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Coadministration of hydroxysafflor yellow A with levodopa attenuates the dyskinesia
Physiology & Behavior 147 (2015) 193–197
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Physiology & Behavior journal homepage: www.elsevier.com/locate/phb
Coadministration of hydroxysafflor yellow A with levodopa attenuates the dyskinesia Tian Wang a,c,1, Si-jin Duan a,1, Shu-yun Wang b, Yan Lu b, Qing Zhu b, Li-jie Wang a, Bing Han b,⁎ a b c
School of Pharmacy, Yantai University, Yantai, Shandong 264005, PR China School of Life Science, Yantai University, Yantai, Shandong 264005, PR China State key laboratory of Long-acting and Targeting Drug Delivery Technologies (luye Pharma Group Ltd.), Yantai, Shandong 264003, PR China
H I G H L I G H T S
G R A P H I C A L
A B S T R A C T
• Coadministration of hydroxysafflor yellow A with levodopa • Attenuates dyskinesia • Regulating the expression of the dopamine D3 receptor
a r t i c l e
i n f o
Article history: Received 10 January 2015 Received in revised form 21 April 2015 Accepted 22 April 2015 Available online 23 April 2015 Keywords: Coadministration Hydroxysafflor yellow A Levodopa Dyskinesia
a b s t r a c t Levodopa (L-DOPA) is used as the most effective drug available for the symptomatic treatment of Parkinson's disease (PD). However, long-term treatment of L-DOPA frequently causes complications, including abnormal involuntary movements such as dyskinesia and response fluctuations in PD patients. In the present work, we investigated whether hydroxysafflor yellow A (HSYA) ameliorates L-DOPA-induced dyskinesia and motor fluctuations in the 6-hydroxydopamine-lesioned rat model of PD. Valid PD rats were treated daily with vehicle, HSYA alone, L-DOPA, or a combination of HSYA plus L-DOPA for 21 days, respectively. L-DOPA (8 mg/kg) and benserazide (15 mg/kg) were treated intraperitoneally. HSYA was administrated intraperitoneally at a dose of 10 mg/kg. The abnormal involuntary movements and rotational behavior were evaluated. The expression of the dopamine D3 receptor in the striatum was also assayed. The results demonstrated that daily administration of L-DOPA to PD rats for 21 days induced a steady expression of dyskinesia. Coadministration of HSYA with LDOPA significantly ameliorated L-DOPA-induced dyskinesia. The combination treatment also prevented the shortening of the motor response duration that defines wearing off motor fluctuations. HSYA also inhibited the increase of expression of the dopamine D3 receptor in the striatum. These findings demonstrated that HSYA provided anti-dyskinetic relief against L-DOPA in a preclinical model of PD via regulating the expression of the dopamine D3 receptor. The combination of L-DOPA and HSYA also reduced the likelihood of wearing off development, and may thus support the utility of such compounds for the improved treatment of PD. © 2015 Elsevier Inc. All rights reserved.
⁎ Corresponding author at: School of Life Science, Yantai University, Yantai, Shandong 264005, PR China. E-mail address: [email protected] (B. Han). 1 Tian Wang and Si-jin Duan contributed equally to this work.
http://dx.doi.org/10.1016/j.physbeh.2015.04.038 0031-9384/© 2015 Elsevier Inc. All rights reserved.
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1. Introduction Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the loss of dopamine neurons in the nigrostriatal pathway, which leads to progressive dopamine depletion in the striatum. The most efficient treatment strategy for PD is replacement of dopamine by an exogenous supplement of its precursor levodopa (LDOPA). In spite of its efficiency, long-term use of L-DOPA is associated with serious side effects consisting of motor response fluctuation and the emergence of drug-induced involuntary movements, so called LDOPA-induced dyskinesia (LID). Ultimately, up to 80% of patients developed dyskinesia within 5 years of treatment, and some of those had to terminate the therapy due to severe LID. The presence of LID is troublesome and limits utility of L-DOPA in patients. It also significantly worsens the quality of life of the patients [1]. Research continues in an effort to resolve L-DOPA-related pathologies. However, current treatment options for LID are limited. The dose of L-DOPA is still the most significant variable in the development of dyskinesia [2], and lowering the dose of L-DOPA is the best strategy for avoiding L-DOPA-induced adverse effects [3]. However, lowering the dose of L-DOPA alone is not an ideal approach. Although a too-low dose is safer, it is less effective at alleviating symptoms and can even lead to extraneous disability [4]. Thus, a novel treatment method allowing an effective L-DOPA treatment with a low dosage is highly important. Increasing evidence implicated that drug combination therapy is a valuable approach to attenuate L-DOPA-induced adverse effects. Coadministration of l-stepholidine (one of the active ingredients of the Chinese herb Stephania intermedia) with L-DOPA significantly ameliorated LID without compromising the therapeutic potency of L-DOPA [5]. Previous study showed that oral coadministration of L-DOPA and rimonabant significantly decreased abnormal involuntary movements and dystonia [6]. Acupuncture and L-DOPA combination therapy reduces the effective dose of L-DOPA and alleviates LID [7]. Marin and colleagues demonstrated that the combination of L-DOPA and entacapone reduced the likelihood of motor fluctuation development [8]. Traditional Chinese medicine has attracted increasing attention as a complementary therapeutic method to Western medicine [9]. Hydroxysafflor yellow A (HSYA) is the main chemical component of the safflower yellow pigments. It was demonstrated that HSYA could attenuate the neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) in mice [10]. Previous findings in our laboratory also supported a role for HSYA in preserving dopamine neuron integrity and motor function in a rodent model of PD [11]. However, the possible prevention of L-DOPA-induced dyskinesia and wearing off with the coadministration of HSYA and L-DOPA is still unknown. In this study, we investigated whether the coadministration of HSYA and L-DOPA can prevent L-DOPA-induced dyskinesia and wearing off in 6hydroxydopamine (6-OHDA)-induced PD in rats. 2. Methods 2.1. Animals Male Sprague–Dawley rats weighing 220–240 g were acquired from the Experimental Animal Center of Shandong Engineering Research Center for Natural Drugs (Yantai, China). Animals were housed in a climate-controlled room, maintained on a 12 h/12 h light/dark cycle, and given food and water ad libitum. The experiments were performed according to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals (publication 86-23, revised in 1986) and were approved by the Local Ethics Committee. 2.2. Drug and chemical agents HSYA (98% purity by HPLC) was obtained from Shandong Luye Pharmaceutical Co., Ltd. (Yantai, China). HYSA was dissolved in normal saline
and then administrated intraperitoneally to the rats. Apomorphine hydrochloride, L-DOPA, 6-hydroxydopamine (6-OHDA), desipramine hydrochloride, and ascorbate were obtained from Sigma Co. (St. Louis, MO, USA). An anti-dopamine D3 receptor was purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Enhanced chemiluminescence (ECL) detection reagents and BCA protein assay kits were obtained from Beyotime Institute of Biotechnology (Haimen, China). 2.3. Unilateral 6-OHDA lesion Surgery was conducted as previously described [5], with minor modifications. Briefly, the rats were anesthetized with sodium pentobarbital (30 mg/kg, i.p.) and placed in a stereotaxic frame with the incisor bar positioned 4.5 mm below the interaura line. Each animal received a 6-OHDA injection (16 μg of 6-OHDA in 4 μL of saline with 0.02% ascorbate) into the left medial forebrain bundle by means of a Harvard infusion pump (Harvard Apparatus Inc., Holliston, MA, USA). Stereotaxic injections were placed 4.0 mm anterior to the interaural line, 1.65 mm lateral to the midline, and 8.0 mm ventral to the surface of the skull. The injection rate was 0.5 μL/min, and the needle was kept in place for an additional 5.0 min before being slowly retracted. To limit the damage to adrenergic neurons, desipramine hydrochloride (25 mg/kg, i.p.) was administered 30 min before the 6-OHDA injections. Three weeks after surgery, apomorphine (0.1 mg/kg, i.p.) was administered to the rats. The rats with contralateral rotations of more than 150 rotations per 30 min were used as a valid PD model. According the rotations, the valid PD model rats were divided randomly into four groups: control group (n = 8, rotations = 177.8 ± 15.1), HSYA group (n = 8, rotations = 178.0 ± 11.2), L-DOPA group (n = 10, rotations = 179.7 ± 13.4), and L-DOPA + HSYA group (n = 10, rotations = 178.2 ± 12.4). 2.4. Drug treatments The rats were administrated intraperitoneally with vehicle, or HSYA (10 mg/kg), or L-DOPA (8 mg/kg with 15 mg/kg benserazide), or LDOPA (8 mg/kg with 15 mg/kg benserazide) plus HSYA (10 mg/kg) daily for 21 consecutive days. For L-DOPA plus HSYA treatment, rats received 10 mg/kg of HSYA 30 min prior to L-DOPA treatment. L-DOPA, benserazide, and HSYA were dissolved in normal saline. Each drug was administered in a final volume of 1 mL/kg body weight. Abnormal involuntary movements (AIMs) were measured on days 1, 7, 14 and 21 of treatment. Rotational behavior was observed on days 1 and 21. The dosage of 10 mg/kg HSYA was chosen based on our pilot study. 2.5. Abnormal involuntary movements Rats were monitored for AIMs using a procedure and score system according to previous methods [12,13,14]. On test days, rats were individually placed in plastic trays (60 × 75 cm) at 5 min before treatments. After L-DOPA injection, rats were observed individually for 1 min every 20 min for a total of 240 min after injection of the drugs or vehicle. The experienced observer was kept blinded to animal grouping and treatment throughout the entire experiment. Each rat was scored for exhibition of the following three categories of AIMs: (1) axial, lateral flexion and axial rotation of the neck and trunk towards the side contralateral to the lesion; (2) limb, repetitive, rhythmic jerky movements or dystonic posturing of the forelimb on the side contralateral to the lesion; (3) orolingual, tongue protrusion without the presence of food or other objects. For each observation period of 1 min, a score of 0–4 was assigned for each category based on the following criteria: 0, absent; 1, present for less than half of the observation time; 2, present for more than half of the observation time; 3, present all the time but suppressible by threatening stimuli; 4, present all the time and not suppressible. The axial, limb and orolingual AIMs will be integrated as total AIMs scores per session. For assessing rotational behavior, each
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rat was placed in a 40-cm-diameter bowl and allowed to acclimate to the environment for 5 min before recording. Contralateral rotations were counted for 5 min, and rats were observed individually for 1 min every 20 min for a total of 240 min following L-DOPA injection, or 5 min following HSYA injection on day 1 and day 21. Rats were rated for AIMs during the first minute and rotational behavior in the second minute. All experiments were carried out between 8:00 and 16:00 h in a quiet room with standard laboratory conditions.
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3.3. Effect of HSYA on the expression of dopamine D3 receptor in the striatum Dopamine D3 receptor protein expression was significantly higher in the L-DOPA group than in the control group. However, the L-DOPA + HSYA group had lower dopamine D3 receptor expression than that of the L-DOPA group (Fig. 3). 4. Discussion
2.6. Western blotting for the detection of dopamine D3 receptor expression Western blotting was performed as previously described [15]. The striatum tissues were collected and then immediately frozen at −80 °C. The tissues of striatum were homogenized on ice and lysed in a lysis buffer containing 0.3 mL of ice-cold buffer with 20 mM Tris– HCl (pH 7.5), 50 mM NaCl, 1% Triton X-100, 30 mM Na4P2O7, 50 mM NaF, 5 μM ZnCl2, 1 mM dithiothreitol, 5 nM okadaic acid, 2.5 μg/mL aprotinin, 3.6 μM pepstatin, 0.5 μM phenylmethylsulfonyl fluoride, 0.5 mM benzamidine, and 5.3 μM leupeptin. The protein content was measured using a BCA protein assay kit. Samples were heated at 100 °C for 5 min before gel loading and were then subjected to SDSPAGE and transferred to polyvinylidene difluoride membranes using an electrophoretic transfer system. The membranes were blocked in Tris-buffered saline mixed with Tween-20 (TBST) containing 5% skim milk for 60 min. Membranes were then incubated overnight at 4 °C with primary antibody against dopamine the D3 receptor (diluted 1:500) or β-actin (diluted 1:2000). After washing with TBST, the membranes were incubated with a secondary antibody (diluted 1:2000) for 1 h at 37 °C. ECL detection reagents detected the binding. For the quantitative analysis of the density of the immunoblot bands, densitometry was performed with the Gel-Pro Analyzer Version 3.0. The ratio of the integrated optical density of the immunoblot bands of the detected protein to that of β-actin was used for statistical analysis. 2.7. Statistical analysis All data were expressed as the means ± SEM. AIMs scores and contralateral rotation data were analyzed with repeated measures analysis of variance (repeated measures ANOVA). Post hoc comparisons were performed with Bonferroni's test. The dopamine D3 protein expression was compared with one-way analysis of variance (ANOVA) followed by least significant difference test. 3. Results 3.1. HSYA attenuated the development of LID The 6-OHDA-lesioned PD rats were treated daily with L-DOPA in the presence or absence of HSYA for 21 days. Rats treated with L-DOPA alone developed dyskinesia as manifested by the increasing AIMs scores of all trunk, limbs and orolingual muscles (p b 0.01), whereas coadministration of L-DOPA and HSYA displayed much less severe dyskinesia compared to that of L-DOPA alone (p b 0.05 or p b 0.01). The control and HSYA groups did not develop any significant axial, limb, and orolingual AIMs (Fig. 1A, B, C and D). 3.2. HSYA prevented wearing off motor fluctuations The temporal course of the rotational response on days 1 and 21 was similar in both the L-DOPA and L-DOPA + HSYA groups at the beginning of the motor response, achieving a significant level of rotations after 20 min of levodopa administration. Time-course curves show that the motor response duration was significantly longer when L-DOPA was administered in association with HSYA (Fig. 2A and B).
The major findings from this study were as follows: HSYA, an active component of the safflower plant, not only attenuated the development of LID when coadministrated with L-DOPA chronically to PD rats, but also inhibited the increase of expression of the dopamine D3 receptor in the striatum. Moreover initial treatment with HSYA and levodopa together reduced the likelihood of wearing off development seen in animals that received L-DOPA alone. In past works studying LID, both MPTP and 6-OHDA animal models are used [16,17]. However, because the main target of LID is mostly related with abnormal plasticity of the dopaminergic system, the 6-OHDA induced hemi-PD rodent model was more frequently used. In this study, rats with unilateral 6-OHDA lesions of the medial forebrain bundle were used as an animal model of PD. Furthermore, in agreement with the previous study [18], we observed that daily repeated administration of LDOPA to 6-OHDA-lesioned rats causes a significant increase of axial, limb, orolingual and total AIMs score. HSYA alone elicited no significant change of behavior. However, coadministration of HSYA showed an antidyskinetic effect against LID without antagonizing the effects of the anti-parkinsonian therapy. The pathophysiology of LID remains poorly understood. The dopamine D3 receptor is present in the striatum and might contribute to the regulation of balance between the direct and indirect pathways. The previous report showed that following repetitive administration of L-DOPA to 6-OHDA-lesioned rodents, the level of striatal D3 receptor expression rose to above that of vehicle-treated animals [19]. Thus, the concept was born that stimulation of striatal D3 receptor expression may be involved in the behavioral sensitization to repeated L-DOPA. In rodent and non-human primate models of LID, dorsolateral striatal D3 receptor expression is elevated specifically in dyskinetic animals [20, 21]. Studies using D3 receptor-selective agonist PD128907 and D3 receptor-selective antagonists nafadotride have also implicated the D3 receptor in development of LID [22]. These reports led to the idea that reduction of D3 receptor expression may be a useful antidyskinetic strategy. Our Western blot analysis revealed that the treatment with L-DOPA alone induced a significant increase of the expression of the D3 receptor in the striatum. However, HSYA could partly block the increase of the expression of the D3 receptor. Therefore, it is reasonable to conclude that the anti-dyskinetic effect of HSYA may be associated with regulating the expression of the dopamine D3 receptor. Wearing off is defined as a gradual decrease in the duration of effect of each dose of L-DOPA medication. It will eventually affect all patients with PD, but it is currently under-recognized and is not considered an early event in the course of treatment [23]. Nevertheless, wearing off can appear within months or a few years of the beginning of therapy, depending on the dose, as observed in a significant proportion of patients in studies of the early use of L-DOPA in PD [24]. Patients with severe wearing off phenomena may not be able to take oral dopamine replacement therapy, and therefore other routes of administration may be required. Modifying the dosing of conventional L-DOPA is a common strategy and can provide short-term benefits. However, this strategy is frequently not helpful since lower doses of L-DOPA do not improve the motor symptoms to the same extent as higher doses. In the present study, HSYA prevented the shortening of the motor response duration that defines wearing off motor fluctuation. HSYA also decreased the frequency of failures to L-DOPA. These results indicated that the combination of L-DOPA and HSYA might reduce the likelihood
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Fig. 1. Coadministration of hydroxysafflor yellow A with levodopa on abnormal involuntary movements (AIMs) in 6-OHDA-lesioned rats. 6-OHDA-lesioned rats were treated daily with vehicle, HSYA, L-DOPA, or a coadministration of HSYA with L-DOPA for 21 days. The AIMs were investigated at the designed times. Data are expressed as means ± SEM. Statistical analyses were performed using repeated measures ANOVA followed by post hoc Bonferroni test #p b 0.05, ##p b 0.01 versus vehicle treatment; *p b 0.05, **p b 0.01 versus L-DOPA alone treatment. A: axial AIMs; B: limb AIMs; C: orolingual AIMs; D: axial, limb and orolingual AIMs scores (total AIMs).
of motor fluctuation development, and thus become a valuable approach to treat PD whenever L-DOPA is needed. The primary cause of L-DOPA-induced dyskinesia is still unclear, but overexpression of dopamine D3 receptor seems to play a key role. It is also demonstrated that stimulation of sensitized dopamine D1 receptor is responsible for the development of LID [25]. For example, D1 receptor agonists trigger dyskinesia in human PD patients [26]. Additionally, D1 receptor antagonism reduces LID, but also lessens the anti-parkinsonian benefit of L-DOPA [27]. Whereas D1 receptor expression itself is not related to dyskinesia, LID is accompanied by an increase of D1 receptor signaling [28]. Based on the previous results, we only evaluated the effect of HSYA on the expression of D3 receptor. It is important to note that D1 and D3 receptor interaction and heteromerization has not been evaluated in this study. Marcellino and colleagues demonstrated that D1 and D3 heteromer exists in the striatum [29]. During L-DOPA therapy, a vicious cycle could thus begin in
which long term and intermittent stimulation of the D1 and D3 heteromer, resulting in the aberrant signaling and trafficking of the D1 receptor, significantly contributes to the development of dyskinesia. Thus, additional studies addressing whether HSYA has an effect on D1 and D3 interaction and heteromerization in striatum tissues of animals with experimental parkinsonism are clearly required. In summary, these findings demonstrated that HSYA provided antidyskinetic relief against L-DOPA in a preclinical model of PD via regulating the expression of the dopamine D3 receptor. The combination of LDOPA and HSYA may also reduce the likelihood of wearing off development, and may thus support the utility of such compounds for the improved treatment of PD. Conflict of interest The authors declare that there are no conflicts of interest.
Fig. 2. Coadministration of hydroxysafflor yellow A with levodopa on rotational behavior in 6-OHDA-lesioned rats. 6-OHDA-lesioned rats were treated daily with vehicle, HSYA, L-DOPA, or a coadministration of HSYA with L-DOPA for 21 days. The rotational behavior were evaluated at the designed times. Data are expressed as means ± SEM. Statistical analyses were performed using repeated measures ANOVA followed by post hoc Bonferroni test. #p b 0.05, ##p b 0.01 versus vehicle treatment; *p b 0.05, **p b 0.01 versus L-DOPA alone treatment. A: Rotational behavior in day 1; B: Rotational behavior in day 21.
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Fig. 3. Coadministration of hydroxysafflor yellow A with levodopa on the expression of D3 receptor in the striatum of 6-OHDA-lesioned rats. 6-OHDA-lesioned rats were treated daily with vehicle, HSYA, L-DOPA, or a coadministration of HSYA with L-DOPA for 21 days. Up lane is D3 receptor. Down lane is actin. Statistical analyses were performed using one-way analysis of variance (ANOVA) followed by a Dunnett multiple comparisons test. ##p b 0.01 versus vehicle treatment; **p b 0.01 versus L-DOPA alone treatment.
Acknowledgments The study was supported by the “major new drug” special projects of the Ministry of Science and Technology of PR China (No. 2013ZX09102017), the Doctoral Foundation of Yantai University (grant no. SM12B19 and YX12B30), and the Taishan Scholar Project (For Prof. Fenghua Fu). The authors would like to thank Professor Lon Clark for the English language revision.
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Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.physbeh.2015.04.038.
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Physiology & Behavior journal homepage: www.elsevier.com/locate/phb
Coadministration of hydroxysafflor yellow A with levodopa attenuates the dyskinesia Tian Wang a,c,1, Si-jin Duan a,1, Shu-yun Wang b, Yan Lu b, Qing Zhu b, Li-jie Wang a, Bing Han b,⁎ a b c
School of Pharmacy, Yantai University, Yantai, Shandong 264005, PR China School of Life Science, Yantai University, Yantai, Shandong 264005, PR China State key laboratory of Long-acting and Targeting Drug Delivery Technologies (luye Pharma Group Ltd.), Yantai, Shandong 264003, PR China
H I G H L I G H T S
G R A P H I C A L
A B S T R A C T
• Coadministration of hydroxysafflor yellow A with levodopa • Attenuates dyskinesia • Regulating the expression of the dopamine D3 receptor
a r t i c l e
i n f o
Article history: Received 10 January 2015 Received in revised form 21 April 2015 Accepted 22 April 2015 Available online 23 April 2015 Keywords: Coadministration Hydroxysafflor yellow A Levodopa Dyskinesia
a b s t r a c t Levodopa (L-DOPA) is used as the most effective drug available for the symptomatic treatment of Parkinson's disease (PD). However, long-term treatment of L-DOPA frequently causes complications, including abnormal involuntary movements such as dyskinesia and response fluctuations in PD patients. In the present work, we investigated whether hydroxysafflor yellow A (HSYA) ameliorates L-DOPA-induced dyskinesia and motor fluctuations in the 6-hydroxydopamine-lesioned rat model of PD. Valid PD rats were treated daily with vehicle, HSYA alone, L-DOPA, or a combination of HSYA plus L-DOPA for 21 days, respectively. L-DOPA (8 mg/kg) and benserazide (15 mg/kg) were treated intraperitoneally. HSYA was administrated intraperitoneally at a dose of 10 mg/kg. The abnormal involuntary movements and rotational behavior were evaluated. The expression of the dopamine D3 receptor in the striatum was also assayed. The results demonstrated that daily administration of L-DOPA to PD rats for 21 days induced a steady expression of dyskinesia. Coadministration of HSYA with LDOPA significantly ameliorated L-DOPA-induced dyskinesia. The combination treatment also prevented the shortening of the motor response duration that defines wearing off motor fluctuations. HSYA also inhibited the increase of expression of the dopamine D3 receptor in the striatum. These findings demonstrated that HSYA provided anti-dyskinetic relief against L-DOPA in a preclinical model of PD via regulating the expression of the dopamine D3 receptor. The combination of L-DOPA and HSYA also reduced the likelihood of wearing off development, and may thus support the utility of such compounds for the improved treatment of PD. © 2015 Elsevier Inc. All rights reserved.
⁎ Corresponding author at: School of Life Science, Yantai University, Yantai, Shandong 264005, PR China. E-mail address: [email protected] (B. Han). 1 Tian Wang and Si-jin Duan contributed equally to this work.
http://dx.doi.org/10.1016/j.physbeh.2015.04.038 0031-9384/© 2015 Elsevier Inc. All rights reserved.
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1. Introduction Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with the loss of dopamine neurons in the nigrostriatal pathway, which leads to progressive dopamine depletion in the striatum. The most efficient treatment strategy for PD is replacement of dopamine by an exogenous supplement of its precursor levodopa (LDOPA). In spite of its efficiency, long-term use of L-DOPA is associated with serious side effects consisting of motor response fluctuation and the emergence of drug-induced involuntary movements, so called LDOPA-induced dyskinesia (LID). Ultimately, up to 80% of patients developed dyskinesia within 5 years of treatment, and some of those had to terminate the therapy due to severe LID. The presence of LID is troublesome and limits utility of L-DOPA in patients. It also significantly worsens the quality of life of the patients [1]. Research continues in an effort to resolve L-DOPA-related pathologies. However, current treatment options for LID are limited. The dose of L-DOPA is still the most significant variable in the development of dyskinesia [2], and lowering the dose of L-DOPA is the best strategy for avoiding L-DOPA-induced adverse effects [3]. However, lowering the dose of L-DOPA alone is not an ideal approach. Although a too-low dose is safer, it is less effective at alleviating symptoms and can even lead to extraneous disability [4]. Thus, a novel treatment method allowing an effective L-DOPA treatment with a low dosage is highly important. Increasing evidence implicated that drug combination therapy is a valuable approach to attenuate L-DOPA-induced adverse effects. Coadministration of l-stepholidine (one of the active ingredients of the Chinese herb Stephania intermedia) with L-DOPA significantly ameliorated LID without compromising the therapeutic potency of L-DOPA [5]. Previous study showed that oral coadministration of L-DOPA and rimonabant significantly decreased abnormal involuntary movements and dystonia [6]. Acupuncture and L-DOPA combination therapy reduces the effective dose of L-DOPA and alleviates LID [7]. Marin and colleagues demonstrated that the combination of L-DOPA and entacapone reduced the likelihood of motor fluctuation development [8]. Traditional Chinese medicine has attracted increasing attention as a complementary therapeutic method to Western medicine [9]. Hydroxysafflor yellow A (HSYA) is the main chemical component of the safflower yellow pigments. It was demonstrated that HSYA could attenuate the neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP) in mice [10]. Previous findings in our laboratory also supported a role for HSYA in preserving dopamine neuron integrity and motor function in a rodent model of PD [11]. However, the possible prevention of L-DOPA-induced dyskinesia and wearing off with the coadministration of HSYA and L-DOPA is still unknown. In this study, we investigated whether the coadministration of HSYA and L-DOPA can prevent L-DOPA-induced dyskinesia and wearing off in 6hydroxydopamine (6-OHDA)-induced PD in rats. 2. Methods 2.1. Animals Male Sprague–Dawley rats weighing 220–240 g were acquired from the Experimental Animal Center of Shandong Engineering Research Center for Natural Drugs (Yantai, China). Animals were housed in a climate-controlled room, maintained on a 12 h/12 h light/dark cycle, and given food and water ad libitum. The experiments were performed according to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals (publication 86-23, revised in 1986) and were approved by the Local Ethics Committee. 2.2. Drug and chemical agents HSYA (98% purity by HPLC) was obtained from Shandong Luye Pharmaceutical Co., Ltd. (Yantai, China). HYSA was dissolved in normal saline
and then administrated intraperitoneally to the rats. Apomorphine hydrochloride, L-DOPA, 6-hydroxydopamine (6-OHDA), desipramine hydrochloride, and ascorbate were obtained from Sigma Co. (St. Louis, MO, USA). An anti-dopamine D3 receptor was purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Enhanced chemiluminescence (ECL) detection reagents and BCA protein assay kits were obtained from Beyotime Institute of Biotechnology (Haimen, China). 2.3. Unilateral 6-OHDA lesion Surgery was conducted as previously described [5], with minor modifications. Briefly, the rats were anesthetized with sodium pentobarbital (30 mg/kg, i.p.) and placed in a stereotaxic frame with the incisor bar positioned 4.5 mm below the interaura line. Each animal received a 6-OHDA injection (16 μg of 6-OHDA in 4 μL of saline with 0.02% ascorbate) into the left medial forebrain bundle by means of a Harvard infusion pump (Harvard Apparatus Inc., Holliston, MA, USA). Stereotaxic injections were placed 4.0 mm anterior to the interaural line, 1.65 mm lateral to the midline, and 8.0 mm ventral to the surface of the skull. The injection rate was 0.5 μL/min, and the needle was kept in place for an additional 5.0 min before being slowly retracted. To limit the damage to adrenergic neurons, desipramine hydrochloride (25 mg/kg, i.p.) was administered 30 min before the 6-OHDA injections. Three weeks after surgery, apomorphine (0.1 mg/kg, i.p.) was administered to the rats. The rats with contralateral rotations of more than 150 rotations per 30 min were used as a valid PD model. According the rotations, the valid PD model rats were divided randomly into four groups: control group (n = 8, rotations = 177.8 ± 15.1), HSYA group (n = 8, rotations = 178.0 ± 11.2), L-DOPA group (n = 10, rotations = 179.7 ± 13.4), and L-DOPA + HSYA group (n = 10, rotations = 178.2 ± 12.4). 2.4. Drug treatments The rats were administrated intraperitoneally with vehicle, or HSYA (10 mg/kg), or L-DOPA (8 mg/kg with 15 mg/kg benserazide), or LDOPA (8 mg/kg with 15 mg/kg benserazide) plus HSYA (10 mg/kg) daily for 21 consecutive days. For L-DOPA plus HSYA treatment, rats received 10 mg/kg of HSYA 30 min prior to L-DOPA treatment. L-DOPA, benserazide, and HSYA were dissolved in normal saline. Each drug was administered in a final volume of 1 mL/kg body weight. Abnormal involuntary movements (AIMs) were measured on days 1, 7, 14 and 21 of treatment. Rotational behavior was observed on days 1 and 21. The dosage of 10 mg/kg HSYA was chosen based on our pilot study. 2.5. Abnormal involuntary movements Rats were monitored for AIMs using a procedure and score system according to previous methods [12,13,14]. On test days, rats were individually placed in plastic trays (60 × 75 cm) at 5 min before treatments. After L-DOPA injection, rats were observed individually for 1 min every 20 min for a total of 240 min after injection of the drugs or vehicle. The experienced observer was kept blinded to animal grouping and treatment throughout the entire experiment. Each rat was scored for exhibition of the following three categories of AIMs: (1) axial, lateral flexion and axial rotation of the neck and trunk towards the side contralateral to the lesion; (2) limb, repetitive, rhythmic jerky movements or dystonic posturing of the forelimb on the side contralateral to the lesion; (3) orolingual, tongue protrusion without the presence of food or other objects. For each observation period of 1 min, a score of 0–4 was assigned for each category based on the following criteria: 0, absent; 1, present for less than half of the observation time; 2, present for more than half of the observation time; 3, present all the time but suppressible by threatening stimuli; 4, present all the time and not suppressible. The axial, limb and orolingual AIMs will be integrated as total AIMs scores per session. For assessing rotational behavior, each
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rat was placed in a 40-cm-diameter bowl and allowed to acclimate to the environment for 5 min before recording. Contralateral rotations were counted for 5 min, and rats were observed individually for 1 min every 20 min for a total of 240 min following L-DOPA injection, or 5 min following HSYA injection on day 1 and day 21. Rats were rated for AIMs during the first minute and rotational behavior in the second minute. All experiments were carried out between 8:00 and 16:00 h in a quiet room with standard laboratory conditions.
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3.3. Effect of HSYA on the expression of dopamine D3 receptor in the striatum Dopamine D3 receptor protein expression was significantly higher in the L-DOPA group than in the control group. However, the L-DOPA + HSYA group had lower dopamine D3 receptor expression than that of the L-DOPA group (Fig. 3). 4. Discussion
2.6. Western blotting for the detection of dopamine D3 receptor expression Western blotting was performed as previously described [15]. The striatum tissues were collected and then immediately frozen at −80 °C. The tissues of striatum were homogenized on ice and lysed in a lysis buffer containing 0.3 mL of ice-cold buffer with 20 mM Tris– HCl (pH 7.5), 50 mM NaCl, 1% Triton X-100, 30 mM Na4P2O7, 50 mM NaF, 5 μM ZnCl2, 1 mM dithiothreitol, 5 nM okadaic acid, 2.5 μg/mL aprotinin, 3.6 μM pepstatin, 0.5 μM phenylmethylsulfonyl fluoride, 0.5 mM benzamidine, and 5.3 μM leupeptin. The protein content was measured using a BCA protein assay kit. Samples were heated at 100 °C for 5 min before gel loading and were then subjected to SDSPAGE and transferred to polyvinylidene difluoride membranes using an electrophoretic transfer system. The membranes were blocked in Tris-buffered saline mixed with Tween-20 (TBST) containing 5% skim milk for 60 min. Membranes were then incubated overnight at 4 °C with primary antibody against dopamine the D3 receptor (diluted 1:500) or β-actin (diluted 1:2000). After washing with TBST, the membranes were incubated with a secondary antibody (diluted 1:2000) for 1 h at 37 °C. ECL detection reagents detected the binding. For the quantitative analysis of the density of the immunoblot bands, densitometry was performed with the Gel-Pro Analyzer Version 3.0. The ratio of the integrated optical density of the immunoblot bands of the detected protein to that of β-actin was used for statistical analysis. 2.7. Statistical analysis All data were expressed as the means ± SEM. AIMs scores and contralateral rotation data were analyzed with repeated measures analysis of variance (repeated measures ANOVA). Post hoc comparisons were performed with Bonferroni's test. The dopamine D3 protein expression was compared with one-way analysis of variance (ANOVA) followed by least significant difference test. 3. Results 3.1. HSYA attenuated the development of LID The 6-OHDA-lesioned PD rats were treated daily with L-DOPA in the presence or absence of HSYA for 21 days. Rats treated with L-DOPA alone developed dyskinesia as manifested by the increasing AIMs scores of all trunk, limbs and orolingual muscles (p b 0.01), whereas coadministration of L-DOPA and HSYA displayed much less severe dyskinesia compared to that of L-DOPA alone (p b 0.05 or p b 0.01). The control and HSYA groups did not develop any significant axial, limb, and orolingual AIMs (Fig. 1A, B, C and D). 3.2. HSYA prevented wearing off motor fluctuations The temporal course of the rotational response on days 1 and 21 was similar in both the L-DOPA and L-DOPA + HSYA groups at the beginning of the motor response, achieving a significant level of rotations after 20 min of levodopa administration. Time-course curves show that the motor response duration was significantly longer when L-DOPA was administered in association with HSYA (Fig. 2A and B).
The major findings from this study were as follows: HSYA, an active component of the safflower plant, not only attenuated the development of LID when coadministrated with L-DOPA chronically to PD rats, but also inhibited the increase of expression of the dopamine D3 receptor in the striatum. Moreover initial treatment with HSYA and levodopa together reduced the likelihood of wearing off development seen in animals that received L-DOPA alone. In past works studying LID, both MPTP and 6-OHDA animal models are used [16,17]. However, because the main target of LID is mostly related with abnormal plasticity of the dopaminergic system, the 6-OHDA induced hemi-PD rodent model was more frequently used. In this study, rats with unilateral 6-OHDA lesions of the medial forebrain bundle were used as an animal model of PD. Furthermore, in agreement with the previous study [18], we observed that daily repeated administration of LDOPA to 6-OHDA-lesioned rats causes a significant increase of axial, limb, orolingual and total AIMs score. HSYA alone elicited no significant change of behavior. However, coadministration of HSYA showed an antidyskinetic effect against LID without antagonizing the effects of the anti-parkinsonian therapy. The pathophysiology of LID remains poorly understood. The dopamine D3 receptor is present in the striatum and might contribute to the regulation of balance between the direct and indirect pathways. The previous report showed that following repetitive administration of L-DOPA to 6-OHDA-lesioned rodents, the level of striatal D3 receptor expression rose to above that of vehicle-treated animals [19]. Thus, the concept was born that stimulation of striatal D3 receptor expression may be involved in the behavioral sensitization to repeated L-DOPA. In rodent and non-human primate models of LID, dorsolateral striatal D3 receptor expression is elevated specifically in dyskinetic animals [20, 21]. Studies using D3 receptor-selective agonist PD128907 and D3 receptor-selective antagonists nafadotride have also implicated the D3 receptor in development of LID [22]. These reports led to the idea that reduction of D3 receptor expression may be a useful antidyskinetic strategy. Our Western blot analysis revealed that the treatment with L-DOPA alone induced a significant increase of the expression of the D3 receptor in the striatum. However, HSYA could partly block the increase of the expression of the D3 receptor. Therefore, it is reasonable to conclude that the anti-dyskinetic effect of HSYA may be associated with regulating the expression of the dopamine D3 receptor. Wearing off is defined as a gradual decrease in the duration of effect of each dose of L-DOPA medication. It will eventually affect all patients with PD, but it is currently under-recognized and is not considered an early event in the course of treatment [23]. Nevertheless, wearing off can appear within months or a few years of the beginning of therapy, depending on the dose, as observed in a significant proportion of patients in studies of the early use of L-DOPA in PD [24]. Patients with severe wearing off phenomena may not be able to take oral dopamine replacement therapy, and therefore other routes of administration may be required. Modifying the dosing of conventional L-DOPA is a common strategy and can provide short-term benefits. However, this strategy is frequently not helpful since lower doses of L-DOPA do not improve the motor symptoms to the same extent as higher doses. In the present study, HSYA prevented the shortening of the motor response duration that defines wearing off motor fluctuation. HSYA also decreased the frequency of failures to L-DOPA. These results indicated that the combination of L-DOPA and HSYA might reduce the likelihood
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Fig. 1. Coadministration of hydroxysafflor yellow A with levodopa on abnormal involuntary movements (AIMs) in 6-OHDA-lesioned rats. 6-OHDA-lesioned rats were treated daily with vehicle, HSYA, L-DOPA, or a coadministration of HSYA with L-DOPA for 21 days. The AIMs were investigated at the designed times. Data are expressed as means ± SEM. Statistical analyses were performed using repeated measures ANOVA followed by post hoc Bonferroni test #p b 0.05, ##p b 0.01 versus vehicle treatment; *p b 0.05, **p b 0.01 versus L-DOPA alone treatment. A: axial AIMs; B: limb AIMs; C: orolingual AIMs; D: axial, limb and orolingual AIMs scores (total AIMs).
of motor fluctuation development, and thus become a valuable approach to treat PD whenever L-DOPA is needed. The primary cause of L-DOPA-induced dyskinesia is still unclear, but overexpression of dopamine D3 receptor seems to play a key role. It is also demonstrated that stimulation of sensitized dopamine D1 receptor is responsible for the development of LID [25]. For example, D1 receptor agonists trigger dyskinesia in human PD patients [26]. Additionally, D1 receptor antagonism reduces LID, but also lessens the anti-parkinsonian benefit of L-DOPA [27]. Whereas D1 receptor expression itself is not related to dyskinesia, LID is accompanied by an increase of D1 receptor signaling [28]. Based on the previous results, we only evaluated the effect of HSYA on the expression of D3 receptor. It is important to note that D1 and D3 receptor interaction and heteromerization has not been evaluated in this study. Marcellino and colleagues demonstrated that D1 and D3 heteromer exists in the striatum [29]. During L-DOPA therapy, a vicious cycle could thus begin in
which long term and intermittent stimulation of the D1 and D3 heteromer, resulting in the aberrant signaling and trafficking of the D1 receptor, significantly contributes to the development of dyskinesia. Thus, additional studies addressing whether HSYA has an effect on D1 and D3 interaction and heteromerization in striatum tissues of animals with experimental parkinsonism are clearly required. In summary, these findings demonstrated that HSYA provided antidyskinetic relief against L-DOPA in a preclinical model of PD via regulating the expression of the dopamine D3 receptor. The combination of LDOPA and HSYA may also reduce the likelihood of wearing off development, and may thus support the utility of such compounds for the improved treatment of PD. Conflict of interest The authors declare that there are no conflicts of interest.
Fig. 2. Coadministration of hydroxysafflor yellow A with levodopa on rotational behavior in 6-OHDA-lesioned rats. 6-OHDA-lesioned rats were treated daily with vehicle, HSYA, L-DOPA, or a coadministration of HSYA with L-DOPA for 21 days. The rotational behavior were evaluated at the designed times. Data are expressed as means ± SEM. Statistical analyses were performed using repeated measures ANOVA followed by post hoc Bonferroni test. #p b 0.05, ##p b 0.01 versus vehicle treatment; *p b 0.05, **p b 0.01 versus L-DOPA alone treatment. A: Rotational behavior in day 1; B: Rotational behavior in day 21.
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Fig. 3. Coadministration of hydroxysafflor yellow A with levodopa on the expression of D3 receptor in the striatum of 6-OHDA-lesioned rats. 6-OHDA-lesioned rats were treated daily with vehicle, HSYA, L-DOPA, or a coadministration of HSYA with L-DOPA for 21 days. Up lane is D3 receptor. Down lane is actin. Statistical analyses were performed using one-way analysis of variance (ANOVA) followed by a Dunnett multiple comparisons test. ##p b 0.01 versus vehicle treatment; **p b 0.01 versus L-DOPA alone treatment.
Acknowledgments The study was supported by the “major new drug” special projects of the Ministry of Science and Technology of PR China (No. 2013ZX09102017), the Doctoral Foundation of Yantai University (grant no. SM12B19 and YX12B30), and the Taishan Scholar Project (For Prof. Fenghua Fu). The authors would like to thank Professor Lon Clark for the English language revision.
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Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.physbeh.2015.04.038.
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