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Modulation of sphingosine-1-phosphate receptor ameliorates harmaline-induced essential tremor in rat
Neuroscience Letters 653 (2017) 376–381
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research article
Modulation of sphingosine-1-phosphate receptor ameliorates harmaline-induced essential tremor in rat Narjes Dahmardeh a,b , Majid Asadi-Shekaari a , Shokouh Arjmand a , Tajpari Kalantaripour c , Mohsen Basiri b , Mohammad Shabani a,∗ a
Intracellular Recording Lab, Kerman Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran Department of Anatomical Sciences, Afzalipour Medical Faculty, Kerman University of Medical Sciences, Kerman, Iran c Department of Physiology, School of Medicine, Islamic Azad University, Branch of Kerman, Kerman, Iran b
h i g h l i g h t s • Sphingosine-1-phosphate analogue typically ameliorated harmaline induced tremor. • FTY affected explorative and gait disturbances induced by harmaline. • FTY improved impairments of anxiety-like behaviors following harmaline administration.
a r t i c l e
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Article history: Received 8 May 2017 Received in revised form 5 June 2017 Accepted 12 June 2017 Available online 13 June 2017 Keywords: Essential tremor Fingolimod (FTY720) Multiple sclerosis Harmaline
a b s t r a c t Essential tremor (ET) is one of the most common movement disorders with unknown etiology. Despite lack of effective clinical treatments, some potential therapeutic factors and modulation of some neurotransmitters have been utilized to ameliorate motor symptoms in the animal models of tremor. In the current study, male Wistar rats (n = 10 in each group) weighing 40–60 g were divided into vehicle control groups (saline or DMSO), saline/DMSO + harmaline (30 mg/kg, i.p.) + fingolimod (FTY720) (1 mg/kg, i.p, 1 h before harmaline injection) groups. Open field, rotarod, wire grip and foot print tests were used to evaluate motor function. The results demonstrated that administration of FTY720 can improve harmaline-induced tremor in rats. Moreover, FTY720 ameliorated gait disturbance. The results showed that FTY720 can recover step width, left and right step length; however, FTY720 failed to recover mobility duration. FTY720 also improved falling time and time spent in wire grip and rotarod, respectively. The current study provides the first evidence for the effectiveness of FTY720 on motor function in the harmaline model of ET. Furthermore, neuroprotective effects of FTY720 demonstrated in this study offer sphingosine-1-phosphate receptor (S1PR) modulators as a potential neuroprotective candidate against substance-induced tremor and a possible strategy for the treatment of patients with tremor. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Tremor is characterized by involuntary, rhythmic and sinusoidal oscillation in one or more body parts [2,41]. Essential tremor (ET) as the most common type of tremors and a prevalent movement disorder in adults [33] has negative impacts on many aspects of the patient’s life [41]. Despite the fact that ET is one of the most common movement disorders [26], its etiology is still unknown [1]. Animal
∗ Corresponding author: Kerman Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, 76198-13159, Iran. E-mail addresses: [email protected], [email protected] (M. Shabani). http://dx.doi.org/10.1016/j.neulet.2017.06.015 0304-3940/© 2017 Elsevier B.V. All rights reserved.
models of tremor have been largely contributed to better understandings to assess possible pathways involved. Harmaline as an indole alkaloid found in the seeds of Peganum harmala (Syria rue) is a widely used tremorigenic compound to experimentally induce tremor in animals [34]. Although the underlying mechanisms of inducing tremor have not been yet clearly elucidated [28], harmaline-induced tremor can be considered as a model to assess the pathogenesis of ET and evaluate possible treatment modalities for this condition [8]. Harmaline acts on the olivo-cerebellar system [29,44], leaving its impacts on the inferior olive nucleus (ION), and can generate tremor by increasing neuronal excitability [25]. Therefore, compounds that are potentially capable of reducing neuronal excitability might be beneficial in the treatment of ET [37].
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Fingolimod (FTY720) is a fungus metabolite [5] that has been proven to be useful in the treatment of inflammatory diseases by exerting immunological and neurobiological effects in the central nervous system (CNS) [23]. FTY720 as an immunosuppressive drug was approved in 2010 for relapsing forms of multiple sclerosis (MS) to attenuate its clinical exacerbation frequency [24]. FTY720 is phosphorylated by sphingosine kinase into its active form, (FTY720-P) in vivo [16]. Neuroprotective effects of FTY720-P in the CNS, as well as FTY720 s ability to inhibit not only inflammatory mediators but also T cells have been proposed to contribute to its pharmacological mode of actions [17]. In fact, FTY720 has shown neuroprotective, anti-apoptotic, and immunomodulatory effects in many animal models of CNS-related diseases such as cerebral ischemia, MS and Huntington’s disease [6,10]. The goal of this study was to investigate whether behavioral recovery could be pharmacologically enhanced by administration of FTY720 in the animal model of tremor. Here, harmaline induced moderate tremor which was manifested by marked deficits in performance in all behavioral tasks employed, and then these marked deficits were reversed by use of a S1PR modulator. 2. Methods and materials 2.1. Animals Male Wistar rats (40–60 g) were used. All procedures in this experiment were carried out according to the Neuroscience Research Center of Kerman Medical University. The animals were maintained on a 12-h light-dark cycle with food and water ad libitum. 2.2. Drug preparation and administration Harmaline hydrochloride dihydrate (Sigma, Germany) was dissolved in normal saline at the concentration of 30 mg/kg. FTY720 purchased from Sigma-Aldrich (Germany) was dissolved in dimethyl sulfoxide (DMSO; maximum DMSO concentration: 1%v /v. ) at the concentration of 1 mg/ml on the day of experiment. The FTY720 group received FTY720 (1 mg/kg; i.p.), 1 h prior to harmaline injection. Animals which only received harmaline without FTY720 pre-administration, received either saline or DMSO 1 h prior to harmaline injection to keep the same number of injections in all groups. Drugs were administered intraperitoneally to a maximum total injection volume of 1 ml. 2.3. Behavioral tasks 2.3.1. Observation The occurrence of tremors was rated by an observer who was blinded to the treatment. Thirty minutes after harmaline administration, during the open field test, the tremor data were acquired and quantitatively scored as follows: 0: No tremor, 1: occasional tremor affecting only the head and neck, 2: intermittent (occasional tremor affecting all body parts), 3: persistent (persistent tremor affecting all body parts and tail), 4: severe (persistent tremor rendering the animal unable to stand and/or walk) [3]. 2.3.2. Open field test (OFT) In this test a Plexiglas arena (90 [W] × 90 [L] × 45 [H] cm) was used that its floor was divided into 16 squares to define central and peripheral regions. Each rat was placed in the center of the field. Vertical (rearing) and horizontal activities were recorded for 5 min and analyzed with subsequent offline analysis (Ethovision 7.1, Noldus Information Technology, Netherland). For each rat, total distance moved (TDM, cm); total duration mobility (s) and immo-
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bility (s) were recorded. At the end of each trial, the field was cleaned with ethanol 70% [1,20]. 2.3.3. Rotarod performance test In this study, for the analysis of motor coordination and balance skills, accelerating rotarod (Hugo Sachs, Germany) was used. Prior to placing the animal on the apparatus, rod rotation was set to 10 rpm. Upon start of the test, the animal was placed on the rod with the linear acceleration rate of 10 rpm/min to a maximum of 60 rpm. All the animals were pre-trained prior to the experiment and underwent three trials accompanied by a 300-s cut off and inter-trial intervals of 5 min [20,36]. The duration for which each animal remained in the apparatus was recorded and the mean for all trials per animal was calculated. 2.3.4. Wire grip test This test evaluates muscle strength and balance. To perform the wire grip test, each rat was suspended with forepaws on a horizontal steel wire (80 cm long, 7 mm in diameter), which was connected between two platforms. While rats were grasping the wire, they were placed in a vertical position. All the animals underwent three trials with 5 min inter-trial interval, and the falling latency was recorded with a stop watch [40]. 2.3.5. Footprint To assess the walking patterns and gait kinematics of the animals, footprint test was used. The hind paws of the rats were marked with a non-toxic ink, and then each rat was allowed to walk along a clear Plexiglas tunnel (100 cm [L] × 10 cm [H] × 10 cm [W]), leading to a darkened cage. A sheet of white absorbent paper (100 cm × 10 cm) was placed on the floor of the runway [7]. The distance between each step on the same side of the body at a right angle was measured as stride lengths and the distance between the centers of the respective paw prints to the opposite side of the body as hind paw stride widths. Footprints at the beginning and end of each run were not considered in the analysis [42]. 2.4. Statistical analysis Graph Pad Prism 6 (Graph Pad Software, USA) were used for statistical analysis of data and figure production. All data were first assessed for normality using a Kolmogorov-Smirnov test. Results found to be normally distributed were analyzed using one-way ANOVA test. Where a main effect was seen in ANOVA tests, pairwise comparisons between groups were then made using Tukey’s post-hoc tests. Results that were not normally distributed were analyzed using Kruskal-Wallis test. All data expressed as median and interquartile range and p < 0.05 was considered statistically significant. 3. Results 3.1. The effects of FTY720 on gait disturbance Harmaline induced a significant and persistent tremor that affected all body parts. The tremor scale score increased in the rats of harmaline treated compared to the control groups (Fig. 1A) and hind paw stride width also significantly increased (Fig. 1B). Median tremor score and hind paw stride width were significantly decreased by FTY720 treatment compared to the saline + harmaline and DMSO + harmaline groups. These results demonstrate that treatment with 30 mg/kg harmaline reliably induced severe tremor associated with significant functional deficits that can be detected and assessed using the tasks employed. Moreover, a main effect of the treatment upon left (Fig. 1C) and right (Fig. 1D) step lengths was not detected.
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Fig. 1. Effects of FTY720 on tremor scores (A), step width (B), left (C) and right step length (D) after harmaline administration. Values are represented as median with interquartile ranges as a box and maxima/minima as whiskers. * and # P < 0.05, significantly different from the vehicle control (DMSO, and saline; i.p.) treated groups, respectively. × and ¤ P < 0.05, significantly different from the saline + harmaline and DMSO + harmaline treated groups, respectively. Legends merged on each bar indicates the group size. No data points were excluded as outliers in the presented analyses.
3.2. The effects of FTY720 on explorative and anxiety-like behaviors Rats of the saline + harmaline and DMSO + harmaline groups exhibited a decrease in TDM as compared to the control vehicle groups (p < 0.05, Fig. 2A). No significant difference was observed among FTY720 and control groups (p > 0.05, Fig. 2A). In the open field test, an overall effective impact of the treatment upon velocity (Fig. 2B), mobility (Fig. 2C), time spent in the center (Fig. 2D) and time spent in the perimeter (Fig. 2E) was found. Results revealed that treatment with FTY720 had no ameliorative effect on harmaline-induced disturbances in velocity and mobility. Post hoc comparisons revealed that saline + harmaline and DMSO + harmaline significantly reduced time spent in the center and increased time spent in the outer zone, while administration of FTY720 could reverse the aforesaid harmaline induced behavioral changes.
3.3. The effects of FTY720 administration on muscle strength and balance function In three consecutive trials, rats of the FTY720 + harmaline group showed a decrease in falling time as compared to the control groups in the wire grip test (p < 0.05, Fig. 3A). Rats of the FTY720 + harmaline group spent shorter duration on the wire grip as compared to the control groups (p < 0.05). Falling time increased significantly in FTY720 pre-treated rats compared to the saline + harmaline and DMSO + harmaline groups (p < 0.05, Fig. 3A).
In the rotarod test, FTY720 pre-treated rats showed overall increased mean time spent on the apparatus which revealed that FTY720 can significantly increase time spent on the rod when compared to saline + harmaline and DMSO + harmaline groups. Balance function was evaluated by averaging three repeated trials of the time stay on the rod; these results were similar to per trial alone. The results demonstrated that FTY720 + harmaline rats spend more time on the rod in comparison to the harmaline treated rats (p < 0.05, Fig. 3B).
4. Discussion It is well known that tremor evoked by harmaline is action dependent. In consistent with previous behavioral studies [1,4,41] which have shown similar effects such as motor deficits, ataxia and catatonia, in the present study, harmaline induced moderate tremor which was manifested as marked deficits in performance, in all of the behavioral tasks employed. These deficits were confirmed by significant elevations in tremor score and stride width, and significant reduction in TDM, mobility duration, movement speed, time on the rotarod and grip strength. We assessed the effects of a non-selective S1PR modulator, FTY720, on harmaline-induced tremor. Pretreatment with FTY720 ameliorated severe ET associated symptoms and such data represent the first behavioral evidence for clinical potential of FTY720 in an established and relevant animal model of ET. Notably, non-selective modulation of S1PR could significantly lessen harmaline-induced tremor score, implying beneficial effects
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Fig. 2. The effects of FTY720 on exploratory and anxiety like behavioral changes induced by harmaline. Total distance moved (A), velocity (B) and mobility duration decreased in harmaline treated groups as compared to control groups; however, there was no significant difference between FTY720 treated groups and control groups in total distance moved. Anxiety like behaviors (D: time spent in center and E: outer zone) altered by the harmaline administration. Moreover this effect reversed by FTY720. *p < 0.05, #p < 0.05, ×p < 0.05 and ¤p < 0.05 as compared to the saline, DMSO, saline + harmaline and DMSO + harmaline groups, respectively. Values are presented as median with interquartile ranges as a box and maxima/minima as whiskers. Legends merged on each bar indicate the group size.
on the primary behavioral and functional deficits exhibited in this model. Recent studies have shown that harmaline generates tremor with kinetic and postural condition that may last from minutes to hours [19]. Evidence indicate that harmaline increases T-type calcium pulses in the ION, so T-type calcium channel blockers probably can exhibit therapeutic potentials for treating tremor associated disorders [30]. Since FTY720 is phosphorylated to FTY720-P in vivo [16], and its active form acts as an agonist for the S1PR [38], it is capable of regulating many cellular responses [35]. Moreover, FTY720 as a S1PR modulator [39] can readily cross the blood–brain barrier (BBB) and target the CNS neurons expressing S1P receptors [45]. Recent
clinical studies have indicated that FTY720 can attenuate neurodeficits [39]. Zhao et al., showed neuroprotective efficacy of FTY720 in Parkinson’s disease and suggested that S1PR modulators can be considered as a potentially beneficial approach for the treatment of patients with neurodegenerative diseases [45]. Since FTY720 reduces caspase activation and subsequently apoptosis in the intracerebral hemorrhage [27] and cerebral ischemia [43] models via calcium channel pathways, it can be assumed that its protective effect to ameliorate tremor probably has resulted from crossing the BBB and its inhibitory effects on the T-type calcium channels. In the current study, our results were indicative that FTY720 can decrease tremor scale and improve balance disorder in rats. The
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Fig. 3. The effects of FTY720 on muscle strength and balance function after harmaline administration: (A): Mean latency to fall in wire grip test, (B): Average falling time in three consecutive trials in rotarod test. *p < 0.05, #p < 0.05, ×p < 0.05 and ¤p < 0.05 as compared to the saline, DMSO, saline + harmaline and DMSO + harmaline groups, respectively.
present findings seem to be consistent with Wei et al., who have found that treatment with FTY720 improves behavioral functions in animals with ischemic stroke [43]. At the cellular level, harmaline may induce tremor by acting on the NMDA (N-methyl-d-aspartic acid) receptors and inducing neuronal death [21]. Deogracias et al., have indicated that FTY720 has a neuroprotective effect by reducing the NMDA-induced cytotoxicity in a brain-derived neurotrophic factor (BDNF) dependent manner [12]. Harmaline disrupted motor and balance coordination through NMDA-induced excitotoxicity, thus, it can be predicted that FTY720 might ameliorate effects of harmaline via blockade of the NMDA receptors [19]. These results are in agreement with Cipriani et al., providing evidence for neuroprotective properties of FTY720 against NMDA-mediated excitotoxicity [9]. Moreover, recent evidence have suggested that FTY720 can increase the production of neurotrophic factors, BDNF, by lipopolysaccharide-activated microglia [31] and promote microglia’s neuroprotective phenotype. Doi et al., also demonstrated that FTY720-P enhances the production of BDNF [15]. Recent studies have shown that FTY720 neutralizes NMDA [13] and increases the neuronal production of BDNF [15]. Notably, modulations of these receptors have been reported to be effective on ET [11], also some lines of evidence have reported that NMDA receptor antagonists may show beneficial effects on ET [32]. Fukumoto et al., inferred that phosphorylated FTY720 affects neurons via increasing the expression of BDNF [18]. In other study, di Nuzzo et al., have found that FTY720 protects neurons against excitotoxic death and also reported that FTY720 reduces the permeability of the BBB by acting on the CNS parenchyma, and subsequently supports neuronal survival which may be mediated by increased levels of BDNF [14]. Our data showed that FTY720 had promising effects on motor function. Consistent with these findings, Hasegawa et al., have evaluated the effects of FTY720 administration on cerebral ischemia, and demonstrated that FTY20 decreases neuronal damage and improves neuro-behavior after cerebral ischemia [22], a report that has been similarly stated by Lu et al., who showed that FTY720 can enhance neurobehavioral recovery [27]. Here we reported that FTY720 might have positive effects on tremor induced by harmaline. In conclusion, FTY720 appears to be a promising therapeutic agent against not only MS but also some neurodegenerative movement diseases, including tremor. However, more investigations are needed to evaluate the exact role of
harmaline and FTY720 on the release of neurotransmitters in the motor centers of the brain. Author contribution Narjes Dahmardeh helped conduct the study and write the manuscript, she has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Majid Asadi-Shekaari helped in designing the study and writing the manuscript, he has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Shokouh Arjmand helped in writing the manuscript, she has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Tajpari Kalantaripour helped in writing the manuscript, she has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Mohsen Basiri helped in writing the manuscript and response to reviewers’ comments. He has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Mohammad Shabani, PhD., is responsible for the study design, data analysis, and manuscript preparation. Mohammad Shabani is the archival author and attests to the integrity of the original data and the analysis reported in this manuscript. Dr. Shabani also attests to approving the final manuscript. Conflict of interest The authors declare no conflicts of interest. Declaration All authors have approved the final article. Acknowledgment Funding for this study was provided by Kerman University of Medical Sciences as a grant for the PhD research of Narjes Dahmardeh. References [1] H. Abbassian, B.J. Whalley, V. Sheibani, M. Shabani, Cannabinoid type 1 receptor antagonism ameliorates harmaline-induced essential tremor in rat, Br. J. Pharmacol. 173 (2016) 3196–3207.
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Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Research article
Modulation of sphingosine-1-phosphate receptor ameliorates harmaline-induced essential tremor in rat Narjes Dahmardeh a,b , Majid Asadi-Shekaari a , Shokouh Arjmand a , Tajpari Kalantaripour c , Mohsen Basiri b , Mohammad Shabani a,∗ a
Intracellular Recording Lab, Kerman Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran Department of Anatomical Sciences, Afzalipour Medical Faculty, Kerman University of Medical Sciences, Kerman, Iran c Department of Physiology, School of Medicine, Islamic Azad University, Branch of Kerman, Kerman, Iran b
h i g h l i g h t s • Sphingosine-1-phosphate analogue typically ameliorated harmaline induced tremor. • FTY affected explorative and gait disturbances induced by harmaline. • FTY improved impairments of anxiety-like behaviors following harmaline administration.
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Article history: Received 8 May 2017 Received in revised form 5 June 2017 Accepted 12 June 2017 Available online 13 June 2017 Keywords: Essential tremor Fingolimod (FTY720) Multiple sclerosis Harmaline
a b s t r a c t Essential tremor (ET) is one of the most common movement disorders with unknown etiology. Despite lack of effective clinical treatments, some potential therapeutic factors and modulation of some neurotransmitters have been utilized to ameliorate motor symptoms in the animal models of tremor. In the current study, male Wistar rats (n = 10 in each group) weighing 40–60 g were divided into vehicle control groups (saline or DMSO), saline/DMSO + harmaline (30 mg/kg, i.p.) + fingolimod (FTY720) (1 mg/kg, i.p, 1 h before harmaline injection) groups. Open field, rotarod, wire grip and foot print tests were used to evaluate motor function. The results demonstrated that administration of FTY720 can improve harmaline-induced tremor in rats. Moreover, FTY720 ameliorated gait disturbance. The results showed that FTY720 can recover step width, left and right step length; however, FTY720 failed to recover mobility duration. FTY720 also improved falling time and time spent in wire grip and rotarod, respectively. The current study provides the first evidence for the effectiveness of FTY720 on motor function in the harmaline model of ET. Furthermore, neuroprotective effects of FTY720 demonstrated in this study offer sphingosine-1-phosphate receptor (S1PR) modulators as a potential neuroprotective candidate against substance-induced tremor and a possible strategy for the treatment of patients with tremor. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Tremor is characterized by involuntary, rhythmic and sinusoidal oscillation in one or more body parts [2,41]. Essential tremor (ET) as the most common type of tremors and a prevalent movement disorder in adults [33] has negative impacts on many aspects of the patient’s life [41]. Despite the fact that ET is one of the most common movement disorders [26], its etiology is still unknown [1]. Animal
∗ Corresponding author: Kerman Neuroscience Research Center, Kerman University of Medical Sciences, Kerman, 76198-13159, Iran. E-mail addresses: [email protected], [email protected] (M. Shabani). http://dx.doi.org/10.1016/j.neulet.2017.06.015 0304-3940/© 2017 Elsevier B.V. All rights reserved.
models of tremor have been largely contributed to better understandings to assess possible pathways involved. Harmaline as an indole alkaloid found in the seeds of Peganum harmala (Syria rue) is a widely used tremorigenic compound to experimentally induce tremor in animals [34]. Although the underlying mechanisms of inducing tremor have not been yet clearly elucidated [28], harmaline-induced tremor can be considered as a model to assess the pathogenesis of ET and evaluate possible treatment modalities for this condition [8]. Harmaline acts on the olivo-cerebellar system [29,44], leaving its impacts on the inferior olive nucleus (ION), and can generate tremor by increasing neuronal excitability [25]. Therefore, compounds that are potentially capable of reducing neuronal excitability might be beneficial in the treatment of ET [37].
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Fingolimod (FTY720) is a fungus metabolite [5] that has been proven to be useful in the treatment of inflammatory diseases by exerting immunological and neurobiological effects in the central nervous system (CNS) [23]. FTY720 as an immunosuppressive drug was approved in 2010 for relapsing forms of multiple sclerosis (MS) to attenuate its clinical exacerbation frequency [24]. FTY720 is phosphorylated by sphingosine kinase into its active form, (FTY720-P) in vivo [16]. Neuroprotective effects of FTY720-P in the CNS, as well as FTY720 s ability to inhibit not only inflammatory mediators but also T cells have been proposed to contribute to its pharmacological mode of actions [17]. In fact, FTY720 has shown neuroprotective, anti-apoptotic, and immunomodulatory effects in many animal models of CNS-related diseases such as cerebral ischemia, MS and Huntington’s disease [6,10]. The goal of this study was to investigate whether behavioral recovery could be pharmacologically enhanced by administration of FTY720 in the animal model of tremor. Here, harmaline induced moderate tremor which was manifested by marked deficits in performance in all behavioral tasks employed, and then these marked deficits were reversed by use of a S1PR modulator. 2. Methods and materials 2.1. Animals Male Wistar rats (40–60 g) were used. All procedures in this experiment were carried out according to the Neuroscience Research Center of Kerman Medical University. The animals were maintained on a 12-h light-dark cycle with food and water ad libitum. 2.2. Drug preparation and administration Harmaline hydrochloride dihydrate (Sigma, Germany) was dissolved in normal saline at the concentration of 30 mg/kg. FTY720 purchased from Sigma-Aldrich (Germany) was dissolved in dimethyl sulfoxide (DMSO; maximum DMSO concentration: 1%v /v. ) at the concentration of 1 mg/ml on the day of experiment. The FTY720 group received FTY720 (1 mg/kg; i.p.), 1 h prior to harmaline injection. Animals which only received harmaline without FTY720 pre-administration, received either saline or DMSO 1 h prior to harmaline injection to keep the same number of injections in all groups. Drugs were administered intraperitoneally to a maximum total injection volume of 1 ml. 2.3. Behavioral tasks 2.3.1. Observation The occurrence of tremors was rated by an observer who was blinded to the treatment. Thirty minutes after harmaline administration, during the open field test, the tremor data were acquired and quantitatively scored as follows: 0: No tremor, 1: occasional tremor affecting only the head and neck, 2: intermittent (occasional tremor affecting all body parts), 3: persistent (persistent tremor affecting all body parts and tail), 4: severe (persistent tremor rendering the animal unable to stand and/or walk) [3]. 2.3.2. Open field test (OFT) In this test a Plexiglas arena (90 [W] × 90 [L] × 45 [H] cm) was used that its floor was divided into 16 squares to define central and peripheral regions. Each rat was placed in the center of the field. Vertical (rearing) and horizontal activities were recorded for 5 min and analyzed with subsequent offline analysis (Ethovision 7.1, Noldus Information Technology, Netherland). For each rat, total distance moved (TDM, cm); total duration mobility (s) and immo-
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bility (s) were recorded. At the end of each trial, the field was cleaned with ethanol 70% [1,20]. 2.3.3. Rotarod performance test In this study, for the analysis of motor coordination and balance skills, accelerating rotarod (Hugo Sachs, Germany) was used. Prior to placing the animal on the apparatus, rod rotation was set to 10 rpm. Upon start of the test, the animal was placed on the rod with the linear acceleration rate of 10 rpm/min to a maximum of 60 rpm. All the animals were pre-trained prior to the experiment and underwent three trials accompanied by a 300-s cut off and inter-trial intervals of 5 min [20,36]. The duration for which each animal remained in the apparatus was recorded and the mean for all trials per animal was calculated. 2.3.4. Wire grip test This test evaluates muscle strength and balance. To perform the wire grip test, each rat was suspended with forepaws on a horizontal steel wire (80 cm long, 7 mm in diameter), which was connected between two platforms. While rats were grasping the wire, they were placed in a vertical position. All the animals underwent three trials with 5 min inter-trial interval, and the falling latency was recorded with a stop watch [40]. 2.3.5. Footprint To assess the walking patterns and gait kinematics of the animals, footprint test was used. The hind paws of the rats were marked with a non-toxic ink, and then each rat was allowed to walk along a clear Plexiglas tunnel (100 cm [L] × 10 cm [H] × 10 cm [W]), leading to a darkened cage. A sheet of white absorbent paper (100 cm × 10 cm) was placed on the floor of the runway [7]. The distance between each step on the same side of the body at a right angle was measured as stride lengths and the distance between the centers of the respective paw prints to the opposite side of the body as hind paw stride widths. Footprints at the beginning and end of each run were not considered in the analysis [42]. 2.4. Statistical analysis Graph Pad Prism 6 (Graph Pad Software, USA) were used for statistical analysis of data and figure production. All data were first assessed for normality using a Kolmogorov-Smirnov test. Results found to be normally distributed were analyzed using one-way ANOVA test. Where a main effect was seen in ANOVA tests, pairwise comparisons between groups were then made using Tukey’s post-hoc tests. Results that were not normally distributed were analyzed using Kruskal-Wallis test. All data expressed as median and interquartile range and p < 0.05 was considered statistically significant. 3. Results 3.1. The effects of FTY720 on gait disturbance Harmaline induced a significant and persistent tremor that affected all body parts. The tremor scale score increased in the rats of harmaline treated compared to the control groups (Fig. 1A) and hind paw stride width also significantly increased (Fig. 1B). Median tremor score and hind paw stride width were significantly decreased by FTY720 treatment compared to the saline + harmaline and DMSO + harmaline groups. These results demonstrate that treatment with 30 mg/kg harmaline reliably induced severe tremor associated with significant functional deficits that can be detected and assessed using the tasks employed. Moreover, a main effect of the treatment upon left (Fig. 1C) and right (Fig. 1D) step lengths was not detected.
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Fig. 1. Effects of FTY720 on tremor scores (A), step width (B), left (C) and right step length (D) after harmaline administration. Values are represented as median with interquartile ranges as a box and maxima/minima as whiskers. * and # P < 0.05, significantly different from the vehicle control (DMSO, and saline; i.p.) treated groups, respectively. × and ¤ P < 0.05, significantly different from the saline + harmaline and DMSO + harmaline treated groups, respectively. Legends merged on each bar indicates the group size. No data points were excluded as outliers in the presented analyses.
3.2. The effects of FTY720 on explorative and anxiety-like behaviors Rats of the saline + harmaline and DMSO + harmaline groups exhibited a decrease in TDM as compared to the control vehicle groups (p < 0.05, Fig. 2A). No significant difference was observed among FTY720 and control groups (p > 0.05, Fig. 2A). In the open field test, an overall effective impact of the treatment upon velocity (Fig. 2B), mobility (Fig. 2C), time spent in the center (Fig. 2D) and time spent in the perimeter (Fig. 2E) was found. Results revealed that treatment with FTY720 had no ameliorative effect on harmaline-induced disturbances in velocity and mobility. Post hoc comparisons revealed that saline + harmaline and DMSO + harmaline significantly reduced time spent in the center and increased time spent in the outer zone, while administration of FTY720 could reverse the aforesaid harmaline induced behavioral changes.
3.3. The effects of FTY720 administration on muscle strength and balance function In three consecutive trials, rats of the FTY720 + harmaline group showed a decrease in falling time as compared to the control groups in the wire grip test (p < 0.05, Fig. 3A). Rats of the FTY720 + harmaline group spent shorter duration on the wire grip as compared to the control groups (p < 0.05). Falling time increased significantly in FTY720 pre-treated rats compared to the saline + harmaline and DMSO + harmaline groups (p < 0.05, Fig. 3A).
In the rotarod test, FTY720 pre-treated rats showed overall increased mean time spent on the apparatus which revealed that FTY720 can significantly increase time spent on the rod when compared to saline + harmaline and DMSO + harmaline groups. Balance function was evaluated by averaging three repeated trials of the time stay on the rod; these results were similar to per trial alone. The results demonstrated that FTY720 + harmaline rats spend more time on the rod in comparison to the harmaline treated rats (p < 0.05, Fig. 3B).
4. Discussion It is well known that tremor evoked by harmaline is action dependent. In consistent with previous behavioral studies [1,4,41] which have shown similar effects such as motor deficits, ataxia and catatonia, in the present study, harmaline induced moderate tremor which was manifested as marked deficits in performance, in all of the behavioral tasks employed. These deficits were confirmed by significant elevations in tremor score and stride width, and significant reduction in TDM, mobility duration, movement speed, time on the rotarod and grip strength. We assessed the effects of a non-selective S1PR modulator, FTY720, on harmaline-induced tremor. Pretreatment with FTY720 ameliorated severe ET associated symptoms and such data represent the first behavioral evidence for clinical potential of FTY720 in an established and relevant animal model of ET. Notably, non-selective modulation of S1PR could significantly lessen harmaline-induced tremor score, implying beneficial effects
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Fig. 2. The effects of FTY720 on exploratory and anxiety like behavioral changes induced by harmaline. Total distance moved (A), velocity (B) and mobility duration decreased in harmaline treated groups as compared to control groups; however, there was no significant difference between FTY720 treated groups and control groups in total distance moved. Anxiety like behaviors (D: time spent in center and E: outer zone) altered by the harmaline administration. Moreover this effect reversed by FTY720. *p < 0.05, #p < 0.05, ×p < 0.05 and ¤p < 0.05 as compared to the saline, DMSO, saline + harmaline and DMSO + harmaline groups, respectively. Values are presented as median with interquartile ranges as a box and maxima/minima as whiskers. Legends merged on each bar indicate the group size.
on the primary behavioral and functional deficits exhibited in this model. Recent studies have shown that harmaline generates tremor with kinetic and postural condition that may last from minutes to hours [19]. Evidence indicate that harmaline increases T-type calcium pulses in the ION, so T-type calcium channel blockers probably can exhibit therapeutic potentials for treating tremor associated disorders [30]. Since FTY720 is phosphorylated to FTY720-P in vivo [16], and its active form acts as an agonist for the S1PR [38], it is capable of regulating many cellular responses [35]. Moreover, FTY720 as a S1PR modulator [39] can readily cross the blood–brain barrier (BBB) and target the CNS neurons expressing S1P receptors [45]. Recent
clinical studies have indicated that FTY720 can attenuate neurodeficits [39]. Zhao et al., showed neuroprotective efficacy of FTY720 in Parkinson’s disease and suggested that S1PR modulators can be considered as a potentially beneficial approach for the treatment of patients with neurodegenerative diseases [45]. Since FTY720 reduces caspase activation and subsequently apoptosis in the intracerebral hemorrhage [27] and cerebral ischemia [43] models via calcium channel pathways, it can be assumed that its protective effect to ameliorate tremor probably has resulted from crossing the BBB and its inhibitory effects on the T-type calcium channels. In the current study, our results were indicative that FTY720 can decrease tremor scale and improve balance disorder in rats. The
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Fig. 3. The effects of FTY720 on muscle strength and balance function after harmaline administration: (A): Mean latency to fall in wire grip test, (B): Average falling time in three consecutive trials in rotarod test. *p < 0.05, #p < 0.05, ×p < 0.05 and ¤p < 0.05 as compared to the saline, DMSO, saline + harmaline and DMSO + harmaline groups, respectively.
present findings seem to be consistent with Wei et al., who have found that treatment with FTY720 improves behavioral functions in animals with ischemic stroke [43]. At the cellular level, harmaline may induce tremor by acting on the NMDA (N-methyl-d-aspartic acid) receptors and inducing neuronal death [21]. Deogracias et al., have indicated that FTY720 has a neuroprotective effect by reducing the NMDA-induced cytotoxicity in a brain-derived neurotrophic factor (BDNF) dependent manner [12]. Harmaline disrupted motor and balance coordination through NMDA-induced excitotoxicity, thus, it can be predicted that FTY720 might ameliorate effects of harmaline via blockade of the NMDA receptors [19]. These results are in agreement with Cipriani et al., providing evidence for neuroprotective properties of FTY720 against NMDA-mediated excitotoxicity [9]. Moreover, recent evidence have suggested that FTY720 can increase the production of neurotrophic factors, BDNF, by lipopolysaccharide-activated microglia [31] and promote microglia’s neuroprotective phenotype. Doi et al., also demonstrated that FTY720-P enhances the production of BDNF [15]. Recent studies have shown that FTY720 neutralizes NMDA [13] and increases the neuronal production of BDNF [15]. Notably, modulations of these receptors have been reported to be effective on ET [11], also some lines of evidence have reported that NMDA receptor antagonists may show beneficial effects on ET [32]. Fukumoto et al., inferred that phosphorylated FTY720 affects neurons via increasing the expression of BDNF [18]. In other study, di Nuzzo et al., have found that FTY720 protects neurons against excitotoxic death and also reported that FTY720 reduces the permeability of the BBB by acting on the CNS parenchyma, and subsequently supports neuronal survival which may be mediated by increased levels of BDNF [14]. Our data showed that FTY720 had promising effects on motor function. Consistent with these findings, Hasegawa et al., have evaluated the effects of FTY720 administration on cerebral ischemia, and demonstrated that FTY20 decreases neuronal damage and improves neuro-behavior after cerebral ischemia [22], a report that has been similarly stated by Lu et al., who showed that FTY720 can enhance neurobehavioral recovery [27]. Here we reported that FTY720 might have positive effects on tremor induced by harmaline. In conclusion, FTY720 appears to be a promising therapeutic agent against not only MS but also some neurodegenerative movement diseases, including tremor. However, more investigations are needed to evaluate the exact role of
harmaline and FTY720 on the release of neurotransmitters in the motor centers of the brain. Author contribution Narjes Dahmardeh helped conduct the study and write the manuscript, she has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Majid Asadi-Shekaari helped in designing the study and writing the manuscript, he has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Shokouh Arjmand helped in writing the manuscript, she has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Tajpari Kalantaripour helped in writing the manuscript, she has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Mohsen Basiri helped in writing the manuscript and response to reviewers’ comments. He has seen the original study data, reviewed the analysis of the data, and approved the final manuscript. Mohammad Shabani, PhD., is responsible for the study design, data analysis, and manuscript preparation. Mohammad Shabani is the archival author and attests to the integrity of the original data and the analysis reported in this manuscript. Dr. Shabani also attests to approving the final manuscript. Conflict of interest The authors declare no conflicts of interest. Declaration All authors have approved the final article. Acknowledgment Funding for this study was provided by Kerman University of Medical Sciences as a grant for the PhD research of Narjes Dahmardeh. References [1] H. Abbassian, B.J. Whalley, V. Sheibani, M. Shabani, Cannabinoid type 1 receptor antagonism ameliorates harmaline-induced essential tremor in rat, Br. J. Pharmacol. 173 (2016) 3196–3207.
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