As an environmental risk factor, psychological stress may trigger the onset or accelerate the progression of Parkinson's disease (PD). Here, we evaluated the effects of acute restraint stress on striatal dopaminergic terminals and the brain metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which has been widely used for creating a mouse model of PD. Exposure to 2 h of restraint stress immediately after injection of a low dose of MPTP caused a severe loss of striatal dopaminergic terminals as indicated by decreases in the dopamine transporter protein and dopamine levels compared with MPTP administration alone. Both striatal 1-methyl-4-phenylpyridinium ion (MPP) and MPTP concentrations were significantly increased by the application of restraint stress. Striatal monoamine oxidase-B, which catalyzes the oxidation of MPTP to MPP, was not changed by the restraint stress. Our results indicate that the enhanced striatal dopaminergic terminal loss in the stressed mice is associated with an increase in the transport of neurotoxin into the brain.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; metabolism ; 1-Methyl-4-phenylpyridinium ; metabolism ; Animals ; Corpus Striatum ; drug effects ; metabolism ; Disease Models, Animal ; Dopaminergic Neurons ; drug effects ; MPTP Poisoning ; chemically induced ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neurotoxins ; metabolism ; Restraint, Physical ; Stress, Psychological ; metabolism

OBJECTIVEIn vivo Proton Magnetic Resonance Spectroscopy (1H-MRS) can be used to evaluate the levels of specific neurochemical biomarkers of pathological mechanisms in the brain.

METHODSWe conducted T2-Weighted Magnetic Resonance Imaging (MRI) and 1H-MRS with a 3.0-Tesla animal MRI system to investigate the early microstructural and metabolic profiles in vivo in the striatum of rats following carbon monoxide (CO) poisoning.

RESULTSCompared to baseline, we found significant cortical surface deformation, cerebral edema changes, which were indicated by the unclear gray/white matter border, and lateral ventricular volume changes in the brain. A significant reduction in the metabolite to total creatine (Cr) ratios of N-acetylaspartate (NAA) was observed as early as 1 h after the last CO administration, while the lactate (Lac) levels increased marginally. Both the Lac/Cr and NAA/Cr ratios leveled off at 6 h and showed no subsequent significant changes. In addition, compared to the control, the choline (Cho)/Cr ratio was slightly reduced in the early stages and significantly increased after 6 h. In addition, a pathological examination revealed mild cerebral edema on cessation of the insult and more severe cerebral injury after additional CO poisoning.

CONCLUSIONThe present study demonstrated that 1H-MRS of the brain identified early metabolic changes after CO poisoning. Notably, the relationship between the increased Cho/Cr ratio in the striatum and delayed neuropsychologic sequelae requires further research.

Animals ; Biomarkers ; Carbon Monoxide Poisoning ; metabolism ; Corpus Striatum ; drug effects ; metabolism ; Magnetic Resonance Spectroscopy ; methods ; Male ; Rats ; Rats, Sprague-Dawley

Neuroprotective effect of scorpion venom on Parkinson's disease (PD) has already been reported. The present study was aimed to investigate whether scorpion venom heat resistant peptide (SVHRP) could attenuate ultrastructural abnormalities in mitochondria and oxidative stress in midbrain neurons of early-stage PD model. The early-stage PD model was established by injecting 6-hydroxydopamine (6-OHDA) (20 μg/3 μL normal saline with 0.1% ascorbic acid) into the striatum of Sprague Dawley (SD) rats unilaterally. The rats were intraperitoneally administered with SVHRP (0.05 mg/kg per day) or vehicle (saline) for 1 week. Two weeks after 6-OHDA treatment, the rats received behavior tests for validation of model. Three weeks after 6-OHDA injection, the immunoreactivity of dopaminergic neurons were detected by immunohistochemistry staining, and the ultrastructure of neuronal mitochondria in midbrain was observed by electron microscope. In the meantime, the activities of monoamine oxidase-B (MAO-B), superoxide dismutase (SOD) and content of malondialdehyde (MDA) in the mitochondria of the midbrain neurons, as well as the inhibitory ability of hydroxyl free radical and the antioxidant ability in the serum, were measured by corresponding kits. The results showed that 6-OHDA reduced the optical density of dopaminergic neurons, induced damage of mitochondrial ultrastructure of midbrain neurons, decreased SOD activity, increased MAO-B activity and MDA content, and reduced the antioxidant ability of the serum. SVHRP significantly reversed the previous harmful effects of 6-OHDA in early-stage PD model. These findings indicate that SVHRP may contribute to neuroprotection by preventing biochemical and ultrastructure damage changes which occur during early-stage PD.
Animals ; Antioxidants ; metabolism ; Corpus Striatum ; Disease Models, Animal ; Dopaminergic Neurons ; drug effects ; Malondialdehyde ; metabolism ; Mesencephalon ; cytology ; Mitochondria ; metabolism ; ultrastructure ; Neuroprotective Agents ; pharmacology ; Oxidative Stress ; Oxidopamine ; Parkinson Disease ; drug therapy ; Peptides ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Scorpion Venoms ; pharmacology ; Superoxide Dismutase ; metabolism

A double toxin-double lesion strategy is well-known to generate a rat model of striatonigral degeneration (SND) such as multiple system atrophy-parkinsonian type. However, with this model it is difficult to distinguish SND from Parkinson's disease (PD). In this study, we propose a new rat model of SND, which is generated by simultaneous injection of 6-hydroxydopamine into the medial forebrain bundle and quinolinic acid into the striatum. Stepping tests performed 30 min after intraperitoneal L-dopa administration at 6 weeks post-surgery revealed an L-dopa response in the PD group but not the SND group. Apomorphine-induced rotation tests revealed no rotational bias in the SND group, which persisted for 2 months, but contralateral rotations in the PD group. MicroPET scans revealed glucose hypometabolism and dopamine transporter impairment on the lesioned striatum in the SND group. Tyrosine hydroxylase immunostaining in the SND group revealed that 74.7% of nigral cells on the lesioned side were lost after lesion surgery. These results suggest that the proposed simultaneous double toxin-double lesion method successfully created a rat model of SND that had behavioral outcomes, multitracer microPET evaluation, and histological aspects consistent with SND pathology. This model will be useful for future study of SND.
Animals ; Apomorphine/pharmacology ; Behavior, Animal/drug effects ; Corpus Striatum/drug effects/pathology ; Disease Models, Animal ; Dopamine Plasma Membrane Transport Proteins/metabolism ; Glucose/metabolism ; Injections, Intraperitoneal ; Levodopa/pharmacology ; Male ; Medial Forebrain Bundle/drug effects/pathology ; Oxidopamine/*toxicity ; Parkinson Disease/metabolism/pathology ; Positron-Emission Tomography ; Quinolinic Acid/*toxicity ; Rats ; Rats, Wistar ; Striatonigral Degeneration/*chemically induced/metabolism/pathology ; Touch/drug effects

The aim of this study is to investigate the protective effect of N-[2-(4-hydroxyphenyl)ethyl]-2-(2, 5-dimethoxyphenyl)-3-(3-methoxy-4-hydroxyphenyl)acrylamide (FLZ), a novel synthetic squamosamide cyclic derivative, against Parkinson's disease (PD) model mice induced by the inflammatory bacterial endotoxin, lipopolysaccharides (LPS) and the neurotoxin 1-methy-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). C57/BL mice were ip injected LPS (5 mg x kg(-1)) once. One week following the LPS injection, mice received a subcutaneous injection of MPTP (25 mg x kg(-1)) once daily for 2 days. Eight weeks later, FLZ (25, 50 and 75 mg x kg(-1)) was orally administered to mice once daily for 60 days. The motor ability of the mice was evaluated by rod climbing test and footprint test. The dopamine (DA) levels in mouse striatum were determined by high performance liquid chromatography system. The tyrosine hydroxylase (TH)-positive cells were showed by immunohistochemical analysis. FLZ treatment significantly improved motor dysfunction of mice challenged by LPS plus MPTP. The increase of TH-positive cell numbers and elevation of DA levels may be contributed to the beneficial effects of FLZ on motor behavior. This study showed FLZ has significant therapeutic effect on LPS plus MPTP induced chronic PD model, which indicates its potential as a new candidate drug to treat PD.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine ; 3,4-Dihydroxyphenylacetic Acid ; metabolism ; Acrylamides ; pharmacology ; Animals ; Caffeic Acids ; pharmacology ; Corpus Striatum ; metabolism ; Dopamine ; metabolism ; Homovanillic Acid ; metabolism ; Lipopolysaccharides ; Male ; Mice ; Mice, Inbred C57BL ; Motor Activity ; drug effects ; Neurons ; drug effects ; metabolism ; Parkinson Disease, Secondary ; chemically induced ; metabolism ; pathology ; physiopathology ; Random Allocation ; Tyrosine 3-Monooxygenase ; metabolism

In order to explore the role of acetylcholine in the pathogenesis of Parkinson's disease (PD), the changes in the concentration of acetylcholine (Ach) in the striatum, the apoptosis of substantia nigra cells, the ultrastructure and the changes of Nissl cells in rats during the morbidity of PD, and the corresponding behaviors in rats with PD were observed. Rat PD model was established by using the modified Thomas method. Eighty-one rats were randomly divided into normal control, sham operation and PD groups and their behavior features were observed at post-operative day (POD) 7, 14 and 21 as three subgroups (n=9 each). The concentration of Ach in the striatum was determined by using high-performance liquid chromatography. The apoptosis of substantia nigra cells was assayed by using TUNEL method. The ultrastructural changes in the substantia nigra were observed under the electron microscopy, and the survival of neurons in the substantia nigra area was examined by using Nissl staining. In PD group at POD 7 to 21, the damage in the substantia nigra area was gradually aggravated, the concentration of Ach, apoptosis rate and turns of rotation were gradually increased, and the number of Nissl cells was gradually reduced over the time as compared with the normal control and sham operation groups (all P<0.05). It was concluded that there exist dynamic changes in Ach concentration, ethology and apoptosis of the substantia nigra cells during the morbidity of PD, suggesting the contribution of apoptosis to the morbidity of PD, and critical role of Ach in the pathogenesis of PD.
Acetylcholine ; pharmacology ; Animals ; Corpus Striatum ; drug effects ; metabolism ; pathology ; Disease Models, Animal ; Male ; Parkinson Disease ; metabolism ; pathology ; Rats ; Rats, Wistar

This study examined the neuroprotective effect of cluster of differentiation molecule 200 (CD200) against methamphetamine (METH)-induced neurotoxicity. In the in vitro experiment, neuron-microglia cultures were treated with METH (20 μmol/L), METH (20 μmol/L)+CD200-Fc (10 μg/mL) or CD200-Fc (10 μg/mL). Those untreated served as control. Microglia activation expressed as the ratio of MHC-II/CD11b was assessed by flow cytometry. The cytokines (IL-1β, TNF-α) secreted by activated microglia were detected by enzyme-linked immunosorbent assay (ELISA). In the in vivo experiment, 40 SD rats were divided into control, METH, METH+CD200-Fc and CD200-Fc groups at random. Rats were intraperitoneally injected with METH (15 mg/kg 8 times at 12 h interval) in METH group, with METH (administered as the same dose and time as the METH group) and CD200-Fc (1 mg/kg at day 0, 2, 4 after METH injection) in METH+CD200-Fc group, with CD200-Fc (1 mg/kg injected as the same time as the METH+CD200-Fc group) or with physiological saline solution in the control group. The level of striatal dopamine (DA) in rats was measured by high-performance liquid chromatography (HPLC). The microglial cells were immunohistochemically detected for the expression of Iba-1, a marker for microglial activation. The results showed that METH could increase the microglia activation in the neuron-microglia cultures and elevate the secretion of IL-1β and TNF-α, which could be attenuated by CD200-Fc. Moreover, CD200-Fc could partially reverse the striatal DA depletion induced by METH and reduce the number of activated microglia, i.e. Iba-1-positive cells. It was concluded that CD200 may have neuroprotective effects against METH-induced neurotoxicity by inhibiting microglial activation and reversing DA depletion in striatum.
Animals ; Animals, Newborn ; Antigens, CD ; administration & dosage ; Cells, Cultured ; Coculture Techniques ; Corpus Striatum ; cytology ; drug effects ; immunology ; Cytokines ; immunology ; Dopamine ; immunology ; Drug Interactions ; Male ; Methamphetamine ; toxicity ; Microglia ; drug effects ; immunology ; Neurons ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo examine the protective effect of nicotinamide on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) in mouse model and its mechanisms.

METHODSParkinson's disease was induced by injection of MPTP in adult male C57BL/6 mice, nicotinamide (500 mg/kg,i.p.) was given prior to subacute (30 mg/kg/d × 5 d,i.p.) MPTP administration. Locomotor activities, striatal dopamine levels, lactate dehydrogenase (LDH) and NO synthase (NOS) activities of whole brains and striatum were analyzed at d5 after last MPTP injections.

RESULTSPretreatment with nicotinamide significantly improved the locomotor activity in the open-field test (P<0.01), but not in the swimming test and grip & climbing test. Nicotinamide administration resulted in sparing striatal dopamine levels from MPTP-induced dopamine depletion. There was no significant difference in LDH and NOS activities in the whole brains among the groups; but the activities in the striatum were drastically elevated after MPTP treatment. Nicotinamide pretreatment markedly inhibited MPTP-induced LDH and NOS activities (P<0.01) and showed no significant difference compared to controls (P>0.05).

CONCLUSIONNicotinamide protects dopaminergic neurons against MPTP-induced neurodegeneration,which suggests that the neuroprotective effects be associated with the inhibition of cell injuries and NOS activities.

Animals ; Corpus Striatum ; drug effects ; metabolism ; Disease Models, Animal ; Dopamine ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Motor Activity ; drug effects ; physiology ; Neurons ; drug effects ; metabolism ; Niacinamide ; pharmacology ; Parkinson Disease ; drug therapy ; metabolism

OBJECTIVETo investigate the effects of early postnatal exposure to dieldrin on striatum synaptic development in lactation, adolescence and adulthood of mice.

METHODSThe pups were divided into 5 groups randomly. Three groups were exposed to dieldrin (0.01% DMSO solution) at doses of 0.2, 2.0 and 20.0 microg/kg and two control groups were exposed to DMSO or saline by intraperitoneal injection of every other day from postnatal days (PND) 3 to PND13. The striatum were isolated from brain in lactation (PND14), adolescence (PND36) and adulthood (PND98). Western blot assay was used to detect the expression levels of striatal synaptic proteins.

RESULTSThe postnatal exposure to dieldrin could reduce the level of growth associated protein (GAP43) of striatum in lactation in a dose-dependent manner. In adolescence, the level of glial fibrillary acidic protein (GFAP) in striatum increased and the levels of tyrosine hydroxylase (TH), GAP43 and post-synaptic density protein 95 (PSD95) decreased with exposure doses. The level of Synapsin I decreased in adolescence male mice. The changes of expression levels of GFAP, TH and PSD95 proteins lasted to adulthood.

CONCLUSIONEarly postnatal exposure to dieldrin could affect the expression level of GAP43 protein in striatum. The expression levels of TH and PSD95 proteins in striatum decreased in adolescence and adulthood. These results indicated that the early postnatal exposure to dieldrin may persistently interfere in the striatal synaptic development.

Animals ; Animals, Newborn ; Corpus Striatum ; drug effects ; growth & development ; Dieldrin ; toxicity ; Female ; Glial Fibrillary Acidic Protein ; metabolism ; Male ; Mice ; Mice, Inbred ICR ; Nerve Tissue Proteins ; metabolism ; Post-Synaptic Density ; drug effects

This study is to investigate the effect of compound B2 on the damage of PC12 cells induced by serum deprivation and to explore its related mechanisms. The binding characteristics of B2 to rat striatum adenosine A2A receptor was studied by radioligand 3H-MSX-2 binding assay. Cell viability was detected by MTT assay. ROS formation was measured after DCFDA fluorescent staining. B2 has affinity to rat adenosine A2A receptor (K1 = 0.37 micromol x L(-1)). B2 remarkably increased PC12 cell survival rate in serum deprivation-induced PC12 cells. The percentage of serum deprivation-induced death of PC12 was 49.6%, and the treatment of B2 (0.1-100 micromol x L(-1)) increased the cell viability to 63.3%, 74.9%, 86.3% and 88.1%, respectively. Adenosine A2A receptor antagonist SCH 58261 could significantly block the protective effect of B2. The cell viability with 0.1 micromol x L(-1) SCH 58261 decreased by 16.1%, 24.0% and 19.8%, in the presence of B2 (0.1-10 micromol x L(-1)). Serum deprivation-induced ROS formation was 3.5 times more than that of control group, and treatment with B2 significantly and dose-dependently inhibited ROS over-formation. The protective effect of B2 may be related with adenosine A2A receptor. Decrease of serum-deprivation induced ROS formation may also be one of the mechanisms.
Adenosine ; analogs & derivatives ; metabolism ; pharmacology ; Adenosine A2 Receptor Antagonists ; pharmacology ; Animals ; Cell Survival ; drug effects ; Corpus Striatum ; metabolism ; Culture Media, Serum-Free ; Female ; Male ; PC12 Cells ; Pyrimidines ; pharmacology ; Rats ; Rats, Wistar ; Reactive Oxygen Species ; metabolism ; Receptor, Adenosine A2A ; metabolism ; Triazoles ; pharmacology