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1‐Kestose (KES), a dietary fiber and prebiotic carbohydrate, benefits various physiological functions. This study aimed to examine whether diets supplemented with KES over three consecutive generations could significantly affect some host physiological aspects, including behavioral phenotypes and gut microbial ecology. Mice that received KES‐supplemented diets for three generations demonstrated increased activity compared with those fed diets lacking KES. Furthermore, the KES group showed increased striatal dopamine (DA) and serotonin (5‐HT) levels. The observed increase in DA levels within the striatum was positively correlated with locomotor activity in the KES group but not in the control (CON) group. The α‐diversities were significantly lower in the KES group compared to the CON group. The three‐dimensional principal coordinate analysis revealed a substantial distinction between the KES and CON groups across each generation. At the genus level, most gut microbiota genera exhibited lower abundances in the KES group than in the CON group, except for Bifidobacteria and Akkermansia. Spearman's rank‐order analysis indicated significant negative correlations between the striatal DA levels and α‐diversity values. These findings suggest that prolonged supplementation with KES may stimulate increased locomotor activity along with elevated striatal DA levels, which are potentially associated with KES‐induced alterations in the gut microbiota. [ABSTRACT FROM AUTHOR]

Background: Sleep disorders are frequently associated with Parkinson's disease. Obstructive sleep apnea syndrome is one of these sleep disorders and is associated with the severity of motor symptoms in Parkinson's disease. Obstructive sleep apnea can lead to dopaminergic neuronal cell degeneration and may impair the clearance of α‐synuclein in Parkinson's disease. Striatal dopamine uptake is a surrogate marker of nigral dopaminergic cell damage. Objective: We aimed to investigate the differences in striatal dopamine availability between Parkinson's disease patients with or without obstructive sleep apnea. Methods: A total of 85 de novo and nonmedicated Parkinson's disease patients were enrolled. Full‐night polysomnography was performed for all patients, and obstructive sleep apnea was diagnosed as apnea/hypopnea index ≥5. Positron emission tomography was performed with 18F‐N‐(3‐fluoropropyl)‐2β‐carbon ethoxy‐3β‐(4‐iodophenyl) nortropane, and the regional standardized‐uptake values were analyzed using a volume‐of‐interest template and compared between groups with or without obstructive sleep apnea. Results: Dopamine availability in the caudate nucleus of the obstructive sleep apnea group was significantly lower than that of the nonobstructive sleep apnea group. On subgroup analysis, such association was found in female but not in male patients. In other structures (putamen, globus pallidus, and thalamus), dopamine availability did not differ between the two groups. Conclusion: This study supports the proposition that obstructive sleep apnea can contribute to reduced striatal dopamine transporter availability in Parkinson's disease. Additional studies are needed to assess the causal association between obstructive sleep apnea and the neurodegenerative process in Parkinson's disease. © 2023 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background: Idiopathic normal pressure hydrocephalus can present with parkinsonism. However, abnormalities of the striatal dopamine reuptake transporter are unclear. Objectives: To explore presence and features of striatal dopaminergic deficit in subjects with idiopathic normal pressure hydrocephalus as compared to Parkinson's disease (PD) patients and healthy controls. Methods: We investigated 50 subjects with idiopathic normal pressure hydrocephalus, 25 with PD, and 40 healthy controls. All participants underwent [123I]‐N‐ω‐fluoropropyl‐2β‐carbomethoxy‐3β‐(4‐iodophenyl)nortropane and single‐photon emission computed tomography to quantify the striatal dopamine reuptake transporter binding. All subjects with idiopathic normal pressure hydrocephalus underwent a levodopa (l‐dopa) challenge test and magnetic resonance imaging to evaluate ventriculomegaly and white matter changes. Gait, cognition, balance, and continence were assessed with the Idiopathic Normal Pressure Hydrocephalus Rating Scale, and parkinsonism with the motor section of the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale. All patients completed a 2‐year follow‐up. Results: A total of 62% of patients with idiopathic normal pressure hydrocephalus featured a reduced striatal dopamine reuptake transporter binding, which correlated with the severity of parkinsonism but not with features of ventriculomegaly or white matter changes. Unlike PD, this dopaminergic deficit in idiopathic normal pressure hydrocephalus was more symmetric and prominent in the caudate nucleus. Conclusions: Subjects with idiopathic normal pressure hydrocephalus can present a reduction of striatal dopamine reuptake transporter binding, which is consistent with the severity of parkinsonism and qualitatively differs from that found in PD patients. Longitudinal interventional studies are needed to prove a role for striatal dopamine reuptake transporter deficit in the pathophysiology of idiopathic normal pressure hydrocephalus. © 2020 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Extracts from Holothuria scabra (HS) have been shown to possess anti-inflammation, anti-oxidant and anti-cancer activities. More recently, it was shown to have neuroprotective potential in Caenorhabditis elegans PD model. Here, we assessed whether HS has neuroprotective and neurorestorative effects on dopaminergic neurons in both mouse and cellular models of PD. We found that both pre-treatment and post-treatment with HS improved motor deficits in PD mouse model induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as determined by grid walk test. This was likely mediated by HS protective and restorative effects on maintaining the numbers of dopaminergic neurons and fibers in both substantia nigra pars compacta (SNpc) and striatum. In a cellular model of PD, HS significantly attenuated 1-methyl-4-phenylpyridinium (MPP+)-induced apoptosis of DAergic-like neurons differentiated from SH-SY5Y cells by enhancing the expression of Bcl-2, suppressing the expression of cleaved Caspase 3 and preventing depolarization of mitochondrial membrane. In addition, HS could stimulate the expression of tyrosine hydroxylase (TH) and suppressed the formation of α-synuclein protein. Taken together, our in vivo and in vitro findings suggested that HS is an attractive candidate for the neuroprotection rather than neurorestoration in PD. [ABSTRACT FROM AUTHOR]

Background: Dopamine transporter (DAT) imaging may enable clinicians to discriminate idiopathic normal pressure hydrocephalus (iNPH) from other parkinsonian disorders. However, a specific pattern of dopaminergic loss in DAT imaging of iNPH patients remains to be further elucidated.Methods: In this preliminary study, 11 patients with iNPH in our hospital between March 2017 and February 2019 were finally enrolled. A diagnosis of iNPH was made according to the two established criteria. For visual analysis of DAT imaging, a striatum was divided into five domains. A semi-quantitative visual assessment was performed with a consensus between a nuclear medicine specialist and an experienced neurologist who were blinded to the clinical diagnosis.Results: Striatal dopaminergic deficits were abnormal in 90.9% (10/11) of patients with iNPH. The degree of dopaminergic reduction was mild and heterogeneous. However, a tendency of preferential striatal DAT loss in the caudate nucleus (90.9%, 10/11) than in the putamen (72.7%, 8/11) was observed, whereas ventral portion (9.1%, 1/11) was relatively preserved.Conclusion: Striatal dopaminergic depletion might be mild and heterogeneous in patients with iNPH. These dopaminergic deficits were more common in the caudate nucleus than in the putamen, suggesting a pattern different from other degenerative parkinsonian disorders. [ABSTRACT FROM AUTHOR]

Aim Huntington's disease ( HD) is an autosomal dominant disorder, for which clinically available drugs offer only symptomatic relief. These prescription drugs are not free of side effects, and the patients usually suffer from anxiety and depression. We investigated quercetin, a dietary flavonoid with free radical scavenging properties, for its beneficial potential if any, in 3-nitropropionic acid (3- NP)-induced HD in rats where both drugs were administered simultaneously. Methods Performance of rats on beam balancing, elevated plus maze and gait traits were investigated following 3- NP and/or quercetin treatments for 4 days. Striatal biogenic amine levels and monoamine oxidase activity were assayed. Striatal sections were examined for Cd11B and glial fibrillary acidic protein immunoreactivity, and for evidences of neuronal lesion. Results Quercetin significantly attenuated 3- NP-induced anxiety, motor coordination deficits, and gait despair. While the dopaminergic hyper-metabolism was unaffected, quercetin provided a significant reduction of 3- NP mediated increase in serotonin metabolism. Quercetin failed to affect 3- NP-induced striatal neuronal lesion, but decreased microglial proliferation, and increased astrocyte numbers in the lesion core. Conclusion These results taken together suggest that quercetin could be of potential use not only for correcting movement disturbances and anxiety in HD, but also for addressing inflammatory damages. [ABSTRACT FROM AUTHOR]

Background. Striatal dopamine activity declines with normal aging. Age-related striatal dopaminergic denervation (SDD) has been implicated in standing balance and unperturbed gait. The goal of this study was to analyze the association between the degree of SDD and the magnitude of an unexpected slip perturbation induced during gait. Methods. Fifty healthy participants aged 20–86 years old underwent dopamine transporter positron emission tomography to classify SDD severity as mild, moderate, or severe. Participants also walked on a floor that was unexpectedly contaminated with a glycerol solution for gait testing. The magnitude of a slip was quantified using the peak slip velocity (PSV), measured at the slipping foot. Data were analyzed for both fast (greater than 1.2 m/s) and slow walkers as gait speed correlated with slip severity. All data analyses were age adjusted. Results. Greater severity of dopaminergic denervation in the caudate nucleus was correlated with higher PSV (p < .01) but only in the fast speed walking group. The relationship between SDD in the putamen and slip severity was not statistically significant in fast and slow walkers. Conclusions. Age-related SDD may impact the ability to recover from large perturbations during walking in individuals who typically walk fast. This effect, prominent in the caudate nucleus, may implicate a role of cognitive frontostriatal pathways in the executive control of gait when balance is challenged by large perturbations. Finally, a cautious gait behavior present in slow walkers may explain the apparent lack of involvement of striatal dopaminergic pathways in postural responses to slips. [ABSTRACT FROM PUBLISHER]

Mitochondrial complex-I dysfunction has been observed in patients of Huntington’s disease (HD). We assessed whether such a defect is present in the 3-nitropropionic acid (3-NP) model of HD. Rats treated with 3-NP (10–20 mg/kg i.p., for 4 days) exhibited weight loss, gait abnormalities, and striatal lesions with increased glial fibrillary acidic protein immunostaining on fifth and ninth days, while increase in striatal dopamine and loss of tyrosine hydroxylase immunoreactivity were observed on fifth day following treatment. We report for the first time a dose-dependent reduction in complex-I activity in the cerebral cortex when analyzed spectrophotometrically and by blue native-polyacrylamide gel electrophoresis following 3-NP treatment. The citrate synthase normalized activities of mitochondrial complex-I, -II, -(I + III) and -IV were decreased in the cortex of 3-NP treated rats. In addition, succinate driven State 3 respiration was also significantly inhibited in vivo and in the isolated mitochondria. These findings taken together with the observation of a significant decrease in vivo but not in vitro of State 3 respiration with NAD+-linked substrates, suggest complex-I dysfunction in addition to irreversible inhibition of complex-II and succinate dehydrogenase activity as a contributing factor in 3-NP-induced cortico-striatal lesion. [ABSTRACT FROM AUTHOR]

A capillary apparatus for in vitro microdialysis was used to investigate melatonin and ascorbic acid effects on dopamine (DA) autoxidation or nitric oxide (NO)-mediated oxidation in suspended PC12 cells. Following high K+ (KCl 75 m m) infusion, secreted DA underwent a partial autoxidation or peroxynitrite-mediated oxidation when the potential peroxynitrite generator 3-morpholinosydnonimine (SIN-1, 1.0 m m) was co-infused with KCl. Ascorbic acid was supplied to the medium by means of intracellular reduction of infused dehydroascorbic acid (DHAA) (5.0 m m). Melatonin (50 μ m) and DHAA showed a synergistic effect in inhibiting DA autoxidation and peroxynitrite-mediated DA oxidation. Moreover, melatonin increased dialysate recovery of ascorbic acid released from PC12 cells. Endogenous melatonin was depleted in rats maintained on a 24-hr light cycle for 1 wk. In melatonin-depleted rats, baseline levels of dialysate ascorbic acid were lower than controls, while those of DA were unaffected. In these rats, intrastriatal infusion of 5.0 m m SIN-1 induced DA increases significantly lower than in controls; in addition, dialysate ascorbic acid concentrations exhibited significant decreases. Melatonin co-infusion restored SIN-1 effects on dialysate DA and antagonized SIN-1-induced ascorbic acid decreases. Melatonin-depleted rats were allowed to recover. In these rats, striatal baseline ascorbic acid, as well as SIN-1-induced increases in dialysate DA did not differ from controls. Taken together, these findings suggest that endogenous melatonin is an active component of the striatal extracellular antioxidant pool, as it maintains endogenous ascorbic acid in its reduced status and co-operates with ascorbic acid in protecting extracellular DA from exogenous NO-mediated oxidation. [ABSTRACT FROM AUTHOR]

Lithium chloride was given to rats i.p. at single doses of 2 and 10 meq/kg, respectively. It produced a suppression of motor activity and an increase in the dopamine content of the striatum. The magnitude of these effects were dose- and time-dependent as well as transient in nature. After 60 min of injection, the higher dose (10 meq/kg) reduced motor activity by 67% and increased striatal dopamine content by 56% while the lower dose (2 meq/kg) reduced motor activity by 42% and elevated striatal dopamine by 36%. These effects vanished 24 h after administration regardless the dose employed. None of the two doses of LiCl altered either dopamine biosynthesis in vivo (measured as the accumulation of a precursor of synthesis after decarboxylase inhibition), or the activity of tyrosine hydroxylase ex vivo under subsaturating conditons (i.e. enzyme activity in the tissues obtained from the animals post mortem). An increased deamination of tyramine by mono-amineoxidase (MAO) was found in striatal homogenates after 60 min of the injection of 2 or 10 meq/kg of LiCl. This was due to a lower K for the substrate as revealed by kinetic studies. LiCl treatment did not change the proportion of MAO A∶B. As neither dopamine synthesis was increased nor the activity of the catabolic enzyme MAO was reduced (but it was oppositely enhanced), the increment in striatal dopamine content might have likely resulted from a reduced release and/or an increased amine reuptake by the neurons. We postulate that the reduced motor activity observed shortly after injection of LiCl would be related to an interference with striatal dopaminergic neurotransmission. [ABSTRACT FROM AUTHOR]

To elucidate the effects of taurine on hypothalamic and striatal dopaminergic neurotransmission we compared its effects to those of γ-aminobutyric acid (GABA) and homotaurine (a GABA-receptor agonist) on hypothalamic and striatal concentrations of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and, in the case of striatum, 3-methoxytyramine (3-MT) in rats. In addition, hypothalamic and striatal 5-hydroxytryptamine (5-HT) und 5-hydroxyindoleacetic acid, hypothalamic noradrenaline (NA) and 3-methoxy-4-hydroxyphenylglycol sulfate, and pituitary DA concentrations were also measured. The amino acids were injected into the lateral brain ventricles of conscious male rats in doses of 10 and 36 μmol/rat, and rat were sacrificed 15 and 60 min later, respectively. Homotaurine (by 11010) but not the other two amino acids elevated striatal DA, whereas hypothalamic DA was increased by both taurine (36%) and homotaurine (31%). All three amino acids at 36 μmol elevated striatal DOPAC, homotaurine (51%) more than taurine (31%) or GABA (30%), and hypothalamic DOPAC, both taurine (102%) and homotaurine (82%) clearly more than GABA (34%). Neither striatal nor hypothalamic HVA was altered by any of the amino acids. At 10 μmol the amino acids decreased striatal 3-MT by about 40%. At 36 μmol taurine and homotaurine reduced 3-MT by about 70%, whereas increasing the dose of GABA did not further reduce 3-MT. Both taurine and homotaurine at 36 μmol decreased hypothalamic NA content. Neither hypothalamic nor striatal 5-HT metabolism was altered. In the neurointermediate lobe of the pituitary gland taurine at 10 μmol but not at 36 μmol slightly (20%) increased DA. These results show that taurine and homotaurine clearly alter the hypothalamic DA metabolism, and give further support to the suggestion that taurine and homotaurine similarly to GABA reduce the release of DA in the striatum. Homotaurine seems to alter the striatal DA metabolism more effectively than taurine or GABA. On the other hand, hypothalamic DA seems to be equally sensitive to taurine and homotaurine, and is clearly less sensitive to GABA. The pronounced elevation of hypothalamic DA and DOPAC after taurine and homotaurine could be related to changes in hypothalamic NA. [ABSTRACT FROM AUTHOR]

This study investigated the relationships between blood pressure, cortical oxygen pressure, and extracellular striatal dopamine in the brain of adult cats during hemorrhagic hypotension and re-transfusion. Oxygen pressure in the blood of the cortex was measured by the oxygen dependent quenching of phosphorescence and extracellular dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) by in vivo microdialysis. Following a 2 h stabilization period after implantation of the microdialysis probe in the striatum, the mean arterial blood pressure (MAP) was decreased in a stepwise manner from 132 ± 2 Torr (control) to 90 Torr, 70 Torr and 50 Torr, holding the pressure at each level for 15 min. The whole blood was then retransfused and measurements were continued for 90 min. As the MAP was lowered there was a decrease in arterial pH, from a control value of 7.37 ± 0.05 to 7.26 ± 0.06. The PaCO2 decreased during bleeding from 32.3 ± 4.8 Torr to 19.6 ± 3.6 Torr and returned to 30.9 ± 3.9 Torr after retransfusion. The PaO2 was 125.9 ± 15 Torr during control conditions and did not significantly change during bleeding. Cortical oxygen pressure decreased with decrease in MAP, from 50 ± 2 Torr (control) to 42 ± 1 Torr, 31 ± 2 Torr and 22 ± 2 Torr, respectively. A statistically significant increase in striatal extracellular dopamine, to 2,580 ± 714% of control was observed when MAP decreased to below 70 Torr and cortical oxygen pressure decreased to below 31 Torr. When the MAP reached 50 Torr, the concentration of extracellular dopamine increased to 18,359 ± 2,764% of the control value. A statistically significant decrease in DOPAC and HVA were observed during the last step of bleeding. The data show that decreases in systemic blood pressure result in decrease in oxygen pressure in the microvasculature of the cortex, suggesting vascular dilation is not sufficient to result in a full compensation for the decreased MAP. The decrease in cortical oxygen pressure to below 32 Torr is accompanied by a marked increase in extracellular dopamine in the striatum, indicating that even such mild hypoxia can induce significant disturbance in brain metabolism. [ABSTRACT FROM AUTHOR]

In the present study we infused taurine (50,150 or 450mM, 2μl/min for 4h) into the dorsal striatum or into the substantia nigra via microdialysis probe and estimated the extracellular concentrations of dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the dorsal striatum of anaesthetised rats. Intrastriatal infusion of taurine elevated striatal dopamine at all concentrations studied. At the 450 mM concentration taurine elevated the extracellular dopamine 10-fold, but only in the first 30min sample after starting the taurine infusion. At 50 and 150mM taurine elevated dopamine throughout the 4h infusion maximally up to 3-4-fold the control level. Extracellular DOPAC was increased by 150 and 450mM taurine (up to about 150-160% of the control level), whereas at all three concentrations taurine decreased HVA to about 85% of the control; however, the decrease caused by 450mM taurine was short-lasting. At all three concentrations taurine infused into the substantia nigra decreased the extracellular dopamine in the ipsilateral striatum to about 40-50% of the control, and increased extracellular DOPAC and HVA maximally to about 150% and 170% of the control, respectively. These results show that the effects of taurine on the concentrations of extracellular dopamine and its metabolites depend on its administration site on nigrostriatal dopaminergic neurons. It elevates the extracellular dopamine when given into the striatum, but when given into the cell body region of the nigrostriatal dopaminergic pathway it decreases the extracellular dopamine in the ipsilateral striatum. [ABSTRACT FROM AUTHOR]

Bilateral Clamping of both Carotid Arteries (BCCA) in normotensive rats is known to cause a transient reduction in cerebral blood flow. Using in vivo transstriatal microdialysis and HPLC/ECD we measured the release of dopamine and DA-metabolites under these oligemic conditions. BCCA caused a substantial stimulation of striatal DA-release (40-fold) and a decrease of the outflow of DA-metabolites. The elevated DA-release returned to baseline levels before the onset of reperfusion. Upon reperfusion, DA-metabolites rose above their initial baseline values. Transstriatal administration of glutamatediethylester (GDEE, 10 mM) attenuated the oligemia-induced DA-release. A sudden reduction of blood flow appears to disrupt the compartmentation of dopamine in striatal dopaminergic nerve endings in a similar but more moderate manner as compared to ischemia. [ABSTRACT FROM AUTHOR]

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Vacuolar protein sorting 35 (VPS35) is a major component of the retromer complex that mediates the retrograde transport of cargo proteins from endosomes to the trans-Golgi network. Mutations such as D620N in the VPS35 gene have been identified in patients with autosomal dominant Parkinson's disease (PD). However, it remains poorly understood whether and how VPS35 deficiency or mutation contributes to PD pathogenesis; specifically, the studies that have examined VPS35 thus far have differed in results and methodologies. We generated a VPS35 D620N mouse model using a Rosa26-based transgene expression platform to allow expression in a spatial manner, so as to better address these discrepancies. Here, aged (20-months-old) mice were first subjected to behavioral tests. Subsequently, DAB staining analysis of substantia nigra (SN) dopaminergic neurons with the marker for tyrosine hydroxylase (TH) was performed. Next, HPLC was used to determine dopamine levels, along with levels of its two metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum. Western blotting was also performed to study the levels of key proteins associated with PD. Lastly, autoradiography (ARG) evaluation of [3H]FE-PE2I binding to the striatal dopamine transporter DAT was carried out. We found that VPS35 D620N Tg mice displayed a significantly higher dopamine level than NTg counterparts. All results were then compared with that of current VPS35 studies to shed light on the disease pathogenesis. Our model allows future studies to explicitly control spatial expression of the transgene which would generate a more reliable PD phenotype. [ABSTRACT FROM AUTHOR]