DA), 3,4-dihydroxyphenylacetic Acid Research Articles

Behavioral and neurotransmitter changes on antiepileptic drugs treatment in the zebrafish pentylenetetrazol-induced seizure model

Epilepsy, a recurrent neurological disorder involving abnormal neurotransmitter kinetics in the brain, has emerged as a global health concern. The mechanism of epileptic seizures is thought to involve a relative imbalance between excitatory and inhibitory neurotransmitters. Despite the recent advances in clinical and basic research on the pathogenesis of epilepsy, the complex relationship between the neurotransmitter changes and behavior with and without antiepileptic drugs (AEDs) during seizures remains unclear. To investigate the effects of AEDs such as levetiracetam (LEV), carbamazepine (CBZ), and fenfluramine (FFR) on key neurotransmitters in the pentylenetetrazol (PTZ)-induced seizures in adult zebrafish, we examined the changes in glutamic acid, gamma-aminobutyric acid (GABA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), choline, acetylcholine, norepinephrine, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), and adenosine. In this study, we observed that 5-HT and DA levels in the brain increased immediately after PTZ-induced seizures. Behavioral tests clearly showed that all of these AEDs suppressed the PTZ-induced seizures. Upon treatment of PTZ-induced seizures with these AEDs, CBZ decreased the glutamic acid and FFR increased the GABA levels; however, no neurotransmitter changes were observed in the brain after LEV administration.Thus, we demonstrated a series of neurotransmitter changes linked to behavioral changes during PTZ-induced epileptic seizures when LEV, CBZ, or FFR were administered. These findings will lead to a more detailed understanding of the pathogenesis of epilepsy associated with behavioral and neurotransmitter changes under AED treatment.

Oxidation of dopamine and related catechols in dopaminergic brain regions in Parkinson's disease and during ageing in non-Parkinsonian subjects.

The present study was performed to examine if catechol oxidation is higher in brains from patients with Parkinson's disease compared to age-matched controls, and if catechol oxidation increases with age. Brain tissue from Parkinson patients and age-matched controls was examined for oxidation of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and 3,4-dihydroxyphenylalanine (DOPA) to corresponding quinones, by measurement of 5-S-cysteinyl-dopamine, 5-S-cysteinyl-DOPAC and 5-S-cysteinyl-DOPA. The cysteinyl catechols are assumed to be biomarkers for DA, DOPAC and DOPA autoxidation and part of the biosynthetic pathway of neuromelanin. The concentrations of the 5-S-cysteinyl catechols were lower, whereas the 5-S-cysteinyl-DA/DA and 5-S-cysteinyl-DOPAC/DOPAC ratios tended to be higher in the Parkinson group compared to controls, which was interpreted as a higher degree of oxidation. High 5-S-cysteinyl-DA/DA ratios were found in the substantia nigra of a sub-population of the Parkinson group. Based on 5-S-cysteinyl-DA/DA ratios, dopamine oxidation was found to increase statistically significantly with age in the caudate nucleus, and non-significantly in the substantia nigra. In conclusion, the occurrence of 5-S-cysteinyl-DA, 5-S-cysteinyl-DOPAC and 5-S-cysteinyl-DOPA was demonstrated in dopaminergic brain areas of humans, a tendency for higher oxidation of DA in the Parkinson group compared to controls was observed as well as a statistically significant increase in DA oxidation with age. Possibly, autoxidation of DA and other catechols are involved in both normal and pathological ageing of the brain. This study confirms one earlier but small study, as well as complements one study on non-PD cases and one study on both PD cases and controls on NM bound or integrated markers or catechols.

The effect of isolation on laboratory rare minnow (Gobiocypris rarus): Growth, behavior and physiology

Laboratory fish play an important role in modern scientific research. More and more researchers have begun to pay attention to the other living environment except the physical and chemical factors of the water body, because it is not only related to animal welfare, but also related to the validity of the experimental results. Unfortunately, laboratory fish are sometimes raised alone, primarily because the impact of isolation of fish is still poorly understood. This study assessed the effects of long-term social isolation (lasting 90 days) on the growth, clustering, anxiety-like behavior, and physiological parameters (cortisol, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA)) of laboratory rare minnow. We found that isolation did not affect the growth, clustering behavior, and anxiety-like behavior of the laboratory rare minnow. However, we found a significant decrease in the levels of cortisol, DOPAC and 5-HT in isolated fish. Our results suggested that isolated environments might impact the responsive ability of rare minnows, and future researchers should thus provide appropriate living environments for them.

Protective effect of compatible herbs in Jin-Gu-Lian formula against Alangium chinense-induced neurotoxicity via oxidative stress, neurotransmitter metabolisms, and pharmacokinetics.

Background: A. chinense frequently used in Miao medicine to treat rheumatic diseases. However, as a famous toxic herb, Alangium chinense and its representative components exhibit ineluctable neurotoxicity, thus creating significant challenges for clinical application. The combined application with compatible herbs in Jin-Gu-Lian formula attenuates such neurotoxicity according to the compatible principle of traditional Chinese medicines. Purpose: We aimed to investigate the detoxification of the compatible herbs in Jin-Gu-Lian formula on A. chinense-induced neurotoxicity and investigate its mechanism. Methods: Neurobehavioral and pathohistological analysis were used to determine the neurotoxicity in rats administered with A. chinense extract (AC), extract of compatible herbs in Jin-Gu-Lian formula (CH) and combination of AC with CH for 14days. The mechanism underlying the reduction of toxicity by combination with CH was assessed by enzyme-linked immunosorbent assays, spectrophotometric assays, liquid chromatography tandem-mass spectrometry and real-time reverse transcription-quantitative polymerase chain reaction. Results: Compatible herbs attenuated the AC-induced neurotoxicity as evidenced by increased locomotor activity, enhanced grip strength, the decreased frequency of AC-induced morphological damage in neurons, as well as a reduction of neuron-specific enolase (NSE) and neurofilament light chain (NEFL) levels. The combination of AC and CH ameliorated AC-induced oxidative damage by modulating the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC). AC treatment significantly reduced the levels of monoamine and acetylcholine neurotransmitters in the brains of rats, including acetylcholine (Ach), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), and serotonin (5-HT). Combined AC and CH treatment regulated the abnormal concentrations and metabolisms of neurotransmitters. Pharmacokinetic studies showed that the co-administration of AC and CH significantly decreased plasma exposure levels of two main components of AC, as evidenced by the reduction of maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) compared to AC. In addition, the AC-induced downregulation in mRNA expression of cytochrome P450 enzymes was significantly reduced in response to combined AC and CH treatment. Conclusion: Compatible herbs in Jin-Gu-Lian formula alleviated the neurotoxicity induced by A. chinense by ameliorating oxidative damage, preventing abnormality of neurotransmitters and modulating pharmacokinetics.

Effect of Rehmanniae Radix on depression-like behavior and hippocampal monoamine neurotransmitters of chronic unpredictable mild stress model rats

To investigate the effect of Rehmanniae Radix on depression-like behavior and monoamine neurotransmitters of chronic unpredictable mild stress(CUMS) model rats. CUMS combined with isolated feeding was used to induce the depression model of rats. The depression-like behavior of rats was evaluated by sucrose preference test, open field test, and forced swim test. Hematoxylin-Eosin(HE) staining was used to investigate the pathological changes of neurons in the CA1 and CA3 area of hippocampus. Ultra performance liquid chromatography-tandem mass spectrometry(UPLC-MS) was used to detect the contents of 5-hydroxytryptamine(5-HT), 5-hydroxyindoleacetic acid(5-HIAA), dopamine(DA), 3,4-dihydroxyphenylacetic acid(DOPAC), homovanillic acid(HVA), norepinephrine(NE), and 3-methoxy-4-hydroxyphenyl glycol(MHPG) in rats. Western blot was used to detect the protein expressions of tryptophan hydroxylase 2(TPH2), serotonin transporter(SERT), and monoamine oxidase A(MAO-A) in the hippocampus of rats. Compared with the normal group, depressive-like behavior of rats was obvious in the model group. The arrangements of neurons in the CA1 and CA3 area of hippocampus were loose and disorderly. The levels of 5-HT, 5-HIAA, and 5-HT/5-HIAA in the hippocampal area were decreased(P<0.01). The protein expression of TPH2 was decreased(P<0.01), but those of SERT and MAO-A were increased(P<0.01). In the Rehmanniae Radix groups with 1.8 g·kg~(-1) and 7.2 g·kg~(-1), the depression-like behavior of CUMS rats and pathological changes of neurons in CA1, CA3 area of hippocampus were improved. The protein expression of TPH2(P<0.05, P<0.01) was increased, and those of SERT and MAO-A were down-regulated(P<0.05, P<0.01). The levels of 5-HT, 5-HIAA, and 5-HT/5-HIAA in hippocampus were increased(P<0.05, P<0.01). The changes in DA, DOPAC, HVA, DA/(DOPAC +HVA), NE, DHPG, and NE/DHPG were not statistically significant. The results suggested that Rehmanniae Radix improved depression-like behavior of CUMS rats, and the mechanism might be related to the regulation of synthesis, transportation, and metabolism of 5-HT neurotransmitter in the hippocampus.

Vitamin D (VD3) Intensifies the Effects of Exercise and Prevents Alterations of Behavior, Brain Oxidative Stress, and Neuroinflammation, in Hemiparkinsonian Rats.

In the present study, we investigated the effects of physical exercise in the presence of Vitamin D3 (VD3), on 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats. The animals were divided into sham-operated (SO), 6-OHDA-lesioned, and 6-OHDA-lesioned plus VD3 (1µg/kg, 21days), in the absence (no exercise, NE) and presence (with exercise, WE) of physical exercise on a treadmill (30min, speed of 20cm/s, once a day/21days). This procedure started, 24h after the stereotaxic surgery (injections of 6-OHDA into the right striatum). The animals were then subjected to behavioral (rotarod, open field, and apomorphine tests) and their brain areas were dissected for neurochemical, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) determinations, and immunohistochemical studies for tyrosine hydroxylase (TH), dopamine transporter (DAT), and vitamin D receptor (VD3R). The effects on the brain oxidative stress: nitrite/nitrate, glutathione (GSH), and malondialdehyde (MDA) measurements were also evaluated. Behavioral changes of the 6-OHDA lesioned group were improved by exercise plus VD3. Similar results were observed in dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations increased by exercise and VD3, compared with SO groups. Additionally, tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunoexpressions were decreased in the 6-OHDA-lesioned groups, with values normalized after exercise and VD3. The VD3 receptor immunoexpression decreased in the 6-OHDA (NE) group, and this was attenuated by exercise, especially after VD3. While 6-OHDA lesions increased, VD3 supplementation decreased the oxidative stress, which was intensified by exercise. VD3 showed neuroprotective properties that were intensified by physical exercise. These VD3 actions on hemiparkinsonian rats are possibly related to its antioxidant and anti-inflammatory effects.

Disturbance of neurotransmitter metabolism in drug-naïve, first-episode major depressive disorder: a comparative study on adult and adolescent cohorts.

Neurotransmitter metabolism plays a critical role in the pathophysiology of major depressive disorder (MDD). However, whether the neurotransmitter metabolism in adolescent MDD is differentiated from adult MDD is still elusive. In the current study, plasma concentrations of monoamine and amino acid neurotransmitters as well as their metabolites, including tryptophan (TRP), kynurenine (KYN), kynurenic acid (KYNA), serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), vanillylmandelic acid (VMA), 3-methoxy-4-hydroxyphenylglycol (MHPG), glutamine (GLN), glutamate (GLU) and gamma-aminobutyric acid (GABA), were measured and compared in two cohorts of subjects (adult cohort: 31 first-episode MDD vs. 35 healthy controls; adolescent cohort: 33 first-episode MDD vs. 30 healthy controls). To assess the effects of antidepressant treatment, we also analyzed the concentrations of these indexes pre- and post-treatment in adult and adolescent cohorts. At baseline, the deficits of neurotransmitter metabolism in adult MDD were manifested in all the neurotransmitter systems. In contrast, for adolescent MDD, the dysregulation of neurotransmission was mainly indicated in the catecholaminergic systems. After antidepressant treatment, adult MDD showed increased TRP, KYN, KYNA and GLU levels, together with decreased levels of 5-HIAA and DOPAC. Adolescent MDD illustrated an increased level of 5-HT and decreased levels of TRP and GABA. The improvements of Hamilton total scores correlated with the changes in plasma TRP and the turnover of KYN/TRP after treatment in all MDD patients. However, these correlations were only manifested in the adult MDD rather than in adolescent MDD patients. The findings highlight the shared and distinguished neurotransmitter pathways in MDD and emphasize the different antidepressant responses between adults and adolescents. Potentially, the neurotransmitters above could serve as diagnostic biomarkers and provide a novel pharmacological treatment strategy for MDD.

The effect of casein glycomacropeptide versus free synthetic amino acids for early treatment of phenylketonuria in a mice model.

Management of phenylketonuria (PKU) is mainly achieved through dietary control with limited intake of phenylalanine (Phe) from food, supplemented with low protein (LP) food and a mixture of free synthetic (FS) amino acids (AA) (FSAA). Casein glycomacropeptide (CGMP) is a natural peptide released in whey during cheese making by the action of the enzyme chymosin. Because CGMP in its pure form does not contain Phe, it is nutritionally suitable as a supplement in the diet for PKU when enriched with specific AAs. Lacprodan® CGMP-20 (= CGMP) used in this study contained only trace amounts of Phe due to minor presence of other proteins/peptides. The aims were to address the following questions in a classical PKU mouse model: Study 1, off diet: Can pure CGMP or CGMP supplemented with Large Neutral Amino Acids (LNAA) as a supplement to normal diet significantly lower the content of Phe in the brain compared to a control group on normal diet, and does supplementation of selected LNAA results in significant lower brain Phe level?. Study 2, on diet: Does a combination of CGMP, essential (non-Phe) EAAs and LP diet, provide similar plasma and brain Phe levels, growth and behavioral skills as a formula which alone consist of FSAA, with a similar composition?. 45 female mice homozygous for the Pahenu2 mutation were treated for 12 weeks in five different groups; G1(N-CGMP), fed on Normal (N) casein diet (75%) in combination with CGMP (25%); G2 (N-CGMP-LNAA), fed on Normal (N) casein diet (75%) in combination with CGMP (19,7%) and selected LNAA (5,3% Leu, Tyr and Trp); G3 (N), fed on normal casein diet (100%); G4 (CGMP-EAA-LP), fed on CGMP (70,4%) in combination with essential AA (19,6%) and LP diet; G5 (FSAA-LP), fed on FSAA (100%) and LP diet. The following parameters were measured during the treatment period: Plasma AA profiles including Phe and Tyr, growth, food and water intake and number of teeth cut. At the end of the treatment period, a body scan (fat and lean body mass) and a behavioral test (Barnes Maze) were performed. Finally, the brains were examined for content of Phe, Tyr, Trp, dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and 5-hydroxyindole-acetic acid (5-HIAA), and the bone density and bone mineral content were determined by dual-energy x-ray absorptiometry. Study 1: Mice off diet supplemented with CGMP (G1 (N-CGMP)) or supplemented with CGMP in combination with LNAA (G2 (N-CGMP-LNAA)) had significantly lower Phe in plasma and in the brain compared to mice fed only casein (G3 (N)). Extra LNAA (Tyr, Trp and Leu) to CGMP did not have any significant impact on Phe levels in the plasma and brain, but an increase in serotonin was measured in the brain of G2 mice compared to G1. Study 2: PKU mice fed with mixture of CGMP and EAA as supplement to LP diet (G4 (CGMP-EAA-LP)) demonstrated lower plasma-Phe levels but similar brain- Phe levels and growth as mice fed on an almost identical combination of FSAA (G5 (FSAA-LP)). CGMP can be a relevant supplement for the treatment of PKU.

Tonic Serotonin Measurements In Vivo Using N-Shaped Multiple Cyclic Square Wave Voltammetry.

Here, we present the development of a novel voltammetric technique, N-shaped multiple cyclic square wave voltammetry (N-MCSWV) and its application in vivo. It allows quantitative measurements of tonic extracellular levels of serotonin in vivo with mitigated fouling effects. N-MCSWV enriches the electrochemical information by generating high dimensional voltammograms, which enables high sensitivity and selectivity against 5-hydroindoleacetic acid (5-HIAA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), histamine, ascorbic acid, norepinephrine, adenosine, and pH. Using N-MCSWV, in combination with PEDOT:Nafion-coated carbon fiber microelectrodes, a tonic serotonin concentration of 52 ± 5.8 nM (n = 20 rats, ±SEM) was determined in the substantia nigra pars reticulata of urethane-anesthetized rats. Pharmacological challenges with dopaminergic, noradrenergic, and serotonergic synaptic reuptake inhibitors supported the ability of N-MCSWV to selectively detect tonic serotonin levels in vivo. Overall, N-MCSWV is a novel voltammetric technique for analytical quantification of serotonin. It offers continuous monitoring of changes in tonic serotonin concentrations in the brain to further our understanding of the role of serotonin in normal behaviors and psychiatric disorders.

Photoperiodic light pulse induces ovarian development in the catfish, Mystus cavasius: Possible roles of dopamine and melatonin in the brain

In the freshwater catfish, Mystus cavasius, locally known as gulsha, ovarian maturation is triggered by long-day conditions. Using dopaminergic neuronal activity in the brain, the purpose of this study was to identify the brain’s detection of a nocturnal light pulse that induced ovarian development. Since direct inhibition of pituitary gonadotropin release is exerted by dopamine (DA), it may serve as a neuromodulator of photoperiodic stimulation in teleosts. We studied functional effects of photoperiodicity on dopaminergic rhythmicity in gulsha brain. Nocturnal illumination and Nanda-Hamner photocycles revealed that ovarian development is induced by a 1 h light pulse between zeitgeber time (ZT) 12 and 13. Daily fluctuations in DA, 3, 4-dihydroxyphenylacetic acid (DOPAC) and DOPAC/DA were observed under a 12L:12D photoperiod. Fish exhibited increased levels during the daytime and decreased levels at night. Rhythmic patterns of dopaminergic activity also showed clear circadian oscillations under constant light, but not constant dark conditions. After 7 days of exposure to long photoperiod (14L:10D), DA, DOPAC and DOPAC/DA in the brain at ZT12 and ZT16 were significantly higher than during a short photoperiod (10L:14D). Melatonin-containing water inhibited the release of DA and DOPAC 6 h and 24 h after treatment, respectively, and DOPAC/DA 6 h after treatment. This inhibition was blocked by the melatonin receptor antagonist, luzindole. These results suggest that a 1 h nocturnal light pulse induces ovarian development through alteration of dopaminergic neuronal excitability in the brain, via oscillation in melatonin triggered by photic stimuli, which may interfere with the reproductive endocrine axis in gulsha.

Granulocyte-colony stimulating factor, a potential candidate for the treatment of Parkinson's disease.

Granulocyte colony-stimulating factor (G-CSF) activates the PI3K/Akt pathway to exert neuroprotective effects. The current study aimed to determine if G-CSF reverses behavioral deficits, even after motor malfunction occurs in Paraquat (PQ)-treated mice. Male C57BL/6 mice (8 weeks old) were divided into 3 groups: PQ + G-CSF-treated group (n=8); PQ + saline-treated group (n=8); and saline-treated control group (n=8). Spontaneous locomotor activity was evaluated together with the pole test. The DA, 3, 4-dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA) levels in the bilateral striatum were determined by HPLC. The number of substantia nigra pars compacta tyrosine hydroxylase (TH)-immunoreactive neurons was calculated using an unbiased cell counting stereology method, the activities of total GSH-PX and SOD, and the malondialdehyde (MDA) content were assessed. After G-CSF treatment, spontaneous motor activity and the Tturn and TLA times in the CSF group were significantly lower than the control group, and the striatal dopamine level in the striatum and the number of TH-positive neurons in the substantia nigra (SN) were significantly increased compared to the control group (5478 ± 654 vs. 3647±488 DA neurons, P < 0.05). Compared to the control group, the GSH-PX and SOD activities were increased, while the MDA level was significantly decreased in the SN (P<0.05). The data strongly suggest that G-CSF reverses behavioral deficits in PQ-treated mice with movement disorders. Thus, G-CSF may be utilized as a prospective drug candidate for the treatment of Parkinson's disease.

Uncaria rhynchophylla ameliorates unpredictable chronic mild stress-induced depression in mice via activating 5-HT1A receptor: Insights from transcriptomics

BackgroundDepression is a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. Uncaria rhynchophylla has been widely used to treat central nervous system diseases for a long history, although its efficacy and potential mechanism are still uncertain. PurposeThe present study aimed to investigate anti-depression effect and potential mechanism of U. rhynchophylla extract (URE). Study design and methodsA mouse depression model was established using unpredictable chronic mild stress (UCMS). Effects of URE on depression-like behaviours, neurotransmitters, and neuroendocrine hormones were investigated in UCMS-induced mice. The potential target of URE was analyzed by transcriptomics and bioinformatics methods and validated by RT-PCR and Western blot. The agonistic effect on 5-HT1A receptor was assayed by dual-luciferase reporter system. ResultsURE ameliorated depression-like behaviours, and modulated levels of neurotransmitters and neuroendocrine hormones, including 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), corticosterone (CORT), corticotropin-releasing hormone (CRH), and adrenocorticotropic hormone (ACTH), in UCMS-induced mice. Transcriptomics and bioinformatics results indicated that URE could regulate glutamatergic, cholinergic, serotonergic, and GABAergic systems, especially neuroactive ligand-receptor and cAMP signaling pathways, revealing that Htr1a encoding 5-HT1A receptor was a potential target of URE. The expression levels of downstream proteins of 5-HT1A signaling pathway 5-HT1A, CREB, BDNF, and PKA were increased in UCMS-induced mice after URE administration, and URE also displayed an agonistic effect against 5-HT1A receptor with an EC50 value of 17.42 μg/ml. ConclusionU. rhynchophylla ameliorated depression-like behaviours in UCMS-induced mice through activating 5-HT1A receptor.

βOHB Protective Pathways in Aralar-KO Neurons and Brain: An Alternative to Ketogenic Diet.

Aralar/AGC1/Slc25a12, the mitochondrial aspartate-glutamate carrier expressed in neurons, is the regulatory component of the NADH malate-aspartate shuttle. AGC1 deficiency is a neuropediatric rare disease characterized by hypomyelination, hypotonia, developmental arrest, and epilepsy. We have investigated whether β-hydroxybutyrate (βOHB), the main ketone body (KB) produced in ketogenic diet (KD), is neuroprotective in aralar-knock-out (KO) neurons and mice. We report that βOHB efficiently recovers aralar-KO neurons from deficits in basal-stimulated and glutamate-stimulated respiration, effects requiring βOHB entry into the neuron, and protects from glutamate excitotoxicity. Aralar-deficient mice were fed a KD to investigate its therapeutic potential early in development, but this approach was unfeasible. Therefore, aralar-KO pups were treated without distinction of gender with daily intraperitoneal injections of βOHB during 5 d. This treatment resulted in a recovery of striatal markers of the dopaminergic system including dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratio, and vesicular monoamine transporter 2 (VMAT2) protein. Regarding postnatal myelination, myelin basic protein (MBP) and myelin-associated glycoprotein (MAG) myelin proteins were markedly increased in the cortices of βOHB-treated aralar-KO mice. Although brain Asp and NAA levels did not change by βOHB administration, a 4-d βOHB treatment to aralar-KO, but not to control, neurons led to a substantial increase in Asp (3-fold) and NAA (4-fold) levels. These results suggest that the lack of increase in brain Asp and NAA is possibly because of its active utilization by the aralar-KO brain and the likely involvement of neuronal NAA in postnatal myelination in these mice. The effectiveness of βOHB as a therapeutic treatment in AGC1 deficiency deserves further investigation.SIGNIFICANCE STATEMENTAralar deficiency induces a fatal phenotype in humans and mice and is associated with impaired neurodevelopment, epilepsy, and hypomyelination. In neurons, highly expressing aralar, its deficiency causes a metabolic blockade hampering mitochondrial energetics and respiration. Here, we find that βOHB, the main metabolic product in KD, recovers defective mitochondrial respiration bypassing the metabolic failure in aralar-deficient neurons. βOHB oxidation in mitochondria boosts the synthesis of cytosolic aspartate (Asp) and NAA, which is impeded by aralar deficiency, presumably through citrate-malate shuttle. In aralar-knock-out (KO) mice, βOHB recovers from the drastic drop in specific dopaminergic and myelin markers. The βOHB-induced myelin synthesis occurring together with the marked increment in neuronal NAA synthesis supports the role of NAA as a lipid precursor during postnatal myelination.

Protective effect of hydrogen sulfide is mediated by negative regulation of epigenetic histone acetylation in Parkinson's disease.

Derangements in monoaminergic transmission in the substantia nigra with disturbed signaling in the hypothalamic-pituitary-adrenal axis are the major characteristics of Parkinson's disease (PD). It has been reported that the administration of hydrogen sulfide (H2S) is in practice to treat PD because of its redundant nature in regulating various neuronal signals. Hence, the current investigation was performed to evaluate the hypothesis that H2S might exert protective action via the inhibition of epigenetic histone acetylation. To test this notion, 6-hydroxydopamine (6-OHDA) was used to induce PD and sodium hydrogen sulfide (SHS) was used as a H2S donor and tubastatin A (TSA) was tested in an in vivo rat model to delineate the signaling mechanism. Induction of PD in rats demonstrated elevated oxidative stress with an evidenced decrease in antioxidant enzymes, while elevated pro-inflammatory cytokines and inflammatory mediators were observed in the striatum of PD rats compared to controls. On the other hand, elevated (p < 0.01) levels of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), mRNA transcript of HDAC-2, -3, -4, -6 and total histone deacetylase (HDAC) were found with reduced levels of histone acetyltransferase (HAT) in the brain tissues of PD induced rats. Diversely, H2S exposure reversed these alterations with reduced HDAC activity. Further, PD rats treated with HDAC inhibitor showed a dramatic upsurge in the level of tyrosine hydroxylase, with a decreased level of glial fibrillary acidic protein, α-synuclein, tumor necrosis factor α, and other cytokines. Thus the results of the study suggest that H2S exerts protection via inhibition of HDAC.

MicroRNA-326 Inhibits Apoptosis and Promotes Proliferation of Dopaminergic Neurons in Parkinson's Disease Through Suppression of KLK7-Mediated MAPK Signaling Pathway.

Parkinson's disease (PD), one of the motor system disorders, is characterized by the loss of dopamine-producing brain cells. Accumulating evidence has highlighted the involvement of microRNAs (miRs) in the development and progression of PD. Hence, we aimed at exploring possible effects of miR-326 on the progression of PD in mice in an attempt to elucidate the underlying mechanism associated with the kallikrein-related peptidase 7 (KLK7)-mediated mitogen-activated protein kinase (MAPK) signaling pathway. In order to identify the regulatory relationship between miR-326 and KLK7 and its biological significance in PD, PD mouse models were established and subsequently treated with mimics or inhibitors of miR-326 or siRNA-KLK7. The content of striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxytyrosine (3-MT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA); positive expression of tyrosine hydroxylase (TH) and inducible nitric oxide synthase (iNOS); and the levels of IL-1, IL-6, TNF-α, INF-γ, and MAPK signaling pathway-related genes were determined accordingly. The results obtained indicated that KLK7 was negatively targeted by miR-326, with lower miR-326 and higher KLK7 detected among PD mice. The overexpression of miR-326 or silencing of KLK7 was demonstrated to increase the content of DA, DOPAC, HVA, 3-MT, SOD, GSH-Px, and TH positive expression, while reducing iNOS positive expression, MDA content and cell apoptosis, as well as inhibited levels of IL-1, IL-6, TNF-α, INF-γ, and mRNA and protein levels of p38, ERK, JNK, and caspase-3. Taken together, these results provided evidence suggesting that miR-326 could inhibit iNOS activation and apoptosis of dopaminergic neurons through inhibiting the MAPK signaling pathway and negatively regulating KLK7 in mice with PD. These findings highlight the potential of miR-326 as a novel target for future PD treatment.

Effect of the 5-HT2C Receptor Agonist WAY-163909 on Serotonin and Dopamine Metabolism across the Rat Brain: A Quantitative and Qualitative Neurochemical Study.

The effects triggered by serotonin2C (5-hydroxytryptamin2C, 5-HT2C) receptor agonists in the brain are often subtle, and methodologies highlighting their widespread actions to account for their multiple modulatory influences on behaviors are still lacking. We report an extended analysis of a neurochemical database on monoamines obtained after the intraperitoneal administration of the preferential 5-HT2C receptor agonist WAY-163909 (0.3 and 3 mg/kg) in 29 distinct rat brain regions. We focused on the metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), the metabolites of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the index of the turnovers 5-HIAA/5-HT and DOPAC/DA. WAY-163909 increased and decreased 5-HIAA tissue levels in the amygdala and dorsolateral orbitofrontal cortex, respectively, and decreased the 5-HT turnover in the infralimbic cortex. It enhanced HVA levels in the medial orbitofrontal cortex and DOPAC levels in the amygdala. WAY-163909 increased and decreased DA turnover in the medial orbitofrontal cortex and the anterior insular cortex, respectively. The correlative analysis of the turnovers between pairs of brain regions revealed low levels of correlations across the brain but presented a distinct pattern of correlations after WAY-163909 was compared to saline-treated rats. WAY-163909, notably at 0.3 mg/kg, favored cortico-cortical and cortico-subcortical correlations of both turnovers separately, and frontal DOPAC/DA ratio with cortical and subcortical 5-HIAA/5-HT ratios at 3 mg/kg. In conclusion, the qualitative, but not the quantitative analysis shows that WAY-163909 alters the pattern of correlations across the brain, which could account for its multiple behavioral influences.

Chrysin protects against behavioral, cognitive and neurochemical alterations in a 6-hydroxydopamine model of Parkinson's disease

Parkinson’s disease (PD) is an age-related neurodegenerative disorder that severely affects quality of life of patients and their families. The flavonoid chrysin (5,7-dihydroxylflavone) is a naturally occurring flavone with several pharmacological activities, including anti-inflammatory and anti-oxidative. We investigated the effects of a 28-day chrysin treatment (10 mg/kg/day, i.g.) on a model of PD induced by 6-OHDA in aged (20-month old) mice. We found a protective effect of chrysin on behavioral and cognitive alterations (rotational behavior, passive avoidance and Barnes maze tests), nitric oxide synthesis (NOx), lipid peroxidation (HNE), glutathione levels (GSH), reactive species levels (RS), neuroinflammation (interleukin-1 beta - IL-1β and tumor necrosis factor alpha - TNF-α), Na+, K+-ATPase and nicotinamide adenine dinucleotide phosphate oxidase activity (NADPH oxidase) activities. In addition, chrysin protected against changes in striatal dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. In conclusion, chrysin improved several behavioral, cognitive and neurochemical parameters in a relevant preclinical model of PD in aged mice.

Electrophoretically Sheathed Carbon Fiber Microelectrodes with Metal/Nitrogen/Carbon Electrocatalyst for Electrochemical Monitoring of Oxygen in Vivo.

Metal/nitrogen/carbon (M/N/C, M = Co or Fe) nanomaterials have been demonstrated to catalyze oxygen reduction reaction (ORR) with implication in fuel cell studies; however, their potential application as sensing materials for in vivo monitoring of oxygen (O2) in the central nervous system has never been reported. This study reports a first demonstration that M/N/C nanomaterials can be used as sensing materials to form an electrochemical assay for in vivo O2 monitoring. To demonstrate this application, the M/N/C nanocomposites prepared by pyrolysis of zeolitic imidazolate framework (ZIF-67) are used as an example and is electrophoretically deposited onto carbon fiber microelectrodes (CFEs) to catalyze a four-electron reduction of O2 without producing cell-toxic hydrogen peroxide intermediate. The M/N/C-sheathed CFEs have high catalytic performance toward ORR in a neutral solution, selectivity toward O2 sensing in the presence of ascorbic acid (AA), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), uric acid (UA), and 5-hydroxytryptamine (5-HT) at their physiological levels in rat brain, and capability to real-time monitor O2 fluctuation during respiring gases. This study offers a new electrochemical approach to in vivo O2 monitoring with nonplatinum catalyst for ORR.

Neurotransmitter disturbances in some parts of the rat brain and their correction under chronic and intermittent alcohol intoxication

The pool of key neuromediators and some neurotransmitter amino acids in cerebellum, hypothalamus and midbrain of rats exposed to chronic and different variants of interrupted alcohol intoxication was investigated. The most pronounced changes were recorded in midbrain. Chronic alcohol intoxication caused an increase in the concentrations of tyrosine, dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), noradrenaline, tryptophan, serotonin, GABA and aspartate in this part of the rat brain. Interrupted alcohol intoxication with 4 days interval is accompanied by an increase in the content of tyrosine, and noradrenaline. Interrupted alcohol intoxication with 1 day interval leaded to an increase in the concentrations of tyrosine, DOPAC, noradrenalin, tryptophan, GABA, glycine and aspartate. The amino acids composition "Titacin" had a pronounced normalizing effect in the midbrain under interrupted alcohol intoxication with 1 day interval.

Cerebrospinal Fluid Concentrations of Biogenic Amines: Potential Biomarkers for Diagnosis of Bacterial and Viral Meningitis.

Catecholamine and serotonin are biogenic amines (BAs) that serve as neurotransmitters and play an important role in the regulation of cardinal functions that are mainly altered during central nervous system (CNS) infections. A total 92 samples of cerebrospinal fluid (CSF) were classified into 4 groups based on their etiology. In these samples, BAs/neurotransmitters i.e., dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5HIAA) were detected and quantified by high performance liquid chromatography with electrochemical detection (HPLC-EC) to determine the neurophysiology of the CNS infections by bacteria (Listeria monocytogenes (Lm) and Neisseria meningitidis (Nm)) and herpes simplex virus (HSV). CSF concentration of DA, DOPAC, HVA, and 5HIAA were found significantly elevated in all test cohorts. Present study highlights that the analysis of BAs is pivotal for the early diagnosis of bacterial and viral meningitis. In addition, coinfections of varied etiology can also be diagnosed by their quantification. Thus, BAs can serve as potential biomarkers of these CNS infections.