, while entinostat (20 mg/kg) was given intraperitoneally. Then, the neurological functions, PD markers, and HDACs were analysed in the control and experimental animals. The results demonstrated that rats that received entinostat displayed progressive motor, behavioural, and neurological function with attenuated α-synuclein and improved tyrosine-hydroxylase compared to control cells. Moreover, the induction of PD in rats demonstrated reduced levels of H2S, dopamine, 3, and 4-dihydroxyphenylacetic acid (DOPAC), and increased monoamine oxidase activity in PD rats. However, the rats that received entinostat demonstrated progressive levels of dopa and DOPAC, with attenuated levels of HDAC-2, -4, and -6 mRNA in the PD rats compared to controls. On the other hand, elevated (p < 0.01) levels of PD marker genes such as GDF3 and NMDA2b were reduced, with a significant increase in neuroprotective genes such as VDAC3 and CBX5 in entinostat-supplemented rats. The study results suggest that inhibition of HDAC systematically improves the neurological functions, and hence treatments, emphasizing that HDACI, as the speculated mechanism, will be a promising mode of treatment in PD.

Inhibition of neuronal mitochondrial complex I or lysosomal glucocerebrosidase is associated with increased dopamine and serotonin turnover

Parkinson's disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic and serotoninergic signalling. A number of pathogenic mechanisms have been implicated including loss of mitochondrial function at the level of complex I, and lysosomal metabolism at the level of lysosomal glucocerebrosidase (GBA1). In order to investigate further the potential involvement of complex I and GBA1 in PD, we assessed the impact of loss of respective enzyme activities upon dopamine and serotonin turnover. Using SH-SY5Y cells, complex I deficiency was modelled by using rotenone whilst GBA1 deficiency was modelled by the use of conduritol B epoxide (CBE). Dopamine, its principal metabolites, and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the extracellular medium were quantified by HPLC. Inhibition of complex I significantly increased extracellular concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-HIAA. Comparable results were observed with CBE. These results suggest increased monoamine oxidase activity and provide evidence for involvement of impaired complex I or GBA1 activity in the dopamine/serotonin deficiency seen in PD. Use of extracellular media may also permit relatively rapid assessment of dopamine/serotonin metabolism and permit screening of novel therapeutic agents.

The role of microsomal oxidation in the regulation of monoamine oxidase activity in the brain and liver of rats

It has been shown in our previous study that monoamine oxidase (MAO) activity in different brain regions are correlated with a microsomal oxidation phenotype. The data obtained in this study, using the microsomal oxidation inhibitor SKF525, and using animals with different duration of hexobarbital sleep, has shown that increased intensity of microsomal oxidation might be associated with increased MAO activity. Since the rats with short hexobarbital sleep time had higher content of hepatic microsomal cytochrome P450 than did rats with long hexobarbital sleep time. In addition, the rats with higher hepatic content of CYP450 had higher activities of MAO-A and MAO-B. Moreover, the microsomal oxidation inhibitor SKF-525 reduced brain and liver activities of MAOA and MAO-B. Consequently, MAO activities in a brain and a liver depend on the microsomal oxidation process.

Dynamics of biochemical changes in anxious-depressed patients under treatment with antidepressants with different mechanisms of action on serotonin reuptake

ObjectivesPharmacodynamics of serotonergic antidepressants differently influencing on serotonin reuptake receptors is poorly investigated.AimTo compare biochemical profiles at patients with anxious depression under treatment with tianeptine–serotonin reuptake enhancer and sertraline–selective serotonin reuptake inhibitor.MethodsPlatelet monoamine oxidase (MAO) and serum amine oxidase (AO) activities, level of middle mass endotoxic molecules (MMEM) and serum albumin functional properties – effective albumin concentration (EAC) and reserve of albumin binding (RAB) were investigated at 43 patients with anxious depression (F 32.1 and F 33.1). Clinical severity of illness was assessed using Hamilton Depression (21 items) and Hamilton Anxiety Scales. All patients were divided in two groups: group I (21 person) received tianeptine (37, 5 mg/day), group II – sertraline (50 mg/day).ResultsIt was established that patients with anxious depression were characterized by significant increase in MAO activity (by 95%) and the level of MMEM (by 86%) and significant decrease in AO activity (by 28%) and EAC and RAB parameters by 43 and 38%, respectively, in comparison with healthy volunteers. Under tianeptine and sertraline treatment, there were revealed contrary directed changes of all investigated parameters.ConclusionResults of study show that both tianeptine and sertraline are equally effective in treatment of anxious depression. Present biochemical investigation, however, suggest that underlying biochemical changes are more complete following tianeptine treatment.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Potential neurobiological ADHD biomarkers

ObjectivesPathogenetic mechanisms of hyperkinetic syndrome (HKS) or attention deficit hyperactivity disorder (ADHD) are not clear.AimTo elucidate some aspects of monoamine involvement in pathogenesis of disorder and response of monoaminergic systems to psychostimulant medication.MethodsLevels of different monoamines, their metabolites and N-methylnicotinamide (end product of kynurenine pathway) were measured in daily samples of urine from children (7–11 years old) with mild and severe HKS using fluorimetric and chromatographic methods as well as platelet monoamine oxidase (MAO) activity. Thirty children with mild HKS received psychostimulant Sydnocarb 5–15 mg daily for 1–1.5 months (for ethical reasons children with severe HKS were not included in study).ResultsHKS was accompanied by activation of dopaminergic and inhibition of noradrenergic systems. There were found metabolic differences between two forms of HKS. Compared with mild HKS, severe HKS was characterized by significant 2-fold increase of MAO activity and L-dopa, dopamine and adrenaline excretion. After sydnocarb treatment children's clinical status improved along with decrease of excretion of homovanillic, vanillylmandelic and 5-hydroxyindoleacetic acids and increase of N-methylnicotinamide.ConclusionsResults indicate that dopaminergic and noradrenergic systems play important role in pathogenesis of HKS. Clinical improvement of HKS children was accompanied by significant increase of N-methylnicotinamide excretion. It is proposed that increased urine excretion of kynurenine metabolite–N-methylnicotinamide and N-methylnicotinamide/5-hydroxyindoleacetic acid ratio can serve as potential biomarkers for evaluation of efficacy of psychostimulant medication. We hypothesize that kynurenine system plays significant role in pathogenesis of HKS/ADHD.Disclosure of interestThe authors have not supplied their declaration of competing interest.

In Vitro and in Vivo Neuroprotective Effects of Walnut (Juglandis Semen) in Models of Parkinson's Disease.

Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamines including dopamine (DA). MAO expression is elevated in Parkinson’s disease (PD). An increase in MAO activity is closely related to age, and this may induce neuronal degeneration in the brain due to oxidative stress. MAO (and particularly monoamine oxidase B (MAO-B)) participates in the generation of reactive oxygen species (ROS), such as hydrogen peroxide that are toxic to dopaminergic cells and their surroundings. Although the polyphenol-rich aqueous walnut extract (JSE; an extract of Juglandis Semen) has been shown to have various beneficial bioactivities, no study has been dedicated to see if JSE is capable to protect dopaminergic neurons against neurotoxic insults in models of PD. In the present study we investigated the neuroprotective potential of JSE against 1-methyl-4-phenylpyridinium (MPP+)- or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicities in primary mesencephalic cells and in a mouse model of PD. Here we show that JSE treatment suppressed ROS and nitric oxide productions triggered by MPP+ in primary mesencephalic cells. JSE also inhibited depletion of striatal DA and its metabolites in vivo that resulted in significant improvement in PD-like movement impairment. Altogether our results indicate that JSE has neuroprotective effects in PD models and may have potential for the prevention or treatment of PD.

Sodium tungstate induced neurological alterations in rat brain regions and their response to antioxidants

Tungsten, recognized recently as an environmental contaminant, is being used in arms and ammunitions as substitute to depleted uranium. We studied the effects of sodium tungstate on oxidative stress, few selected neurological variables like acetylcholinesterase, biogenic amines in rat brain regions (cerebral cortex, hippocampus and cerebellum) and their prevention following co-administration of N-acetylcysteine (NAC), naringenin and quercetin. Animals were sub-chronically exposed to sodium tungstate (100 ppm in drinking water) and orally co-supplemented with different antioxidants (0.30 mM) for three months. Sodium tungstate significantly decreased the activity of acetylcholinesterase, dopamine, nor-epinephrine and 5-hydroxytryptamine levels while it increased monoamine oxidase activity in different brain regions. Tungstate exposure produced a significant increase in biochemical variables indicative of oxidative stress while, neurological alterations were more pronounced in the cerebral cortex compared to other regions. Co-administration of NAC and flavonoids with sodium tungstate significantly restored glutathione, prevented changes in the brain biogenic amines, reactive oxygen species (ROS) and TBARS levels in the different brain regions. The protection was more prominent in the animals co-administered with NAC. We can thus conclude that sodium tungstate induced brain oxidative stress and the alterations in some neurological variables can effectively be reduced by co-supplementation of NAC.

Antipsychotic activity of standardized Bacopa extract against ketamine-induced experimental psychosis in mice: Evidence for the involvement of dopaminergic, serotonergic, and cholinergic systems

Context: Schizophrenia is a chronic disabling psychiatric disorder affecting 1% of the population worldwide. Due to the adverse effects of available antipsychotic medications, recent investigations have focused on the search for well-tolerated, safe molecules from natural resources to control the severity and progression of schizophrenia.Objective: To screen the standardized extract of Bacopa monniera Linn. (Scrophulariaceae) (BM) for its antipsychotic potential in the ketamine-induced psychosis model with mice.Materials and methods: Graded dose of BM (40, 80, and 120 mg/kg, p.o.) were given to the mice 1 h prior to ketamine administration and tested for positive symptoms and cognitive deficits. A chronic ketamine treatment regimen was used to study the effect of BM on negative symptoms such as immobility enhancement. Each mouse was used once for the behavioral studies.Results: BM reduced ketamine-induced hyperactivity with an EC50 value of 76.60 mg/kg. The 80 mg/kg dose was used for all other behavior analysis. Pretreatment with BM at 80 mg/kg showed two-fold increases in transfer latency time (TLT) in passive avoidance task. Chronic BM pretreatment (80 mg/kg p.o. daily × 10 d) ameliorated the ketamine-induced enhanced immobility effect by 21% in the forced swim test. BM treatment reversed ketamine-induced increase in monoamine oxidase activity in both cortex and striatum and normalized the acetylcholinesterase activity and the glutamate levels in the hippocampus.Discussion and conclusion: Overall our findings suggest that BM possesses antipsychotic properties which might be due to its modulatory action on dopamine, serotonin, and glutamate neurotransmission.

Role of dopaminergic and serotonergic neurotransmitters in behavioral alterations observed in rodent model of hepatic encephalopathy

The present study was designed to evaluate the role of biogenic amines in behavioral alterations observed in rat model of hepatic encephalopathy (HE) following bile duct ligation (BDL). Male Wistar rats subjected to BDL developed biliary fibrosis after four weeks which was supported by altered liver function tests, increased ammonia levels and histological staining (Sirius red). Animals were assessed for their behavioral performance in terms of cognitive, anxiety and motor functions. The levels of dopamine (DA), serotonin (5-HT), epinephrine and norepinephrine (NE) were estimated in different regions of brain viz. cortex, hippocampus, striatum and cerebellum using HPLC along with activity of monoamine oxidase (MAO). Cognitive assessment of BDL rats revealed a progressive decline in learning, memory formation, retrieval, exploration of novel environment and spontaneous locomotor activity along with decrease in 5-HT and NE levels. This was accompanied by an increase in MAO activity. Motor functions of BDL rats were also altered which were evident from decrease in the time spent on the rotating rod and higher foot faults assessed using narrow beam walk task. A global decrease was observed in the DA content along with an increase in MAO activity. Histopathological studies using hematoxylin–eosin (H&E) and cresyl violet exhibited marked neuronal degeneration, wherein neurons appeared more pyknotic, condensed and damaged. The results reveal that dopaminergic and serotonergic pathways are disturbed in chronic liver failure post-BDL which may be responsible for behavioral impairments observed in HE.

DJ‐1 deficiency triggers microglia sensitivity to dopamine toward a pro‐inflammatory phenotype that is attenuated by rasagiline

DJ-1 is an oxidative stress sensor that localizes to the mitochondria when the cell is exposed to oxidative stress. DJ-1 mutations that result in gene deficiency are linked to increased risk of Parkinson's disease (PD). Activation of microglial stress conditions that are linked to PD may result in neuronal death. We postulated that DJ-1 deficiency may increase microglial neurotoxicity. We found that down-regulation of DJ-1 in microglia using an shRNA approach increased cell sensitivity to dopamine as measured by secreted pro-inflammatory cytokines such as IL-1β and IL-6. Furthermore, we discovered that DJ-1-deficient microglia had increased monoamine oxidase activity that resulted in elevation of intracellular reactive oxygen species and nitric oxide leading to increased dopaminergic neurotoxicity. Rasagaline, a monoamine oxidase inhibitor approved for treatment of PD, reduced the microglial pro-inflammatory phenotype and significantly reduced neurotoxicity. Moreover, we discovered that DJ-1-deficient microglia have reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), previously suggested as a risk factor for pro-inflammation in neurodegenerative diseases. Further studies of DJ-1-mediated cellular pathways in microglia may contribute useful insights into the development of PD providing future avenues for therapeutic intervention