CD200 attenuates methamphetamine-induced microglial activation and dopamine depletion

J Huazhong Univ Sci Technol［Med Sci］ 32(3):2012

415

CD200 Attenuates Methamphetamine-induced Microglial Activation and Dopamine Depletion*

Xia YUE (岳霞)1†, Dongfang QIAO (乔东访)1†, Aifeng WANG (王爱枫)1, Xiaohui TAN (谭晓辉)1, Yanhong LI (李艳红)2, Chao LIU (刘超)3，Huijun WANG (王慧君)1# 1Department of Forensic Science, Southern Medical University, Guangzhou 510515, China 2Department of Forensic science, Nanchang University, Nanchang 330006, China 3Guangzhou Criminal Science & Technology Institute, Guangzhou 510030, China © Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2012

Summary: This study examined the neuroprotective effect of cluster of differentiation molecule 200 (CD200) against methamphetamine (METH)-induced neurotoxicity. In the in vitro experiment, neu-ron-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- /CD11b was assessed by flow cytometry. The cytokines (ILⅡ -1β, TNF-α) secreted by activated microglia were detected by enzyme-linked immunosorbent assay (ELISA). In the in vivo ex-periment, 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 in-jected 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 in-duced by METH and reduce the number of activated microglia, i.e. Iba-1-positive cells. It was con-cluded that CD200 may have neuroprotective effects against METH-induced neurotoxicity by inhibiting microglial activation and reversing DA depletion in striatum. Key words: methamphetamine; microglia; cluster of differentiation molecule 200; dopamine; striatum

1 Methamphetamine (METH) is one of the psy-chostimulants, which has a highly addictive effect on the central nervous system (CNS), and it has become a major abusive drug all over the world[1]. Researches indicated that METH can cause severe neurotoxicity and the mechanism may involve oxidative stress, excitotoxicity and mitochondrial dysfunction, etc, which results in the damage to dopamine (DA) and 5-HT terminals[2, 3]. In addition, it was found that METH could damage the cell bodies of amine-containing neurons and blood-brain bar-rier in several brain areas[4, 5].

Microglia, a type of antigen-presenting cells located in the CNS, are sensitive to various stimuli and prone to develop inflammation[6]. It is generally believed that mi-

Xia YUE, E-mail: [email protected] †These authors contributed equally to this work. #Corresponding author, E-mail: [email protected] *This study was supported by grants from the National Natural Science Foundation of China (No. 30572090 and No. 30872918).

croglia activation also plays an important role in the METH neurotoxicity. Microglia was revealed to be acti-vated prior to the dopaminergic neuropathology and they participated in this neurotrosis by secreting reactive oxygen species, nitric oxide and proinflammatory cyto-kines in the animal models of METH neurotoxicity[7]. Antioxidant drugs were found effective to attenuate METH-induced overexpression of proinflammatory cy-tokines in microglial cells[8] and certain pharmacological agents were effective in attenuating METH-induced neurotoxicity through blockade of microglial activation, such as MK-801[9]. Thus, compounds that can inhibit microglia activation may contribute to the survival of neurons subjected to the METH-induced neurotoxicity.

Cluster of differentiation molecule 200 (CD200), a kind of membrane glycoproteins, is expressed in CNS neurons[10]. And its receptor, CD200R, is only expressed in the microglia in the CNS[11]. It has been reported that CD200 may interact with CD200R of microglia to down-regulate the microglia activation. The inducible nitric oxide synthase was observed highly expressed in the inflammatory microglia in CD200-deficient mice[12].

32(3):415-421,2012

J Huazhong Univ Sci Technol［Med Sci］

10.1007/s11596-012-0072-0


416

These data suggested that CD200 expressed by neurons, might silence and down-regulate the innate immune function of microglia. But so far, whether CD200-CD200R interaction could attenuate METH neurotoxicity has not yet been clear.

Based on these observations, our present study aimed to investigate whether CD200 could attenuate the METH-induced neurotoxicity through inhibiting micro-glia activation. CD200 Fc region (CD200-Fc) was used to block METH-induced microglial activation in the cul-tured neuron/microglia. In addition, the effect of CD200-Fc against METH-induced neurotoxicity to DA neurons was examined in the rat striatum. Our study at-tempted to prove that suppression of the microglial acti-vation cascade may attenuate METH-induced damage to DA neurons. 1 MATERIALS AND METHODS 1.1 Cell Culture 1.1.1 Striatum Mixed Neuron/Glia Cultures Primary mixed neuron/glia cultures were prepared by the method as previously reported[13] with some modifications. In brief, striatum tissues were isolated from newborn SD rats and dissociated with a mild trituration. The dispersed cells were seeded at 5×105/well in the 24-well plate. The cultured cells were incubated at 37°C in a humidified atmosphere of 5% CO2 and 95% air in minimum essen-tial medium (MEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS) and 10% heat-inactivated horse serum (HS), 1 g/L glucose, 2 mmol/L L-glutamine, 1 mmol/L sodium pyruvate, 100 µmol/L non-essential amino acids, 50 U/mL penicillin, and 50 µg/mL streptomycin. After 7-day culture, the me-dium was replaced by MEM containing 2% FBS, 2% HS, 2 mmol/L L-glutamine, 1 mmol/L sodium pyruvate, 50 U/mL penicillin and 50 µg/mL streptomycin. 1.1.2 Striatum Neuron-enriched Cultures Briefly, the above mentioned striatum neuron/glia cultures were treated with 5 µmol/L cytosine β-D-arabinofur anoside (Ara-C) for 48 h after seeded at 3×105/well in 48-well plates. Two days later, fresh maintenance medium was used to replace the Ara-C-containing medium. At day 7 after seeding, cultures were treated with methyl phenyl pridine ion (MPP+). 1.1.3 Microglia-enriched Cultures Primary micro-glia-enriched cultures were prepared from whole brains of 1-day-old SD rats as previously described[14] with some modifications. Briefly, brain tissues, devoid of meninges and blood vessels, were dissociated by a mild mechanical trituration. The isolated cells (5×107) were seeded in the 150 cm2 culture flasks in DMEM/F12 con-taining 10% FBS, 2 mmol/L L-glutamine, 1 mmol/L so-dium pyruvate, 100 μmol/L nonessential amino acids, 50 U/mL penicillin, and 50 μg/mL streptomycin. The cul-tures were maintained at 37°C in a humidified atmos-phere of 5% CO2/95% air, and the medium was changed 4 d later. On reaching confluence (12–14 d), the micro-glia were separated from astrocytes by shaking the flasks for 5 h at 180 r/min. 1.1.4 Striatum Mixed Neuron-microglia Cultures Primary mixed neuron-microglia cultures were attained by adding microglia back to neuron-enriched cultures;

about 5×104/well microglia were added to 48-well plates. Before other treatments, the mixed cultures were incu-bated for 24 h. 1.2 Animals

A total of 40 male SD rats, weighing from 200 to 220 g (provided by the Experimental Animal Center of Southern Medical University, China) were housed in a room maintained at 22°C on a 12 h light/12 h dark schedule with access to food and water ad libitum. Ani-mals were habituated to the animal facilities for 3 days before use. 1.3 Drug Treatment

In the in vitro cell culture experiments, neu-ron-microglia cultures were incubated with four different media: normal media, media added with METH (20 μmol/L), media with METH (20 μmol/L) and CD200-Fc (10 μg/mL, R&D Systems) and media with CD200-Fc (10 μg/mL) alone. In all cases, cells were harvested for analysis of MHC- /CD11b ratio at various time points Ⅱafter addition of drugs (1, 2, 4, 8, 12 and 24 h) and the supernatants were collected 24 h later for assessing the level of inflammatory cytokines TNF-α and IL-1β.

In the animal experiment, METH neurotoxity was induced in 200 to 220 g male SD rats by intraperitoneal (i.p.) injections of METH (eight injections, 15 mg/kg/injection, at a 12-h interval). Controls received i.p. injections of physiological saline on the same schedule as METH. In the METH+CD200-Fc group, CD200-Fc (1 mg/kg, i.p. injection) was administrated on days 0, 2 and 4 after the first injection of METH. Rats in the CD200-Fc alone group received i.p. injection of CD200-Fc without METH. Core body temperatures were recorded non-invasively by using the DAS-5001 console system (Bio Medic, Netherlands) immediately after every METH injection. All animal experiments were approved by the Local Ethics Review Process Committee. Rats were sacrificed 24 h after the last injection of drug for neurochemical analyses. 1.4 Flow Cytometry for CD-11b and MHC-Ⅱ

The neuron-microglia culture cells were resus-pended in PBS (containing goat blood serum) to prevent non-specific binding, incubated with the monoclonal antibody CD-11b (mice-anti rats, Chemicon, USA) for 30 min and labeled with fluorescence-conjugated secon-dary antibody (goats-anti mice, Alexa Fluor, USA). Then FITC-labeled monoclonal antibody MHC-Ⅱ (mice-anti rats, Harlan Bioproducts, USA) was added into tube and cells were incubated on ice for another 30 min. After washing twice with PBS, all stained cells were finally resuspended in 1% formaldehyde/PBS. Each sample was analyzed using a FACSC auto-flowcytometer with Cell Quest software (BD Biosciences, USA). 1.5 Enzyme-linked Immunosorbent Assay (ELISA) for TNF-α and IL-1β

TNF-α and IL-1β levels of neuron-microglia culture were measured by using ELISA according to the manu-facturer’s instructions (Chemicon, USA). Briefly, the cultured cells were centrifuged at 1×104 r/min for 10 min at 4°C and the supernatants were collected for test. Mi-crotiter plates were coated with the test supernatant at 37°C. Two hours later, the plates were washed four times with the cleaning mixture, and a monoclonal anti-TNF-α and IL-1β rat antibody diluted to 1:1000 was added to


417

each well and incubated for 1 h at 37°C. After washing, a peroxidase conjugated antibody (diluted 1:1000) was added to each well and incubated at 37°C for 1 h. After addition of enzyme, substrate and stop solution, the amount of TNF-α and IL-1β was determined and ex-pressed as absorbance (A) at the wavelength of 492 nm. 1.6 High-performance Liquid Chromatography (HPLC) for Determination of DA

The striatum were separated, weighed and homoge-nized with an ultrasonic-homogenizer in 0.1 mol/L per-chloric acid on ice. The homogenate was then centri-fuged (30 min, 15000 r/min, 4°C), and the supernatant was collected and filtered using a cellulose–acetate membrane disk (Tosoh, Japan). HPLC was used to measure the endogenous levels of DA (column: TSK, ODS80 column, 4.6×150 mm, Tosoh, Japan). All values are expressed as ng/g tissue. 1.7 Immunohistochemistry for Iba-1

The striatum was disassociated, post-fixed in the paraformaldehyde for 6 h and sunk in 30% sucrose for 12 h. Coronal sections (20 μm thick) were prepared with a cryostat, and immunostaining was performed on free-floating sections. Pre-blocking of tissue sections was performed with 10% normal goat serum and 0.2% Triton X-100 in PBS for 1 h at room temperature. Sections were incubated for 6 h at 37°C with the primary antibodies (anti-Iba-1, 1:600, Santa Cruz biotechnology, USA). The sections were incubated in the biotinylated secondary antibody (Santa Cruz biotechnology, USA), treated with the ABC reagent (Sigma-Aldrich, USA) and the tis-sue-bound peroxidase was developed by using diamino-benzidine as chromogen (DAB, Sigma-Aldrich, USA; 0.05% plus 0.01% hydrogen peroxidase solution). After redyed with haematoxylin, sections were mounted onto slides, air-dried, dehydrated, cleared and permanently mounted. Standard control experiments were performed by omission of either the primary or secondary antibody, and yielded no cellular labeling. Cell counts were sam-pled from a 1.2 mm2 area of the striatum by a person blinded to the treatment conditions. Cells were counted from three independent sections from all like-treated rats, bilaterally, which generated an average count for each treated subject. 1.8 Statistical Analysis

ANOVA was used to statistically analyze the effects of CD200-Fc on METH-induced microglial activation and inflammatory factors secretion, and the effects of METH or METH+CD200-Fc on striatal DA content and microglial counts. Individual treatment groups were compared with appropriate controls for DA and micro-glial counts with Dunnett’s Multiple Comparison Test, and comparisons of one treatment group with another were made with Tukey’s Multiple Comparison Test in SPSS10.0. Differences were considered significant if a P value was less than 0.05. 2 RESULTS 2.1 Effect of CD200-Fc on the METH-induced Micro-glial Activation In Vitro

The ability of CD200-Fc to directly modulate mi-croglial activation was tested in neuron/microglia cul-tures. CD11b is a prototypical molecule expressed on the

membrane of all microglia, while MHC-II is specially expressed by the reactive microglia. The ratio of MHC-II/CD11b was used as an index for microglia acti-vation. The results showed that a rapid (i.e., 1 h exposure of neuron/microglia cells to METH) and significant in-crease in the ratio of MHC-II/CD11b (fig. 1) was found in the METH group. By contrast, this ratio was very low in the control group. Additionally, CD200-Fc was found to significantly suppress the METH-induced activation of microglia (P<0.05). Treated with CD200-Fc alone, the cultured cells had a similar low ratio of MHC-II/CD11b to the control group.

Fig. 1 Effects of CD200-Fc on METH-induced microglial acti-

vation After different treatments, cells in neuron/microglia cultures were harvested at different time and analyzed for MHC-II/CD11b ratio by flow cytometry. Data are presented as ±s . *P<0.05 vs. control group; #P<0.05 vs. METH group

The activated microglia can secrete IL-1β and

TNF-α, so the ability of CD200-Fc to suppress the secre-tion of these two inflammatory factors was examined to reflect the effect of CD200-Fc against METH toxicity. In the present study, the levels of IL-1β and TNF-α were undetectable at 0 h and they were increased to 0.07±0.03 and 1.16±0.20 ng/mL respectively 24 hours later in the control group (fig. 2). This demonstrated that only few microglia were activated and exerted physiological func-tion in neuron/microglia cultures when there were no extra stimuli. With cultures treated with METH alone, the levels of these two cytokines were significantly ele-vated to 0.27±0.04 and 3.41±0.29 ng/mL (P<0.05, fig. 2). CD200-Fc could decrease IL-1β and TNF-α secretion caused by METH to 0.13±0.03 and 2.07±0.30 ng/mL respectively (P<0.05, fig. 2). CD200-Fc alone did not alter the level of IL-1β and TNF-α secreted by microglia cells. 2.2 Effect of CD200-Fc on the METH-induced DA Depletion

The effect of CD200-Fc was examined in an in vivo model of METH neurotoxicity. A neurotoxic regimen of METH caused a significant reduction in the levels of striatal DA in rats. As shown in fig. 3, DA was decreased to 20% of control 24 h after the last METH injection. This reduction of striatal DA by METH was statistically significant (P<0.01). Treatment of rats with CD200-Fc during METH injection significantly reduced the extent of DA depletion by 50%, by comparison to the METH treatment alone (P<0.01). CD200-Fc when given alone did not change the striatum DA level which was similar


418

to that in the control group.

Fig. 2 Effects of CD200-Fc on the level of IL-1β and TNF-α

secreted by activated microglial cells The neuron/microglia cells were treated with different drugs, and culture media were assayed for IL-1β and TNF-α by ELISA. Results are presented as ±s . *P<0.05 vs. control group; #P<0.05 vs. METH group

Fig. 3 Striatal DA levels determined by using HPLC 24 h after

the last drug injection CD200-Fc could significantly rescue the DA depletion caused by METH. Results are presented as ±s and each group contained 5 rats. *P<0.05, **P <0.01 vs. con-trol group; ##P<0.01 vs. METH group

2.3 Effect of CD200-Fc on METH-induced Microglia Activation in Striatum

In the in vivo experiment, microglial activation was assessed by staining the brain sections with an antibody against Iba-1 which was considered to be a marker of activated microglia. The results showed the neurotoxic regimen of METH caused a substantial increase in num-ber of Iba-1-positive microglia (fig. 4B). CD200-Fc at-tenuated the promoting effects of METH on microglial activation (fig. 4). CD200-Fc alone did not significantly change the number of Iba-1-positive microglia in stria-tum as compared with control group (fig. 4D).

The neurotoxic regimen of METH used in the study caused a mild hyperthermia as shown in fig. 5, increasing body temperatures 1–2°C above controls. When rats were treated with CD200-Fc during METH injection, the body temperatures had no significant difference from those of rats treated with the METH alone. The rats re-ceiving CD200-Fc alone had the similar body tempera-

ture to the controls with no significant difference found.

Fig. 4 The effect of CD200-Fc on the METH-induced activa-tion of microglia in striatum METH-induced activation of microglia was reflected by the number of Iba-1-positive microglial cells (n=37±4, 201±13, 115±11, 42±3 in control, METH, METH+CD200-Fc and CD200-Fc groups, respectively). A: Control group; B: METH group; C: METH+CD200-Fc group; D: CD200-Fc alone group. Horizontal scale bar =100 μm

Fig. 5 Effects of different treatments on core body temperature Rats were treated with METH, METH+CD200-Fc or CD200-Fc alone. Controls received physiological saline according to the same injection schedule as the METH group. Core body temperatures of mice were recorded immediately after every drug injection. Data are pre-sented as mean core body temperature for each group at the indicated time (n=5 rats/group). SEM was omitted for clarity. CD200-Fc did not change body temperatures when given alone.

3 DISCUSSION

METH is potentially toxic to the CNS. It was found to induce significant nerve terminal damage in animal models[15], create permanent disturbances in the dopa-minergic system of the brain [16, 17], and cause structural abnormalities of the brain[18]. The mechanisms by which METH causes these damage are unclear, but previous researches suggested that increased levels of superox-ide[19, 20], glutamate[21, 22], nitric oxide[23, 24], and inter-leukin 1β[25] as possible factors after METH intoxication. These factors, especially pro-inflammatory cytokines and


419

free radicals[26–28], might lead to neuroinflammation in the pathology of neurodegenerative disease. In particular, microglia is the only immunocyte in the CNS that can be activated by various stimuli such as injury, disease, or inflammation[6, 29]. After activation, microglia can secrete proinflammatory cytokines and reactive oxygen species, many of which have been found to be associated with METH-induced neurotoxicity. Recently, mounting evi-dence documented that microglia participate in METH-induced neurotoxicity[30–34]. Additionally, some study revealed that CD200 might interact with CD200R of microglia to down-regulate the microglia activation[12]. In the present study, we attempted to determine if CD200 could exert protective effects on METH neurotoxicity through suppressing microglial activation.

Our study employed neuron/microglia cocultures which well mimicked the in vivo environment in which neurons and microglia may interact with each other. Pre-viously, many in vitro experiments focused on METH-induced neurotoxicity in the neuron-enriched cultures or cell lines without the presence of microglia, which could not simulate the real condition in vivo. Moreover, the concentrations of METH which led to neuronal damage in cultured cells were in the millimolar range[35], significantly higher than micromole in the in vivo model[36]. The underlying mechanism about the in vivo METH toxicity might involve multifactorial and systemically interactive or synergistic responses[35]. So, we believed neuron/microglia cultures in vitro could ex-clude possible complicated physiological feedback in-teractions under the in vivo microenvironment, which allowed us to focus on the modulatory effect of CD200-CD200R pathway on the METH-induced neuro-toxicity.

Firstly, we examined whether CD200-Fc could di-rectly suppress METH-induced activation of microglia in neuron/microglia cultures. We added METH into the cultured cells and found the enhanced MHC-II/CD11b ratio and secretion of TNF-α and IL-1β, which demon-strated that METH was toxic to the culture cells and it could enhance the activation of microglia. Moreover, CD200-Fc was found to partially suppress METH-in-duced activation of microglia. And CD200-Fc alone did not enhance the microglial activation. These results sug-gested that CD200-Fc might directly act on the cultured microglia to inhibit their activation. Next, CD200-Fc was tested for the ability to attenuate METH damaged by inhibiting microglial activation in the in vivo METH model of neurotoxicity. We found that CD200-Fc could significantly reduce METH-induced activation of striatal microglia and it could protect against DA nerve terminal damage.

Our observation that CD200-Fc could significantly lower the extent of microglial activation while attenuat-ing METH neurotoxicity indicated a causal link between these two processes. It was also reported that CD200 could prevent the neuronal damage in inflammation[37] by inhibiting microglial activation and CD200-CD200R dysfunction exacerbated neurodegeneration in a model of Parkinson’s disease[38]. However, the present results showed that CD200-Fc could not completely alleviate the METH-induced neurotoxicity. We speculated that the possible reason was that METH-induced damage was a

complicated process, which might involve many factors apart from the microglial activation. Inhibiting the acti-vation of microglia could not completely reverse neu-ronal damage. It was also possible that some microglia were insensitive to CD200-Fc and can still be activated by various stimuli even in the presence of CD200-Fc. This suggested that CD200-Fc might better exert its neu-roprotective effects on the METH-induced neurotoxicity when combined with other protective procedures.

A large number of studies reported that almost any treatment which could prevent METH-induced hyper-thermia always protected against neurotoxicity[39–42]. And hypothermia could suppress microglial activation and might perform neuroprotective effect via this mecha-nism[43, 44]. So in this study we also tested the core body temperature to investigate the influence of CD200-Fc on thermoregulation. Our results showed that CD200-Fc alone had no effect on the body temperature and could not decrease METH-induced hyperthermia, which sug-gested that the decreased microglia activation in our study was not caused by the change of body temperature.

In conclusion, our study demonstrated that CD200 could suppress the microglial activation by interacting with CD200 receptor and, furthermore, it could attenuate the METH-induced DA depletion. But CD200 could not completely recover the METH-induced neurotoxicity. Acknowledgements

We would like to thank Li Xuefeng, a postgraduate of Department of Forensic Science, Southern Medical University, for his technical assistance during this research. REFERENCES 1 United Nations Office on Drugs and Crime. World drug

report volume 1. Analysis. Vienna: United Nations Office on Drugs and Crime. 2007, 1-280

2 Fleckenstein AE, Volz TJ, Riddle EL, et al. New insights into the mechanism of action of amphetamines. Annu Rev Pharmacol Toxicol, 2007,47(1):681-698

3 Yamamoto BK, Raudensky J. The role of oxidative stress, metabolic compromise, and inflammation in neuronal in-jury produced by amphetamine-related drugs of abuse. J Neuroimmune Pharmacol, 2008,3(4):203-217

4 Bowyer JF, Robinson B, Ali S, et al. Neurotoxic-related changes in tyrosine hydroxylase, microglia, myelin, and the blood-brain barrier in the caudate-putamen from acute methamphetamine exposure. Synapse, 2008,62(3):193- 204

5 Yamamoto BK, Moszczynska A, Gudelsky GA. Am-phetamine toxicities classical and emerging mechanisms. Ann NY Acad Sci, 2010,1187:101-121

6 Liu B, Hong JS. Role of microglia in inflammation-me-diated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther, 2003,304(1):1-7

7 LaVoie MJ, Card JP, Hastings TG. Microglial activation precedes dopamine terminal pathology in methampheta-mine-induced neurotoxicity. Exp Neurol, 2004,187(1): 47-57

8 Tocharus J, Khonthun C, Chongthammakun S, et al. Me-


420

latonin attenuates methamphetamine-induced overex-pression of pro-inflammatory cytokines in microglial cell lines. J Pineal Res, 2010,48(4):347-352

9 Thomas DM, Kuhn DM. MK-801 and dextromethorphan block microglial activation and protect against metham-phetamine-induced neurotoxicity. Brain Res, 2005,1050(1-2):190-198

10 Webb M, Barclay AN. Localisation of the MRC OX-2 glycoprotein on the surfaces of neurons. J Neurochem, 1984,43(4):1061-1067

11 Neumann H. Control of glial immune function by neu-rons. Glia, 2001,36(2):191-199

12 Hoek RM, Ruuls SR, Murphy CA, et al. Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science, 2000,290 (5497):1768-1771

13 Wang T, Pei Z, Zhang W, et al. MPP+-induced COX-2 activation and subsequent dopaminergic neurodegenera-tion. FASEB J, 2005,19(9):1134-1136

14 Gao HM, Hong JS, Zhang W, et al. Distinct role for mi-croglia in rotenone-induced degeneration of dopaminer-gic neurons. J Neurosci, 2002,22(3):782-790

15 Kita T, Wagner GC, Nakashima T. Current research on methamphetamine-induced neurotoxicity: animal models of monoamine disruption. J Pharmacol Sci, 2003,92(3):178-195

16 Volkow ND, Chang L, Wang GJ, et al. Loss of dopamine transporters in methamphetamine abusers recovers with protracted abstinence. J Neurosci, 2001,21(23):9414- 9418

17 Volkow ND, Chang L, Wang GJ, et al. Association of dopamine transporter reduction with psychomotor im-pairment in methamphetamine abusers. Am J Psychiatry, 2001,158(3):377-382

18 Thompson PM, Hayashi KM, Simon SL, et al. Structural abnormalities in the brains of human subjects who use methamphet Amine. J Neurosci, 2004,24(26): 6028-6036

19 Cadet JL, Ladenheim B, Baum I, et al. CuZn-superoxide dismutase (CuZnSOD) transgenic mice show resistance to the lethal effects of methylenedioxyamphetamine (MDA) and of methylenedioxy methamphetamine (MDMA). Brain Res, 1994,655(1-2):259- 262

20 Cadet JL, Sheng P, Ali S, et al. Attenuation of metham-phetamine- induced neurotoxicity in copper/zinc super-oxide dismutase transgenic mice. J Neurochem, 1994,62(1):380-383

21 Pu C, Broening HW, Vorhees CV. Effect of metham-phetamine on glutamate-positive neurons in the adult and developing rat somatosensory cortex. Synapse, 1996,23(8):328-334

22 Stephans S, Yamamoto B. Methamphetamine pretreat-ment and the vulnerability of the striatum to metham-phetamine neurotoxicity. Neuroscience, 1996, 72(3):593-600

23 Itzhak Y, Gandia C, Huang PL, et al. Resistance of neu-ronal nitric oxide synthase-deficient mice to metham-phetamine-induced dopaminergic neurotoxicity. J Phar-macol Exp Ther, 1998,284(3):1040-1047

24 Itzhak Y, Martin JL, Ali SF. Methamphetamine- and

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity in inducible nitric oxide syn-thase-deficient mice. Synapse, 1999,34(4):305-312

25 Flora G, Lee YW, Nath A, et al. Methamphetamine poten-tiates HIV-1 Tat protein-mediated activation of re-dox-sensitive pathways in discrete regions of the brain. Exp Neurol, 2003,179(1):60-70

26 Perry G, Cash AD, Smith MA. Alzheimer disease and oxidative stress. J Biomed Biotechnol, 2002,2(3):120- 123

27 Tuppo EE, Arias HR. The role of inflammation in Alz-heimer’s disease. Int J Biochem Cell Biol, 2005,37(2):289-305

28 Chinta SJ, Andersen JK. Redox imbalance in Parkinson’s disease. Biochim Biophys Acta, 2008,1780(11):1362- 1367

29 Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci, 1996,19(8): 312-318

30 Thomas DM, Walker PD, Benjamins JA, et al. Metham-phetamine neurotoxicity in dopamine nerve endings of the striatum is associated with microglial activation. J Pharmacol Exp Ther, 2004,311(1):1-7

31 Centers for Disease Control and Prevention-NIOSH Morgantown, West Biginia, USA. Defining “neuroin-flammation” lessons from MPTP- and methampheta-mine-induced neurotoxicity. Ann NY Acad Sci, 2008,1139(1):318-330

32 Yoshimoto S, Yasuomi O, Genichi S, et al. Metham-phetamine causes microglial activation in the brains of human abusers. J Neurosci, 2008,28(22):5756-5761

33 David MT, Dina MF, Donald MK. Methampheta-mine-induced neurotoxicity and microglial activation are not mediated by fractalkine receptor signaling. J Neuro-chem, 2008,106(2):696-705

34 Osamu K, Toshiaki T, Elaine LW, et al. Microglial and astroytic changes in the striatum of methamphetamine abusers. Leg Med, 2010,12(2):57-62

35 Huang YN, Wu CH, Lin TC, et al. Methamphetamine induces hemeoxygenase-1 expression in cortical neurons and glia to prevent its toxicity. Toxicol Appl Pharmacol, 2009,240(3):315-326

36 Melega WP, Williams AE, Schmitz DA, et al. Pharma-cokinetic and pharmacodynamic analysis of the actions of D-amphetamine and D-methamphetamine on the dopa-mine terminal. J Pharmacol Exp Ther, 1995,274(1): 90-96

37 Chitnis T, Imitola J, Wang Y, et al. Elevated neuronal expression of CD200 protects wlds mice from inflamma-tion-mediated neurodegeneration. Am J Pathol, 2007,170(5):1695-1712

38 Zhang S, Wang XJ, Tian LP, et al. CD200-CD200R dys-function exacerbates microglial activation and dopa-minergic neurodegeneration in a rat model of Parkinson’s disease. J Neuroinflammation, 2011,8(6): 154

39 Bowyer JF, Davies DL, Schmued L, et al. Further studies of the role of hyperthermia in methamphetamine neuro-toxicity. J Pharmacol Exp Ther, 1994, 268(3):1571-1580

40 Bowyer JF, Tank AW, Newport GD, et al. The influence of environmental temperature on the transient effects of


421

methamphetamine on dopamine levels and dopamine re-lease in rat striatum. J Pharmacol Exp Ther, 1992,260(2):817-824

41 Miller DB, O’Callaghan JP. Environment-, drug- and stress-induced alterations in body temperature affect the neurotoxicity of substituted amphetamines in the C57BL/6J mouse. J Pharmacol Exp Ther, 1994,270(2): 752-760

42 O’Callaghan JP, Miller DB. Neurotoxicity profiles of substituted amphetamines in the C57BL/6J mouse. J

Pharmacol Exp Ther, 1994,270(2):741-751 43 Gibbons H, Sato TA, Dragunow M. Hypothermia sup-

pressesinducible nitric oxide synthase and stimulates cyclooxygenase-2 in lipopolysaccharide stimulated BV-2 cells. Brain Res Mol Brain Res, 2003,110(1): 63-75

44 Kataoka K, Yanase H. Mild hypothermia—A revived counter-measure against ischemic neuronal damages. Neurosci Res, 1998,32(2):103-117

(Received Jan. 4, 2012)

Documents

CD200 attenuates methamphetamine-induced microglial activation and dopamine depletion