Preventive treatments to slow substantia nigra damage and Parkinson's disease progression: A critical perspective review.

Restoring the lost physiological functions of the substantia nigra in Parkinson's disease (PD) is an important goal of PD therapy. The present article reviews a) novel drug targets that should be targeted to slow PD progression, and b) clinical and experimental research data reporting new treatments targeting immune-inflammatory and oxidative pathways. A systematic search was performed based on the major databases, i.e., ScienceDirect, Web of Science, PubMed, CABI Direct databases, and Scopus, on relevant studies performed from 1900 to 2020. This review considers the crucial roles of mitochondria and immune-inflammatory and oxidative pathways in the pathophysiology of PD. High levels of oxidative stress in the substantia nigra, as well as modifications in glutathione regulation, contribute to mitochondrial dysfunction, with a decline in complex I of the mitochondrial electron transport chain reported in PD patients. Many papers suggest that targeting antioxidative systems is a crucial aspect of preventive and protective therapies, even justifying the utilization of N-acetylcysteine (NAC) supplementation to fortify the protection afforded by intracellular glutathione. Dietary recommended panels including ketogenetic diet, muscular exercise, nutraceutical supplementation including NAC, glutathione, nicotine, caffeine, melatonin, niacin, and butyrate, besides to nonsteroidal anti-inflammatory drugs (NSAIDs), and memantine treatment are important aspects of PD therapy. The integration of neuro-immune, antioxidant, and nutritional approaches to treatment should afford better neuroprotection, including by attenuating neuroinflammation, nitro-oxidative stress, mitochondrial dysfunction, and neurodegenerative processes. Future research should clarify the efficacy, and interactions, of nicotine receptor agonists, gut microbiome-derived butyrate, melatonin, and NSAIDs in the treatment of PD.

Abnormal Functional Relationship of Sensorimotor Network With Neurotransmitter-Related Nuclei via Subcortical-Cortical Loops in Manic and Depressive Phases of Bipolar Disorder.

OBJECTIVE: Manic and depressive phases of bipolar disorder (BD) show opposite psychomotor symptoms. Neuronally, these may depend on altered relationships between sensorimotor network (SMN) and subcortical structures. The study aimed to investigate the functional relationships of SMN with substantia nigra (SN) and raphe nuclei (RN) via subcortical-cortical loops, and their alteration in bipolar mania and depression, as characterized by psychomotor excitation and inhibition. METHOD: In this resting-state functional magnetic resonance imaging (fMRI) study on healthy (n = 67) and BD patients (n = 100), (1) functional connectivity (FC) between thalamus and SMN was calculated and correlated with FC from SN or RN to basal ganglia (BG)/thalamus in healthy; (2) using an a-priori-driven approach, thalamus-SMN FC, SN-BG/thalamus FC, and RN-BG/thalamus FC were compared between healthy and BD, focusing on manic (n = 34) and inhibited depressed (n = 21) patients. RESULTS: (1) In healthy, the thalamus-SMN FC showed a quadratic correlation with SN-BG/thalamus FC and a linear negative correlation with RN-BG/thalamus FC. Accordingly, the SN-related FC appears to enable the thalamus-SMN coupling, while the RN-related FC affects it favoring anti-correlation. (2) In BD, mania showed an increase in thalamus-SMN FC toward positive values (ie, thalamus-SMN abnormal coupling) paralleled by reduction of RN-BG/thalamus FC. By contrast, inhibited depression showed a decrease in thalamus-SMN FC toward around-zero values (ie, thalamus-SMN disconnection) paralleled by reduction of SN-BG/thalamus FC (and RN-BG/thalamus FC). The results were replicated in independent HC and BD datasets. CONCLUSIONS: These findings suggest an abnormal relationship of SMN with neurotransmitters-related areas via subcortical-cortical loops in mania and inhibited depression, finally resulting in psychomotor alterations.

Electroacupuncture Therapy Ameliorates Motor Dysfunction via Brain-Derived Neurotrophic Factor and Glial Cell Line-Derived Neurotrophic Factor in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by dopaminergic neuron loss in the substantia nigra. However, specific sensory stimulation via electroacupuncture (EA) therapy may attenuate this loss by promoting the expression of endogenous neurotrophic factors in a manner similar to physical therapy. We investigated the potential protective effects of EA on dopaminergic neurons in a mouse model of PD and whether these effects are associated with the promotion of endogenous brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Mouse models of PD were generated using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine. Motor performance was assessed using behavioral tests, and Western blot experiments, enzyme-linked immunosorbent assays (ELISAs), and immunohistochemical assays were performed. In both mouse models, EA treatment ameliorated motor impairments and dopaminergic neuron loss; these changes were accompanied by increases in BDNF and GDNF. In the MPTP group, EA treatment improved motor dysfunction by attenuating dopaminergic neuron loss in the substantia nigra, similar to the effects of levodopa. EA treatment significantly upregulated BDNF and GDNF expression in both the substantia nigra and striatum. Moreover, EA treatment induced the expression of cAMP response element binding protein (CREB) as well as Akt and Pitx3 in dopaminergic neurons in the substantia nigra. However, levodopa treatment did not induce BDNF/GDNF activation or related signaling factors. Thus, EA therapy may exert protective effects on dopaminergic neurons by upregulating the expression of BDNF, GDNF, and related signaling factors, thereby improving motor function. Hence, EA may represent an effective adjuvant therapy for motor deficits in patients with PD.

Gintonin Mitigates MPTP-Induced Loss of Nigrostriatal Dopaminergic Neurons and Accumulation of α-Synuclein via the Nrf2/HO-1 Pathway.

Gintonin, a ginseng-derived glycolipoprotein isolated from ginseng, has been shown to be neuroprotective in several neurological disorders such as Alzheimer's disease models and depressive-like behaviors. In this study, we sought to investigate the potential protective mechanisms of gintonin in an in vivo MPTP and in vitro MPP+-mediated Parkinson's disease (PD) model. We hypothesized that activation of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 (Nrf2/HO-1, potential therapeutic targets for neurodegeneration) with gintonin could abrogate PD-associated neurotoxicity by modulating the accumulation of α-synuclein, neuroinflammation, and apoptotic cell death in an MPTP/MPP+ models of PD. Our in vivo and in vitro findings suggest that the neuroprotective effects of gintonin were associated with the regulation of the Nrf2/HO-1 pathway, which regulated the expression of proinflammatory cytokines and nitric oxide synthase and apoptotic markers in the substantia nigra and striatum of the mice. Moreover, the neuroprotective effects of gintonin were also associated with a reduction in α-synuclein accumulation in the mouse substantia nigra and striatum. The neuroprotective effects of gintonin were further validated by analyzing the effects of gintonin on MPP+-treated SH-SY5Y cells, which confirmed the protective effects of gintonin. It remains for future basic and clinical research to determine the potential use of gintonin in Parkinson's disease. However, to the best of our knowledge, marked alterations in biochemical and morphological setup of midbrain dopaminergic pathways by gintonin in MPTP mice model have not been previously reported. We believe that gintonin might be explored as an important therapeutic agent in the treatment of PD.

Efficacy of vitamin D replacement therapy in restless legs syndrome: a randomized control trial.

PURPOSE: Restless legs syndrome is a movement sleep disorder that may be linked to dopaminergic dysfunction and in which vitamin D may play a role. This 12-week randomized, placebo-controlled trial elucidated the efficacy of vitamin D supplements in decreasing restless legs syndrome symptom severity. METHODS: Thirty-five subjects with restless legs syndrome, diagnosed using the International Restless Legs Syndrome Study Group criteria, were enrolled. The subjects were randomized to orally receive either vitamin D (50,000 IU caplets) or a placebo. All medications were administered weekly using a direct observation technique. Clinical assessments, including those for restless legs syndrome severity, were conducted at baseline and the end of the study using the International Restless Legs Syndrome Study Group rating scale. The serum vitamin D levels and bone profiles were measured at baseline and every 4 weeks. The primary endpoint was the change in the restless legs syndrome severity score from baseline to week 12. There were 17 and 18 patients in the vitamin D and placebo groups, respectively. RESULTS: The groups did not differ with respect to age, sex, restless legs syndrome severity, or vitamin D levels. Participants in the vitamin D group showed no significant change in the mean restless legs syndrome severity score compared with the placebo group. CONCLUSIONS: The results suggest that vitamin D supplementation does not improve restless legs syndrome symptoms. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov : NCT02256215 (available from: https://clinicaltrials.gov/ct2/show/NCT02256215 ).

Self-regulation of the dopaminergic reward circuit in cocaine users with mental imagery and neurofeedback.

BACKGROUND: Enhanced drug-related reward sensitivity accompanied by impaired sensitivity to non-drug related rewards in the mesolimbic dopamine system are thought to underlie the broad motivational deficits and dysfunctional decision-making frequently observed in cocaine use disorder (CUD). Effective approaches to modify this imbalance and reinstate non-drug reward responsiveness are urgently needed. Here, we examined whether cocaine users (CU) can use mental imagery of non-drug rewards to self-regulate the ventral tegmental area and substantia nigra (VTA/SN). We expected that obsessive and compulsive thoughts about cocaine consumption would hamper the ability to self-regulate the VTA/SN activity and tested if real-time fMRI (rtfMRI) neurofeedback (NFB) can improve self-regulation of the VTA/SN. METHODS: Twenty-two CU and 28 healthy controls (HC) were asked to voluntarily up-regulate VTA/SN activity with non-drug reward imagery alone, or combined with rtfMRI NFB. RESULTS: On a group level, HC and CU were able to activate the dopaminergic midbrain and other reward regions with reward imagery. In CU, the individual ability to self-regulate the VTA/SN was reduced in those with more severe obsessive-compulsive drug use. NFB enhanced the effect of reward imagery but did not result in transfer effects at the end of the session. CONCLUSION: CU can voluntary activate their reward system with non-drug reward imagery and improve this ability with rtfMRI NFB. Combining mental imagery and rtFMRI NFB has great potential for modifying the maladapted reward sensitivity and reinstating non-drug reward responsiveness. This motivates further work to examine the use of rtfMRI NFB in the treatment of CUD.

Acute dopamine receptor blockade in substantia nigra pars reticulata: a possible model for drug-induced Parkinsonism.

Dopamine (DA) depletion modifies the firing pattern of neurons in the substantia nigra pars reticulata (SNr), shifting their mostly tonic firing toward irregularity and bursting, traits of pathological firing underlying rigidity and postural instability in Parkinson's disease (PD) patients and animal models of Parkinsonism (PS). Drug-induced Parkinsonism (DIP) represents 20-40% of clinical cases of PS, becoming a problem for differential diagnosis, and is still not well studied with physiological tools. It may co-occur with tardive dyskinesia. Here we use in vitro slice preparations including the SNr to observe drug-induced pathological firing by using drugs that most likely produce it, DA-receptor antagonists (SCH23390 plus sulpiride), to compare with firing patterns found in DA-depleted tissue. The hypothesis is that SNr firing would be similar under both conditions, a prerequisite to the proposal of a similar preparation to test other DIP-producing drugs. Firing was analyzed with three complementary metrics, showing similarities between DA depletion and acute DA-receptor blockade. Moreover, blockade of either nonselective cationic channels or Cav3 T-type calcium channels hyperpolarized the membrane and abolished bursting and irregular firing, silencing SNr neurons in both conditions. Therefore, currents generating firing in control conditions are in part responsible for pathological firing. Haloperidol, a DIP-producing drug, reproduced DA-receptor antagonist firing modifications. Since acute DA-receptor blockade induces SNr neuron firing similar to that found in the 6-hydroxydopamine model of PS, output basal ganglia neurons may play a role in generating DIP. Therefore, this study opens the way to test other DIP-producing drugs. NEW & NOTEWORTHY Dopamine (DA) depletion enhances substantia nigra pars reticulata (SNr) neuron bursting and irregular firing, hallmarks of Parkinsonism. Several drugs, including antipsychotics, antidepressants, and calcium channel antagonists, among others, produce drug-induced Parkinsonism. Here we show the first comparison between SNr neuron firing after DA depletion vs. firing found after acute blockade of DA receptors. It was found that firing in both conditions is similar, implying that pathological SNr neuron firing is also a physiological correlate of drug-induced Parkinsonism.

Loss of Substantia Nigra Hyperintensity at 3.0-T MR Imaging in Idiopathic REM Sleep Behavior Disorder: Comparison with 123I-FP-CIT SPECT.

Purpose To examine whether the loss of nigral hyperintensity (NH) on 3.0-T susceptibility-weighted (SW) magnetic resonance (MR) images can help identify high synucleinopathy risk in patients with idiopathic rapid eye movement sleep behavior disorder (iRBD). Materials and Methods Between March 2014 and April 2015, 18 consecutively recruited patients with iRBD were evaluated with 3.0-T SW imaging and iodine 123-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT) single photon emission computed tomography and compared with 18 healthy subjects and 18 patients with Parkinson disease (PD). Two readers blinded to clinical diagnosis independently assessed the images. 123I-FP-CIT uptake ratios were compared by using the Kruskal-Wallis test, and intra- and interobserver agreements were assessed with the Cohen κ. The synucleinopathy conversion according to NH status was evaluated in patients with iRBD after follow-up. Results NH was intact in seven patients with iRBD and lost in 11. The 123I-FP-CIT uptake ratios were comparable between those with intact NH (mean, 3.22 ± 0.47) and healthy subjects (mean, 3.37 ± 0.47) (P = .495). The 123I-FP-CIT uptake ratios in the 11 patients with iRBD and NH loss (mean, 2.48 ± 0.44) were significantly lower than those in healthy subjects (mean, 3.37 ± 0.47; P < .001) but higher than those in patients with PD (mean, 1.80 ± 0.33; P < .001). The intra- and interobserver agreements were excellent (κ > 0.9). Five patients with iRBD and NH loss developed symptoms of parkinsonism or dementia 18 months after neuroimaging. Conclusion NH loss at 3.0-T SW imaging may be a promising marker for short-term synucleinopathy risk in iRBD. © RSNA, 2017 Online supplemental material is available for this article.

Abnormal Resting-State Connectivity in a Substantia Nigra-Related Striato-Thalamo-Cortical Network in a Large Sample of First-Episode Drug-Naïve Patients With Schizophrenia.

Objective: The dopamine hypothesis is one of the most influential theories of the neurobiological background of schizophrenia (SCZ). However, direct evidence for abnormal dopamine-related subcortical-cortical circuitry disconnectivity is still lacking. The aim of this study was therefore to test dopamine-related substantia nigra (SN)-based striato-thalamo-cortical resting-state functional connectivity (FC) in SCZ. Method: Based on our a priori hypothesis, we analyzed a large sample resting-state functional magnetic resonance imaging (fMRI) dataset from first-episode drug-naïve SCZ patients (n = 112) and healthy controls (n = 82) using the SN as the seed region for an investigation of striato-thalamo-cortical FC. This was done in the standard band of slow frequency oscillations and then in its subfrequency bands (Slow4 and Slow5). Results: The analysis showed in SCZ: (1) reciprocal functional hypo-connectivity between SN and striatum, with differential patterns for Slow5 and Slow4; (2) functional hypo-connectivity between striatum and thalamus, as well as functional hyper-connectivity between thalamus and sensorimotor cortical areas, specifically in Slow4; (3) correlation of thalamo-sensorimotor functional hyper-connectivity with psychopathological symptoms. Conclusions: We demonstrate abnormal dopamine-related SN-based striato-thalamo-cortical FC in slow frequency oscillations in first-episode drug-naive SCZ. This suggests that altered dopaminergic function in the SN leads to abnormal neuronal synchronization (as indexed by FC) within subcortical-cortical circuitry, complementing the dopamine hypothesis in SCZ on the regional level of resting-state activity.

Electroacupuncture Promotes Recovery of Motor Function and Reduces Dopaminergic Neuron Degeneration in Rodent Models of Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disease. The pathological hallmark of PD is a progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta in the brain, ultimately resulting in severe striatal dopamine deficiency and the development of primary motor symptoms (e.g., resting tremor, bradykinesia) in PD. Acupuncture has long been used in traditional Chinese medicine to treat PD for the control of tremor and pain. Accumulating evidence has shown that using electroacupuncture (EA) as a complementary therapy ameliorates motor symptoms of PD. However, the most appropriate timing for EA intervention and its effect on dopamine neuronal protection remain unclear. Thus, this study used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model (systemic-lesioned by intraperitoneal injection) and the 1-methyl-4-phenylpyridinium (MPP⁺)-lesioned rat model (unilateral-lesioned by intra-SN infusion) of PD, to explore the therapeutic effects and mechanisms of EA at the GB34 (Yanglingquan) and LR3 (Taichong) acupoints. We found that EA increased the latency to fall from the accelerating rotarod and improved striatal dopamine levels in the MPTP studies. In the MPP⁺ studies, EA inhibited apomorphine induced rotational behavior and locomotor activity, and demonstrated neuroprotective effects via the activation of survival pathways of Akt and brain-derived neurotrophic factor (BDNF) in the SN region. In conclusion, we observed that EA treatment reduces motor symptoms of PD and dopaminergic neurodegeneration in rodent models, whether EA is given as a pretreatment or after the initiation of disease symptoms. The results indicate that EA treatment may be an effective therapy for patients with PD.

Magnetic resonance imaging of local and remote vascular remodelling after experimental stroke.

The pattern of vascular remodelling in relation to recovery after stroke remains largely unclear. We used steady-state contrast-enhanced magnetic resonance imaging to assess the development of cerebral blood volume and microvascular density in perilesional and exofocal areas from (sub)acutely to chronically after transient stroke in rats. Microvascular density was verified histologically after infusion with Evans Blue dye. At day 1, microvascular cerebral blood volume and microvascular density were reduced in and around the ischemic lesion (intralesional borderzone: microvascular cerebral blood volume = 72 ± 8%; microvascular density = 76 ± 8%) (P < 0.05), while total cerebral blood volume remained relatively unchanged. Perilesional microvascular cerebral blood volume and microvascular density subsequently normalized (day 7) and remained relatively stable (day 70). In remote ipsilateral areas in the thalamus and substantia nigra - not part of the ischemic lesion - microvascular density gradually increased between days 1 and 70 (thalamic ventral posterior nucleus: microvascular density = 119 ± 9%; substantia nigra: microvascular density = 122 ± 8% (P < 0.05)), which was confirmed histologically. Our data indicate that initial microvascular collapse, with maintained collateral flow in larger vessels, is followed by dynamic revascularization in perilesional tissue. Furthermore, progressive neovascularization in non-ischemic connected areas may offset secondary neuronal degeneration and/or contribute to non-neuronal tissue remodelling. The complex spatiotemporal pattern of vascular remodelling, involving regions outside the lesion territory, may be a critical endogenous process to promote post-stroke brain reorganization.

Central nervous system regulation of eating: Insights from human brain imaging.

Appetite and body weight regulation are controlled by the central nervous system (CNS) in a rather complicated manner. The human brain plays a central role in integrating internal and external inputs to modulate energy homeostasis. Although homeostatic control by the hypothalamus is currently considered to be primarily responsible for controlling appetite, most of the available evidence derives from experiments in rodents, and the role of this system in regulating appetite in states of hunger/starvation and in the pathogenesis of overeating/obesity remains to be fully elucidated in humans. Further, cognitive and affective processes have been implicated in the dysregulation of eating behavior in humans, but their exact relative contributions as well as the respective underlying mechanisms remain unclear. We briefly review each of these systems here and present the current state of research in an attempt to update clinicians and clinical researchers alike on the status and future directions of obesity research.

Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit.

Anxiety and social deficits, often involving communication impairment, are fundamental clinical features of fragile X syndrome. There is growing evidence that dysregulation in reward processing is a contributing factor to the social deficits observed in many psychiatric disorders. Hence, we hypothesized that transgenic fragile X mental retardation 1 gene (fmr1) KO (FX) rats would display alterations in reward processing. To this end, awake control and FX rats were imaged for changes in blood oxygen level dependent (BOLD) signal intensity in response to the odor of almond, a stimulus to elicit the innate reward response. Subjects were 'odor naive' to this evolutionarily conserved stimulus. The resulting changes in brain activity were registered to a three-dimensional segmented, annotated rat atlas delineating 171 brain regions. Both wild-type (WT) and FX rats showed robust brain activation to a rewarding almond odor, though FX rats showed an altered temporal pattern and tended to have a higher number of voxels with negative BOLD signal change from baseline. This pattern of greater negative BOLD was especially apparent in the Papez circuit, critical to emotional processing and the mesolimbic/habenular reward circuit. WT rats showed greater positive BOLD response in the supramammillary area, whereas FX rats showed greater positive BOLD response in the dorsal lateral striatum, and greater negative BOLD response in the retrosplenial cortices, the core of the accumbens and the lateral preoptic area. When tested in a freely behaving odor-investigation paradigm, FX rats failed to show the preference for almond odor which typifies WT rats. However, FX rats showed investigation profiles similar to WT when presented with social odors. These data speak to an altered processing of this highly salient novel odor in the FX phenotype and lend further support to the notion that altered reward systems in the brain may contribute to fragile X syndrome symptomology.

[A study of divalent metal transporter 1 and ferroportin 1 in brain of rats with manganese-induced parkinsonism].

OBJECTIVE: To study the changes in the expression of divalent metal transporter 1 (DMT1) and ferroportin 1 (FP1) in the substantia nigra (SN) of rats with manganese-induced parkinsonism. METHODS: Eighty Sprague-Dawley rats were randomly divided into four groups. Rats in the control group were injected intraperitoneally with saline solution. Rats in the low-dose, medium-dose, and high-dose groups were injected intraperitoneally with 5, 15, and 20 mg/kg MnC12 solution, respectively, for 16 weeks. Three behavioral tests were performed at the 16th week. The concentration of Mn2+ in the SN was determined by inductively coupled plasma-atomic emission spectrometry (ICP-AES), and the positive expression of tyrosine hydroxylase (TH) was measured by immunohistochemical staining to determine whether rats with manganese-induced parkinsonism were successfully produced. The expression of DMT1 and FP1 in SN was measured by immunohistochemical staining and fluorescent quantitative polymerase chain reaction. RESULTS: Rats with manganese-induced parkinsonism were successfully produced using the above method. Compared with that in the control group, the concentrations of Mn2+ in the SN of rats exposed to 5, 15, and 20 mg/kg Mn2+ were significantly higher (1.72?0.33 vs 0.56 ± 0.20 µg/g, P<0.01; 2.92±0.77 vs 0.56±0.20 µg/g, P<0.01; 5.65±1.60 vs 0.56±0.20 µg/g, P<0.01). The mean ODs of TH-positive cells in the SN of rats exposed to 5, 15, and 20 mg/kg Mn+ were significantly lower than that in the control group (0.054±0.008 vs 0.109±0.019, P<0.01; 0.016±0.004 vs 0.109±0.019, P<0.01; 0.003±0.001 vs 0.109±0.019, P<0.01). Compared with that in the control group, the mean optical densities (ODs) of DMT1-positive cells in the SN of rats exposed to 15, and 20 mg/kg Mn2+ were significantly higher (0.062±0.004 vs 0.015±0.007, P<0.01; 0.116±0.064 vs 0.015±0.007, P<0.01). The mean ODs of FP1-positive cells in the SN of rats exposed to 5, 15, and 20 mg/kg Mn2+ were significantly lower than that in the control group (0.092±0.011 vs 0.306±0.081, P<0.01; 0.048±0.008 vs 0.306±0.081, P<0.01; 0.008±0.002 vs 0.306±0.081, P< 0.01). Rats exposed to 15 and 20 mg/kg Mn2+ had significantly higher expression of DMT1 mRNA in the SN than those in the control group (0.052±0.0126 vs 0.001±0.0004, P<0.05; 0.124±0.0299 vs 0.001±0.0004, P<0.05). However, rats exposed to 5, 15, and 20 mg/kg Mn2 had significantly lower expression of FP1 mRNA in the SN than those in the control group (0.059±0.0076 vs 0.162±0.0463, P<0.05; 0.033±0.0094 vs 0.162±0.0463, P< 0.05; 0.002±0.0007 vs 0.162±0.0463, P<0.05). CONCLUSION: The increased expression of DMT1 and reduced expression of FP1 may be involved in the processes of Mn2+ accumulation in the SN and dopaminergic neuron loss in rats with manganese-induced parkinsonism.

NMDA receptor antagonism potentiates the L-DOPA-induced extracellular dopamine release in the subthalamic nucleus of hemi-parkinson rats.

Long term treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) is associated with several motor complications. Clinical improvement of this treatment is therefore needed. Lesions or high frequency stimulation of the hyperactive subthalamic nucleus (STN) in Parkinson's disease (PD), alleviate the motor symptoms and reduce dyskinesia, either directly and/or by allowing the reduction of the L-DOPA dose. N-methyl-D-aspartate (NMDA) receptor antagonists might have similar actions. However it remains elusive how the neurochemistry changes in the STN after a separate or combined administration of L-DOPA and a NMDA receptor antagonist. By means of in vivo microdialysis, the effect of L-DOPA and/or MK 801, on the extracellular dopamine (DA) and glutamate (GLU) levels was investigated for the first time in the STN of sham and 6-hydroxydopamine-lesioned rats. The L-DOPA-induced DA increase in the STN was significantly higher in DA-depleted rats compared to shams. MK 801 did not influence the L-DOPA-induced DA release in shams. However, MK 801 enhanced the L-DOPA-induced DA release in hemi-parkinson rats. Interestingly, the extracellular STN GLU levels remained unchanged after nigral degeneration. Furthermore, administration of MK 801 alone or combined with L-DOPA did not alter the STN GLU levels in both sham and DA-depleted rats. The present study does not support the hypothesis that DA-ergic degeneration influences the STN GLU levels neither that MK 801 alters the GLU levels in lesioned and non-lesioned rats. However, NMDA receptor antagonists could be used as a beneficial adjuvant treatment for PD by enhancing the therapeutic efficacy of l-DOPA at least in part in the STN.

Bidirectional control of absence seizures by the basal ganglia: a computational evidence.

Absence epilepsy is believed to be associated with the abnormal interactions between the cerebral cortex and thalamus. Besides the direct coupling, anatomical evidence indicates that the cerebral cortex and thalamus also communicate indirectly through an important intermediate bridge-basal ganglia. It has been thus postulated that the basal ganglia might play key roles in the modulation of absence seizures, but the relevant biophysical mechanisms are still not completely established. Using a biophysically based model, we demonstrate here that the typical absence seizure activities can be controlled and modulated by the direct GABAergic projections from the substantia nigra pars reticulata (SNr) to either the thalamic reticular nucleus (TRN) or the specific relay nuclei (SRN) of thalamus, through different biophysical mechanisms. Under certain conditions, these two types of seizure control are observed to coexist in the same network. More importantly, due to the competition between the inhibitory SNr-TRN and SNr-SRN pathways, we find that both decreasing and increasing the activation of SNr neurons from the normal level may considerably suppress the generation of spike-and-slow wave discharges in the coexistence region. Overall, these results highlight the bidirectional functional roles of basal ganglia in controlling and modulating absence seizures, and might provide novel insights into the therapeutic treatments of this brain disorder.

Orally delivered water soluble Coenzyme Q10 (Ubisol-Q10) blocks on-going neurodegeneration in rats exposed to paraquat: potential for therapeutic application in Parkinson's disease.

BACKGROUND: Paraquat, still used as an herbicide in some parts of the world, is now regarded as a dangerous environmental neurotoxin and is linked to the development Parkinson's disease (PD). Paraquat interacts with cellular redox systems and causes mitochondrial dysfunction and the formation of reactive oxygen species, which in turn, plays a crucial role in the pathophysiology of PD. Various antioxidant therapies have been explored with the expectations that they deliver health benefits to the PD patients, however, no such therapies were effective. Here we have tested the neuroprotective efficacy of a novel water-soluble CoQ10 (Ubisol-Q10), in a rat model of paraquat-induced neurodegeneration in order to evaluate its potential application in the management of PD. RESULTS: We have developed a rat model of progressive nigrostriatal degeneration by giving rats five intraperitoneal injections of paraquat (10 mg/kg/injection), once every five days. Neuronal death occurred over a period of 8 weeks with close to 50% reduction in the number of tyrosine hydroxylase-positive cells. Ubisol-Q10, at 6 mg CoQ10/kg body weight/day, was delivered as a supplement in drinking water. The intervention begun after the completion of paraquat injections when the neurodegenerative process had already began and about 20% of TH-positive neurons were lost. Ubisol-Q10 treatment halted the progression of neurodegeneration and remaining neurons were protected. The outcomes were evaluated based on the number of surviving tyrosine hydroxylase-positive neurons in the substantia nigra region and improved motor skills in response to the Ubisol-Q10 intervention. To maintain this neuroprotection, however, continuous Ubisol- Q10 supplementation was required, if withdrawn, the neuronal death pathway resumed, suggesting that the presence of CoQ10 was essential for blocking the pathway. CONCLUSION: The CoQ10, given orally as Ubisol-Q10 in drinking solution, was effective in blocking the progression of neurodegeneration when administered therapeutically (post-toxin injection), at a much lower concentration than other previously tested oil soluble formulations and well within the acceptable daily intake of 12 mg/kg/day. Such unprecedented neuroprotection has never been reported before. These results are very encouraging and suggest that Ubisol-Q10 should be further tested and developed as a therapy for halting the progression of PD.

Berberine prevents nigrostriatal dopaminergic neuronal loss and suppresses hippocampal apoptosis in mice with Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of nigral dopaminergic neurons and a reduction in striatal dopaminergic fibers, which result in tremors, rigidity, bradykinesia and gait disturbance. In addition to motor dysfunction, dementia is a widely recognized symptom of patients with PD. Berberine, an isoquinoline alkaloid isolated from Berberis vulgaris L., is known to exert anxiolytic, analgesic, anti-inflammatory, antipsychotic, antidepressant and anti-amnesic effects. In the present study, we investigated the effects of berberine on short-term memory in relation to dopamine depletion and hippocampal neurogenesis using a mouse model of PD, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/P) treatment. Mice in the berberine-treated groups were orally administered berberine once a day for a total of 5 weeks. Our results revealed that the injection of MPTP/P induced dopaminergic neuronal death in the substantia nigra and fiber loss in the striatum. This resulted in impaired motor balance and coordination, as assessed by the beam walking test. We further demonstrated that MPTP/P-induced apoptosis in the hippocampus deteriorated short-term memory, as shown by the step-down avoidance task. By contrast, neurogenesis in the hippocampal dentate gyrus, which is a compensatory adaptive response to excessive apoptosis, was increased upon PD induction. However, treatment with berberine enhanced motor balance and coordination by preventing dopaminergic neuronal damage. Treatment with berberine also improved short-term memory by inhibiting apoptosis in the hippocampus. Berberine demonstrated maximal potency at 50 mg/kg. Based on these data, treatment with berberine may serve as a potential therapeutic strategy for the alleviation of memory impairment and motor dysfunction in patients with PD.

[Serotonin and dopamine brain metabolism in mice with different predisposition to catalepsy].

Catalepsy usually is caused by imbalance of dopamine (DA) and serotonin (5-HT) systems of brain. The aim of our work was to verify if this imbalance plays an important role in the mechanism of hereditary catalepsy in mice. Maintenance of DA, 5-HT and their main metabolites--5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, homovanilic acid was determined in cortex, hypothalamus, hippocampus, striatum, substantia nigra and nuclei raphes in catalepsy-resistant AKR/J mice strain and catalepsy-prone CBA/LacJ mice strain and recombinant mice AKR/J.CBA-D13Mit76 (D13) strain. The latest strain was selected by transferring of a fragment of the chromosome 13 from CBA/LacJ carrying the main gene of hereditary catalepsy to AKR/J genome. There were no interstrain differences in concentration of biogenic amines and their metabolites in all brain regions. As a result of our work the hypothesis about the important role of 5-HT and/or DA systems of brain in the mechanism of hereditary catalepsy in mice was denied.

Dopamine-dependent long-term depression at subthalamo-nigral synapses is lost in experimental parkinsonism.

Impairments of synaptic plasticity are a hallmark of several neurological disorders, including Parkinson's disease (PD) which results from the progressive loss of dopaminergic neurons of the substantia nigra pars compacta leading to abnormal activity within the basal ganglia (BG) network and pathological motor symptoms. Indeed, disrupted plasticity at corticostriatal glutamatergic synapses, the gateway of the BG, is correlated to the onset of PD-related movement disorders and thus has been proposed to be a key neural substrate regulating information flow and motor function in BG circuits. However, a critical question is whether similar plasticity impairments could occur at other glutamatergic connections within the BG that would also affect the inhibitory influence of the network on the motor thalamus. Here, we show that long-term plasticity at subthalamo-nigral glutamatergic synapses (STN-SNr) sculpting the activity patterns of nigral neurons, the main output of the network, is also affected in experimental parkinsonism. Using whole-cell patch-clamp in acute rat brain slices, we describe a molecular pathway supporting an activity-dependent long-term depression of STN-SNr synapses through an NMDAR-and D1/5 dopamine receptor-mediated endocytosis of synaptic AMPA glutamate receptors. We also show that this plastic property is lost in an experimental rat model of PD but can be restored through the recruitment of dopamine D1/5 receptors. Altogether, our findings suggest that pathological impairments of subthalamo-nigral plasticity may enhance BG outputs and thereby contribute to PD-related motor dysfunctions.