Norepinephrine Synthesis Research Articles

Analysis of Rare Variants in 470,000 Exome-Sequenced UK Biobank Participants Implicates Novel Genes Affecting Risk of Hypertension

Introduction: A previous study of 200,000 exome-sequenced UK Biobank participants to test for association of rare coding variants with hypertension implicated two genes at exome-wide significance, DNMT3A and FES. A total of 42 genes had an uncorrected p value <0.001. These results were followed up in a larger sample of 470,000 exome-sequenced participants. Methods: Weighted burden analysis of rare coding variants in a new sample of 97,050 cases and 172,263 controls was carried out for these 42 genes. Those showing evidence for association were then analysed in the combined sample of 167,127 cases and 302,691 controls. Results: The association of DNMT3A and FES with hypertension was replicated in the new sample and they and the previously implicated gene NPR1, which codes for a membrane-bound guanylate cyclase, were all exome-wide significant in the combined sample. Also exome-wide significant as risk genes for hypertension were GUCY1A1, ASXL1, and SMAD6, while GUCY1B1 had a nominal p value of <0.0001. GUCY1A1 and GUCY1B1 code for subunits of a soluble guanylate cyclase. For two genes, DBH, which codes for dopamine beta hydroxylase, and INPPL1, rare coding variants predicted to impair gene function were protective against hypertension, again with exome-wide significance. Conclusion: The findings offer new insights into biological risk factors for hypertension which could be the subject of further investigation. In particular, genetic variants predicted to impair the function of either membrane-bound guanylate cyclase, activated by natriuretic peptides, or soluble guanylate cyclase, activated by nitric oxide, increase risk of hypertension. Conversely, variants impairing the function of dopamine beta hydroxylase, responsible for the synthesis of norepinephrine, reduce hypertension risk.

Norepinephrine and dopamine contribute to distinct repetitive behaviors induced by novel odorant stress in male and female mice

Exposure to unfamiliar odorants induces an array of repetitive defensive and non-defensive behaviors in rodents which likely reflect adaptive stress responses to the uncertain valence of novel stimuli. Mice genetically deficient for dopamine β-hydroxylase (Dbh−/−) lack the enzyme required to convert dopamine (DA) into norepinephrine (NE), resulting in globally undetectable NE and supranormal DA levels. Because catecholamines modulate novelty detection and reactivity, we investigated the effects of novel plant-derived odorants on repetitive behaviors in Dbh−/− mice and Dbh+/− littermate controls, which have catecholamine levels comparable to wild-type mice. Unlike Dbh+/− controls, which exhibited vigorous digging in response to novel odorants, Dbh−/− mice displayed excessive grooming. Drugs that block NE synthesis or neurotransmission suppressed odorant-induced digging in Dbh+/− mice, while a DA receptor antagonist attenuated grooming in Dbh−/− mice. The testing paradigm elicited high circulating levels of corticosterone regardless of Dbh genotype, indicating that NE is dispensable for this systemic stress response. Odorant exposure increased NE and DA abundance in the prefrontal cortex (PFC) of Dbh+/− mice, while Dbh−/− animals lacked NE and had elevated PFC DA levels that were unaffected by novel smells. Together, these findings suggest that novel odorant-induced increases in central NE tone contribute to repetitive digging and reflect psychological stress, while central DA signaling contributes to repetitive grooming. Further, we have established a simple method for repeated assessment of stress-induced repetitive behaviors in mice, which may be relevant for modeling neuropsychiatric disorders like Tourette syndrome or obsessive-compulsive disorder that are characterized by stress-induced exacerbation of compulsive symptoms.

Modeling the Progression of Cardiac Catecholamine Deficiency in Lewy Body Diseases.

BackgroundLewy body diseases (LBDs) feature deficiency of the sympathetic neurotransmitter norepinephrine in the left ventricular myocardium and sympathetic intra‐neuronal deposition of the protein alpha‐synuclein (αS). LBDs therefore are autonomic synucleinopathies. Computational modeling has revealed multiple functional abnormalities in residual myocardial sympathetic noradrenergic nerves in LBDs, including decreased norepinephrine synthesis, vesicular storage, and recycling. We report an extended model that enables predictions about the progression of LBDs and effects of genetic predispositions and treatments on that progression.Methods and ResultsThe model combines cardiac sympathetic activation with autotoxicity mediated by the dopamine metabolite 3,4‐dihydroxyphenylacetaldehyde. We tested the model by its ability to predict longitudinal empirical data based on cardiac sympathetic neuroimaging, effects of genetic variations related to particular intra‐neuronal reactions, treatment by monoamine oxidase inhibition to decrease 3,4‐dihydroxyphenylacetaldehyde production, and post‐mortem myocardial tissue contents of catecholamines and αS. The new model generated a triphasic decline in myocardial norepinephrine content. This pattern was confirmed by empirical data from serial cardiac 18F‐dopamine positron emission tomographic scanning in patients with LBDs. The model also correctly predicted empirical data about effects of genetic variants and monoamine oxidase inhibition and about myocardial levels of catecholamines and αS.ConclusionsThe present computational model predicts a triphasic decline in myocardial norepinephrine content as LBDs progress. According to the model, disease‐modifying interventions begun at the transition from the first to the second phase delay the onset of symptomatic disease. Computational modeling coupled with biomarkers of preclinical autonomic synucleinopathy may enable early detection and more effective treatment of LBDs.

0810 Management of Narcolepsy In A Patient With Severe Chronic Iron Deficiency: The Importance of Addressing Nutritional Deficiencies In The Treatment of Narcolepsy and Hypersomnias

Abstract Introduction Since iron is a cofactor used in the synthesis of CNS dopamine, some of which is then converted into norepinephrine, CNS iron deficiency will have an impact on the availability of dopamine and norepinephrine. Medications for narcolepsy and hypersomnia, such as stimulants and wakefulness medications, are dependent on the availability of these neurotransmitters to achieve their clinical response. Unrecognized and untreated nutritional deficiencies may contribute to inadequate responses to treatment of these sleep disorders. Report of Cases: A 26-year-old female with a history of iron deficiency since her pre-kindergarten health evaluation had a history of inadequate responses to stimulants and wakefulness medications. Additional labs were drawn to evaluate for nutritional deficiencies that could be contributing to the combination of fatigue and hypersomnolence. These revealed continued severe iron deficiency along with vitamin B6, B12, and D deficiencies. The treatment plan then expanded to include treatment of the nutritional deficiencies and a trial of pitolisant, which works to increase histamine levels in the brain. Sadly, pitolisant resulted in intolerable headaches, so it was discontinued. Conclusion This author feels that patients with hypersomnia warrant a broader approach that includes evaluating for nutritional deficiencies which may contribute to fatigue and hypersomnolence. In this case, the plan was to address the patient’s nutritional deficiencies and switch to pitolisant which mediates increased CNS histamine levels. This was unsuccessful due to the side effect of increased frequency and intensity of headaches related to pitolisant. Treating her iron deficiency with iron infusions should increase CNS synthesis of dopamine and norepinephrine. She may now have a better response to stimulants or wakefulness medications which depend on the availability of these neurotransmitters. She may also benefit from combination therapy by adding sodium oxybate to one of these medications. Support (If Any)

α-synuclein enfolds tyrosine hydroxylase and dopamine ß-hydroxylase, potentially reducing dopamine and norepinephrine synthesis.

Parkinson's disease (PD) results from degeneration of dopamine and norepinephrine neurons due to α-synuclein aggregates that likely have their origin in the gut. Tyrosine hydroxylase (TH) catalyses the formation of L-DOPA, the rate-limiting step in the biosynthesis of dopamine. A second enzyme, DOPA decarboxylase (DDC), catalyzes the conversion of L-DOPA to dopamine. A third enzyme, dopamine ß-hydroxylase (DBH), catalyzes the conversion of dopamine to norepinephrine. To analyze possible interactions of α-synuclein with TH, DDC and DBH, we performed in silico protein-protein docking. Protein data bank (pdb) entries were searched on the RCSB Protein Data Bank. We identified four structures that allowed us to examine the relationship of α-synuclein with TH, DDC, and DBH: (1) Human micelle-bound alpha-synuclein, (2) solution structure of the regulatory domain of tyrosine hydroxylase (Rattus norvegicus), (3) crystal structure of human aromatic L-amino acid decarboxylase (DOPA decarboxylase) in the apo form and (4) crystal structure of human dopamine ß-hydroxylase at 2.9 angstrom resolution. We used the ClusPro server (https://cluspro.org) for protein-protein docking. The protein structures were visualized with PyMOL v 2.3.4. α-synuclein partially enfolds tyrosine hydroxylase and dopamine ß-hydroxylase, potentially reducing dopamine and norepinephrine synthesis. α-synuclein may dock too far away from DOPA decarboxylase to affect its function directly. Our in silico finding of α-synuclein partly enfolding tyrosine hydroxylase and dopamine ß-hydroxylase suggests that α-synuclein docking inhibition could increase dopamine and norepinephrine biosynthesis, ameliorating PD symptoms. Small molecules that bind to α-synuclein have already been identified. Further studies may lead to new small molecule drugs that block α-synuclein enfolding of tyrosine hydroxylase and dopamine ß-hydroxylase.

Clinical efficacy and safety of vitamin C in the treatment of septic shock patients: systematic review and meta-analysis.

Vitamin C deficiency is common in sepsis patients and is related to disease severity. At present, sepsis still has a high incidence and fatality rate. In sepsis, the body may develop microcirculation disorders and even develop organ failure. Exogenous vitamin C supplementation may be one of the effective adjuvant treatment measures for sepsis, which can not only improve the microcirculation of the body, but also affect the prognosis of patients by participating in the synthesis of norepinephrine, improving peripheral vascular resistance and increasing perfusion pressure. The efficacy and safety of vitamin C adjuvant therapy for septic shock are inconsistent in many studies, so it is very important to systematically evaluate the adjuvant effect of intravenous vitamin C in the treatment of septic shock. Literature search of PubMed, EMBASE, The Cochrane Library, Web of Science, Wanfang, China Biology Medicine (CBM), and China National Knowledge Infrastructure (CNKI) electronic databases for vitamin C data since August 2021 for the treatment of patients with sepsis and septic shock. After screening, data extraction and quality evaluation were performed according to inclusion criteria, and meta-analysis was conducted using RevMan 5.3. The final 13 studies comprised 6 cohort studies and 7 randomized controlled trials (RCTs), with a total of 1,423 patients enrolled. Meta-analysis showed no significant effect of intravenous vitamin C on reducing in-hospital mortality rate [odds ratio (OR) =0.91, 95% confidence interval (CI): 0.76-1.08, P=0.27], intensive care unit (ICU) mortality rate (OR =0.84, 95% CI: 0.69-1.01, P=0.07), ICU stay (OR =0.88, 95% CI: 0.72-1.08, P=0.23) or total stay (OR =0.91, 95% CI: 0.68-1.21, P=0.51) in sepsis patients, nor did it improve the 72-h sequential organ failure assessment (72-h SOFA) score (OR =0.95, 95% CI: 0.77-1.18, P=0.66). Intravenous vitamin C showed no efficacy in the treatment of sepsis.

Altered locus coeruleus activity and neurochemistry in the presence of Alzheimer's disease-like hyperphosphorylated tau pathology.

The locus coeruleus (LC), the main source of norepinephrine (NE) in the brain, develops tau pathology prior to other brain regions and later degenerates in Alzheimer's disease (AD). Emergence of prodromal symptoms before cognitive impairment is evident, such as anxiety, agitation, and sleep disturbances, parallels development of hyperphosphorylated tau in the LC. Although pathogenic tau can alter the activity of other neurons, and noradrenergic dysfunction likely contributes to prodromal AD symptoms, the consequences of hyperphosphorylated tau on LC function are unknown. TgF344-AD rats, which develop hyperphosphorylated tau in the LC prior to other brain regions, and wild-type (WT) littermates aged 6 and 15 months (3-10 rats/group) were used. Baseline and footshock (0.5ms and 5ms 10mA)-evoked single unit LC activity (27-111 neurons/group) were recorded in chloral hydrate anesthetized rats. LC sections from duplicate groups of rats were immunostained for tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) to proxy NE synthesis capacity, NE transporter (NET) to assess somatodendritic LC integrity and NE uptake, monoamine oxidase A (MAOA) to evaluate NE metabolism, galanin to measure peptide co-transmitter levels, and GAD67 to investigate local inhibitory networks (3-4 slices/animal, 2-7 animals/group). Grayscaled fluorescence was measured in ImageJ. Electrophysiology revealed a trend towards increased LC baseline firing rates in WT and TgF344-AD rats at 15 months vs 6 months, with no genotype differences. Footshock-evoked LC activity tended to be exaggerated in TgF344-AD rats at 6 months, but blunted or unchanged at 15 months compared to WT. Immunofluorescence indicated decreased NET in TgF344-AD rats at 6 months, with both genotypes showing a reduction at 15 months compared to younger animals. GAD67 was significantly higher in 15-month animals compared to 6 months, with no genotype differences. No significant effects of genotype or age were found for MAOA, DBH, or galanin. These results suggest early LC dysfunction that coincides with the onset of hyperphosphorylated tau pathology. Further studies investigating the time course of LC dysfunction in AD, as well as therapies aimed at correcting these abnormalities, are warranted.

Acute inhibition of dopamine β-hydroxylase attenuates behavioral responses to pups in adult virgin California mice (Peromyscus californicus)

In biparental species, in which both parents care for their offspring, the neural and endocrine mediators of paternal behavior appear to overlap substantially with those underlying maternal behavior. Little is known, however, about the roles of classical neurotransmitters, such as norepinephrine (NE), in paternal care and whether they resemble those in maternal care. We tested the hypothesis that NE facilitates the initiation of nurturant behavior toward pups in virgin male and female California mice (Peromyscus californicus), a biparental rodent. Virtually all parents in this species are attracted to familiar and unfamiliar pups, while virgins either attack, avoid, or nurture pups, suggesting that the neurochemical control of pup-related behavior changes as mice transition into parenthood. We injected virgin males and females with nepicastat, a selective dopamine β-hydroxylase inhibitor that blocks NE synthesis (75 mg/kg, i.p.), or vehicle 2 h before exposing them to a novel pup, estrous female (males only), or pup-sized novel object for 60 min. Nepicastat significantly reduced the number of males and females that approached the pup and that displayed parental behavior. In contrast, nepicastat did not alter virgins' interactions with an estrous female or a novel object, suggesting that nepicastat-induced inhibition of interactions with pups was not mediated by changes in generalized neophobia, arousal, or activity. Nepicastat also significantly reduced NE levels in the amygdala and prefrontal cortex and increased the ratio of dopamine to NE in the hypothalamus. Our results suggest that NE may facilitate the initiation of parental behavior in male and female California mice.

The Locus Coeruleus in Aging and Alzheimer's Disease: A Postmortem and Brain Imaging Review.

The locus coeruleus (LC), a tiny nucleus in the brainstem and the principal site of noradrenaline synthesis, has a major role in regulating autonomic function, arousal, attention, and neuroinflammation. LC dysfunction has been linked to a range of disorders; however particular interest is given to the role it plays in Alzheimer’s disease (AD). The LC undergoes significant neuronal loss in AD, thought to occur early in the disease process. While neuronal loss in the LC has also been suggested to occur in aging, this relationship is less clear as the findings have been contradictory. LC density has been suggested to be indicative of cognitive reserve and the evidence for these claims will be discussed. Recent imaging techniques allowing visualization of the LC in vivo using neuromelanin-sensitive MRI are developing our understanding of the role of LC in aging and AD. Tau pathology within the LC is evident at an early age in most individuals; however, the relationship between tau accumulation and neuronal loss and why some individuals then develop AD is not understood. Neuromelanin pigment accumulates within LC cells with age and is proposed to be toxic and inflammatory when released into the extracellular environment. This review will explore our current knowledge of the LC changes in both aging and AD from postmortem, imaging, and experimental studies. We will discuss the reasons behind the susceptibility of the LC to neuronal loss, with a focus on the role of extracellular neuromelanin and neuroinflammation caused by the dysfunction of the LC-noradrenaline pathway.

Tyrosine Supplementation A Nutraceutical Approach to Counter Heat Stress Induced Cognitive Decline

Supplementation of tyrosine, non-essential amino acid, and precursor of catecholamine was found to ameliorate the heat-induced alterations in latencies of event-related potential P300 and contingent negative variation. Here we present the effect of tyrosine supplementation on heat stress (exposure to ambient temperature 45 oC and relative humidity 30 %) induced alterations in behavior (attention, mood) and levels of plasma monoamines. Ten healthy male participants received a placebo food bar or tyrosine-containing food bar (6.5 g in 50 g) 90 min before heat stress exposure of 90 min. Plasma and urine samples were assayed for catecholamine levels, their precursor, and metabolites using high-performance liquid chromatography. A computer-based automated test battery was used to assess attention and mood by profile of mood states questionnaire. A significantly higher plasma tyrosine (p&lt;0.001) leading to an increased norepinephrine (p&lt;0.05) levels in the tyrosine supplemented group was observed. Selective (p&lt;0.001) and sustained attention (p&lt;0.02) in the tyrosine group were significantly better compared to the placebo group. Reaction time and anger scores decreased (p&lt;0.001) with tyrosine supplementation. It may be concluded that tyrosine supplementation improves heat stress-induced decrement in attention by maintaining the synthesis and turnover of norepinephrine.

Serum tyrosine is associated with better cognition in Lewy body dementia

Amino acids’ neuroactivity, and roles in excitotoxity and oxidative stress are linked to dementia. We aimed to investigate whether circulating amino acid concentrations were associated with cognitive decline in patients with mild Alzheimer’s disease (AD) and Lewy body dementia (LBD). Baseline serum amino acid concentrations were measured in 89 patients with AD and 65 with LBD (13 with Parkinson’s disease dementia and 52 with dementia with Lewy bodies). The Mini-Mental State Examination (MMSE) was administered at baseline and annually for five years. Associations between baseline amino acid concentrations and longitudinal MMSE score were assessed using a linear-mixed effects model stratified by diagnosis with adjustment for multiple comparisons. The results of the study indicated that serum tyrosine was positively associated with MMSE performance during the five-year follow-up period in patients with LBD (q-value = 0.012), but not AD. In conclusion, higher baseline serum concentrations of tyrosine, the precursor amino acid in dopamine and norepinephrine synthesis, was associated with better cognitive performance in patients with LBD, but not AD, throughout the 5-year follow-up period.

Dopamine in Auditory Nuclei and Lemniscal Projections is Poised to Influence Acoustic Integration in the Inferior Colliculus.

Dopamine (DA) modulates the activity of nuclei within the ascending and descending auditory pathway. Previous studies have identified neurons and fibers in the inferior colliculus (IC) which are positively labeled for tyrosine hydroxylase (TH), a key enzyme in the synthesis of dopamine. However, the origins of the tyrosine hydroxylase positive projections to the inferior colliculus have not been fully explored. The lateral lemniscus (LL) provides a robust inhibitory projection to the inferior colliculus and plays a role in the temporal processing of sound. In the present study, immunoreactivity for tyrosine hydroxylase was examined in animals with and without 6-hydroxydopamine (6-OHDA) lesions. Lesioning, with 6-OHDA placed in the inferior colliculus, led to a significant reduction in tyrosine hydroxylase immuno-positive labeling in the lateral lemniscus and inferior colliculus. Immunolabeling for dopamine beta-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT), enzymes responsible for the synthesis of norepinephrine (NE) and epinephrine (E), respectively, were evaluated. Very little immunoreactivity for DBH and no immunoreactivity for PNMT was found within the cell bodies of the dorsal, intermediate, or ventral nucleus of the lateral lemniscus. The results indicate that catecholaminergic neurons of the lateral lemniscus are likely dopaminergic and not noradrenergic or adrenergic. Next, high-pressure liquid chromatography (HPLC) analysis was used to confirm that dopamine is present in the inferior colliculus and nuclei that send projections to the inferior colliculus, including the cochlear nucleus (CN), superior olivary complex (SOC), lateral lemniscus, and auditory cortex (AC). Finally, fluorogold, a retrograde tracer, was injected into the inferior colliculus of adult rats. Each subdivision of the lateral lemniscus contained fluorogold within the somata, with the dorsal nucleus of the lateral lemniscus showing the most robust projections to the inferior colliculus. Fluorogold-tyrosine hydroxylase colocalization within the lateral lemniscus was assessed. The dorsal and intermediate nuclei neurons exhibiting similar degrees of colocalization, while neurons of the ventral nucleus had significantly fewer colocalized fluorogold-tyrosine hydroxylase labeled neurons. These results suggest that several auditory nuclei that project to the inferior colliculus contain dopamine, dopaminergic neurons in the lateral lemniscus project to the inferior colliculus and that dopaminergic neurotransmission is poised to play a pivotal role in the function of the inferior colliculus.

Elevated norepinephrine metabolism is linked to cortical thickness in the context of Alzheimer's disease pathology

Advanced Alzheimer's disease (AD) is characterized by higher noradrenaline metabolite levels that may be associated with AD pathology. The locus coeruleus (LC) is the main site for cerebral noradrenaline synthesis and LC volume loss occurs as early as Braak stage 1. This study investigates the association between noradrenergic turnover and brain morphology, and the modifying effect of AD pathology. The study sample included 77 memory clinic patients (37 cognitively unimpaired and 40 cognitively impaired (mild cognitive impairment or AD dementia)). Cortical thickness and volumetric analyses were performed using FreeSurfer. Cerebrospinal fluid was analyzed for noradrenergic metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), Aβ42 and phosphorylated tau. Higher MHPG was associated with lower cortical thickness and hippocampal volume at lower, but subthreshold, levels of Aβ42 and at higher p-tau levels. These associations remained significant after adding APOE-E4 or cognitive status as covariates. Our results suggest that greater MHPG together with worse AD pathology contributes to neurodegeneration, possibly before significant amyloidosis. The noradrenergic system may play an important role in early detection of AD-related processes.

Correlation between Interleukin-6 Levels and Total PANSS Scores in Batak People with Schizophrenia

BACKGROUND: Schizophrenia is an illness characterized by distorted thoughts, hallucinations, and reduced ability to feel normal emotions, and this has been linked to immunity, environment, and heredity factors. The particular interest in this context is the stimulating effects of pro-inflammatory cytokines on dopamine, noradrenaline synthesis, and release.&#x0D; AIM: The aim of the study was to investigate the correlation between interleukin (IL)-6 levels and total PANSS scores in people with schizophrenia from the Batak tribe.&#x0D; METHODS: This study was a numeric-numeric correlation analytic study. The research subjects were 47 inpatients (n = 47) at Prof. M. Ildrem Mental Hospital Medan, Indonesia, who were diagnosed based on the criteria of the international classification of disease-10 in the acute phase of treatment aged 15–45 years. IL-6 levels were obtained from blood serum enzyme-linked immunosorbent assay. Statistical analysis used the statistical package for the social science software.&#x0D; RESULTS: The study found that there was a positive correlation between IL-6 levels and total PANSS scores in Batak people with schizophrenia (p = 0.001; r = 0.657); IL-6 levels and positive symptom (p = 0.001; r = 0.696); and IL-6 levels and negative symptom (p = 0.001; r = 0.532). However, there was no correlation between IL-6 levels and general psychopathological scores in Batak people with schizophrenia.&#x0D; CONCLUSION: There was a correlation between IL-6 levels and the total PANSS score, positive symptom scores, and negative symptom scores in people with schizophrenia from the Batak tribe.

Clioquinol inhibits dopamine-β-hydroxylase secretion and noradrenaline synthesis by affecting the redox status of the copper chaperone ATOX1

Clioquinol, a chelator and ionophore of copper/zinc, was extensively used as an amebicide to treat indigestion and diarrhea in the mid-1900s. However, it was withdrawn from the market in Japan because its use was epidemiologically linked to an increase in the incidence of subacute myelo-optic neuropathy (SMON). Yet, the pathogenesis of SMON has not been fully elucidated. A reporter assay revealed that clioquinol activated metal response element-dependent transcription in human neuroblastoma SH-SY5Y cells. Clioquinol significantly increased the cellular level of zinc within 1 h, possibly due to its ionophore effects. On the other hand, clioquinol significantly increased the cellular level of copper within 24 h. Clioquinol induced the oxidation of the copper chaperone antioxidant 1 (ATOX1), suggesting its inactivation and inhibition of copper transport. The secretion of dopamine-β-hydroxylase (DBH) and lysyl oxidase, both of which are copper-dependent enzymes, was inhibited by clioquinol, along with decreased noradrenaline levels. In fact, disruption of the ATOX1 gene suppressed the secretion of DBH. Taken together, the disturbance of cellular copper transport by the inactivation of ATOX1 may be one of the mechanisms involved in clioquinol-induced neurotoxicity in SMON.

Tetrahydrobiopterin deficiency in schizophrenia as a new target for personalized medicine

Summary. Tetrahydrobiopterin (BH4) is an important cofactor, that involved in the synthesis of dopamine, norepinephrine, and serotonin, as well as affecting the production of nitric oxide (NO) and regulating the activity of the glutamatergic system. A few foreign studies have shown, that patients with schizophrenia had a markedly reduced level of BH4 compared to the healthy population. The aim of this work was to study the association of BH4 deficiency with the risk of schizophrenia among Russian patients by comparison with a group of healthy volunteers.Materials and methods: 50 patients with schizophrenia and 36 healthy volunteerswere randomly selected and underwent a biochemical study of the BH4 level using the method of competitive enzyme immunoassay (ELISA) on a spectrophotometer (Sunrise, Tecan) with a set of CEG421Ge (CloudClone Corp).Results: it was found that the BH4 level was significantly lower in patients than in the controlgroup (3684.75 [1283.00; 4815.00] versus 4260.60 [4057.40; 5236.85] pmol / l, respectively, p = 0 , 0016). The proportion of patients with a BH4 level below the lower limit of the interquartile range in healthy volunteers (4057.40 pmol / l) is 30/50 (60%), the proportion of healthy volunteers with a BH4 level below this border is 9/36 (25%), the difference is statistically significant, χ2 = 10.35; p = 0.002; OR = 4.5; 95% CI [1.75; 11.56](CI — confidence interval). The correlation of BH4 level with the duration of the disease, gender, age of the subjects is very weak and not statistically significant.Conclusion: further interdisciplinary studies are required to identify the causes and molecular mechanisms for the development of BH4 deficiency in schizophrenia and to develop approaches to personalized pharmacological intervention.

Time-Dependent Effects of Acute Handling on the Brain Monoamine System of the Salmonid Coregonus maraena.

The immediate stress response involves the activation of the monoaminergic neurotransmitter systems including serotonin, dopamine and noradrenaline in particular areas of the fish brain. We chose maraena whitefish as a stress-sensitive salmonid species to investigate the influence of acute and chronic handling on the neurochemistry of monoamines in the brain. Plasma cortisol was quantified to assess the activation of the stress axis. In addition, we analyzed the expression of 37 genes related to the monoamine system to identify genes that could be used as markers of neurophysiological stress effects. Brain neurochemistry responded to a single handling (1 min netting and chasing) with increased serotonergic activity 3 h post-challenge. This was accompanied by a modulated expression of monoaminergic receptor genes in the hindbrain and a significant increase of plasma cortisol. The initial response was compensated by an increased monoamine synthesis at 24 h post-challenge, combined with the modulated expression of serotonin-receptor genes and plasma cortisol concentrations returning to control levels. After 10 days of repeated handling (1 min per day), we detected a slightly increased noradrenaline synthesis and a down-regulated expression of dopamine-receptor genes without effect on plasma cortisol levels. In conclusion, the changes in serotonergic neurochemistry and selected gene-expression profiles, together with the initial plasma cortisol variation, indicate an acute response and a subsequent recovery phase with signs of habituation after 10 days of daily exposure to handling. Based on the basal expression patterns of particular genes and their significant regulation upon handling conditions, we suggest a group of genes as potential biomarkers that indicate handling stress on the brain monoamine systems.

SUBMICROSCOPIC TRANSFORMATIONS OF THE HYPOTHALAMUS STRUCTURE UNDER CONDITIONS OF 24-HOUR LIGHTING

Light information that is perceived by the retinal photoreceptors is transmitted along the retinohypothalamic pathway (the retinal ganglion cells present in it) and supraoptic fibers, suprachiasmatic, paraventricular, arcuate nuclei of the hypothalamus, through the trunk of the upper thoracic region and lateral intermedial nuclei of the spinal cord, sym- pathic neurons of the superior cervical ganglion in the pineal gland. In the dark, signals from the suprachiasmatic nucleus enhance the synthesis and release of norepinephrine from sympathetic endings. The experiments were carried out on 40 sexually mature male outbred white rats weighing 0.15-0.18 kg. The animals were kept in cages at a constant temperature, air humidity and free access to water and food. Experimental animals were divided into two series, in each of which the biomaterial was taken at 14.00 and 02.00 h. The selected timing of the experiment is due to the different functional activity of the pineal gland in the indicated time periods of the day. Submicroscopic studies of the supraoptic nuclei of the hypothalamus of intact animals at 14:00 showed that the majority of neurosecretory cells are round-oval in shape with rare invaginations and nuclei of irregular shape with shallow invaginations of the karyolem. The karyoplasm contains lumps of chromatin and a dense osmiophilic nucleolus. Neuroplasm occupies a small volume, in it the tubules of the granular endoplasmic reticulum are tightly packed with a small lumen, where there are many ribosomes and polysomes, as well as a small amount of evenly distributed granules. In the Golgi complex, secretory granules of different sizes are formed. Mitochondria, small with a dense matrix, contain few cristae. Some of them are in an energetically stressed state, are able to hypertrophy and partially lose their cristae or die. The ultramicroscopic organization of neurosecretory cells of the supraoptic nuclei of the anterior hypothalamus of rats was investigated. Under the standard illumination mode (12.00C: 12.00T), the ultrastructure of neurons indicates a decrease in their functional activity during the light period of the day and growth - in the dark period of the day. Light stress (24.00C: 00T) leads to significant desynchronosis and causes destructive changes in the components of the structures under study, more pronounced at 02.00 h.

ЗГАСЛА ЯСКРАВА ЗІРКА В СУЗІР’Ї ВИДАТНИХ НЕЙРОНАУКОВЦІВ (спомин про Олега Горникевича)

Oleh Hornykiewicz, one of the most accomplished neuropharmacologists of the 20th century passed away on May 26, 2020 at the age of 93. In 1939, Oleh’s father, a Ukrainian Catholic priest, fled with his young family from Soviet-occupied Ukraine and settled in Vienna. During his medical studies, Oleh became fascinated by pharmacology and in 1956 was awarded a fellowship to Oxford University (U.K.) where he worked with Dr. Hermann Blaschko, a pioneer in the study of enzymes of catecholamine synthesis and metabolism. At that time, it was still thought that dopamine was merely an intermediate in the synthesis of norepinephrine. Dr. Hornykiewicz demonstrated that even after its breakdown had been blocked, administration of dopamine or its precursor L-DOPA could elevate blood pressure in animal models. Dopamine was bioactive per se. Upon his return to Vienna in 1958, the young scientist began studying dopamine in the brain. Familiar with Parkinson’s Disease and intrigued by Arvid Carlsson’s finding that L-DOPA could counteract the akinesia of the reserpenized rat, Dr. Hornyckiewicz began to suspect that a dopamine deficiency mediated the motor symptoms of Parkinson’s disease. He developed new techniques, applied these to the study of postmortem brains, and demonstrated that Parkinson’s disease was associated with a dopamine deficiency in the basal ganglia. Shortly afterwards, he and Walter Birkmeyer observed how the intravenous administration of L-DOPA could awaken mute and akinetic patients with Parkinson’s disease. For the first time, a discreet chemical was both implicated in a complex brain disorder and could be used as a treatment. This stands as one of the seminal discoveries in neuropharmacology. To this day, L-DOPA remains a mainstay in the treatment of Parkinson’s disease. Over the following half-century Dr. Hornykiewicz continued his own work, generously mentored others and established brain banks in Vienna as well as in Toronto, Canada where he worked for many years. He received numerous awards, and was nominated for but not awarded the Nobel Prize in Medicine, in a decision that has remained controversial. He will remain forever, a brilliant star in the history of neuropharmacology.

Central deficiency of norepinephrine synthesis and norepinephrinergic neurotransmission contributes to seizure-induced respiratory arrest

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of mortality in patients with intractable epilepsy. However, the pathogenesis of SUDEP seems to be poorly understood. Our previous findings showed that the incidence of seizure-induced respiratory arrest (S-IRA) was markedly reduced by atomoxetine in a murine SUDEP model. Because the central norepinephrine α-1 receptor (NEα-1R) plays a vital role in regulating respiratory function, we hypothesized that the suppression of S-IRA by atomoxetine was mediated by NE/NEα-1R interactions that can be reversed by NEα-1R antagonism. We examined whether atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or pentylenetetrazole (PTZ) in DBA/1 mice can be reversed by intraperitoneal (IP) and intracerebroventricular (ICV) administration of prazosin, a selective antagonist of NEα-1R. The content and activity of tyrosine hydroxylase (TH), a rate-limiting enzyme for NE synthesis, in the lower brainstem was measured by ELISA. Electroencephalograms (EEG) were obtained from using the PTZ-evoked SUDEP model. In our models, atomoxetine-mediated suppression of S-IRA evoked by either acoustic stimulation or PTZ was significantly reversed by low doses of IP and ICV prazosin. Neither repetitive acoustic stimulation nor S-IRA reduced TH levels in lower brainstem. However, the enzyme activity of TH levels in lower brainstem was significantly increased by mechanical ventilation with DBA/1 mice, which makes the dying DBA/1 mice suffering from S-IRA and SUDEP recover. EEG data showed that although the protective effect of atomoxetine was reversed by prazosin, neither drug suppressed EEG activity. These data suggest that deficient synthesis of NE and norepinephrinergic neurotransmission contributed to S-IRA and that the NEα-1R is a potential therapeutic target for the prevention of SUDEP.