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Mohammadreza Zarrindast - One of the best experts on this subject based on the ideXlab platform.
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Harmaline potentiates morphine induced antinociception via affecting the ventral hippocampal gaba a receptors in mice
European Journal of Pharmacology, 2021Co-Authors: Sakineh Alijanpour, Fatemeh Khakpai, Samira Jafaripour, Zahra Ghasemzadeh, Mohammadreza ZarrindastAbstract:Abstract Morphine is one of the most effective medications for treatment of pain, but its side effects limit its use. Therefore, identification of new strategies that can enhance morphine-induced antinociception and/or reduce its side effects will help to develop therapeutic approaches for pain relief. Considering antinociceptive efficacy of Harmaline and also highlighted the important role of GABA-A receptors in the pain perception, this research aimed to determine whether the ventral hippocampal (vHip) GABA-A receptors are involved in the possible Harmaline-induced enhancement of morphine antinociception. To achieve this, vHip regions of adult male mice were bilaterally cannulated and pain sensitivity was measured in a tail-flick apparatus. Intraperitoneally administration of morphine (0, 2, 4 and 6 mg/kg) or Harmaline (0, 1.25, 5 and 10 mg/kg) increased the percentage of maximal possible effect (%MPE) and induced antinociception. Interestingly, co-administration of sub-effective doses of Harmaline (5 mg/kg) and morphine (2 mg/kg) induced antinociception. Intra-vHip microinjection of muscimol (0, 200 and 300 ng/mice), a GABA-A receptor agonist, enhanced the anti-nociceptive effects of Harmaline (2.5 mg/kg)+morphine (2 mg/kg) combination. Microinjection of the same doses of muscimol into the vHip by itself did not alter tail-flick latency. Intra-vHip microinjection of bicuculline (100 ng/mouse), a GABA-A receptor antagonist, did not cause a significant change in MPE%. Bicuculline (60 and 100 ng/mouse, intra-vHip) was administered with the Harmaline (5 mg/kg)+morphine (2 mg/kg), and inhibited the potentiating effect of Harmaline on morphine response. These findings favor the notion that GABAergic mechanisms in the vHip facilitate Harmaline-induced potentiation of morphine response in the tail-flick test in part through GABA-A receptors. These findings shall provide insights and strategies into the development of pain suppressing drugs.
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synergistic antidepressant and anxiolytic like effects of Harmaline along with cinanserin in acute restraint stress treated mice
Psychopharmacology, 2021Co-Authors: Sajedeh Mosaffa, Fatemeh Khakpai, Hanieh Ahmadi, Mohaddeseh Ebrahimighiri, Mohammadreza ZarrindastAbstract:Acute restraint stress (ARS) is an experimental paradigm used for the induction of rodent models of stress-produced neuropsychiatric disorders, such as depression and anxiety. β-carbolines and serotonin (5-HT) systems are involved in the modulation of depression and anxiety behaviors. This study was designed to examine the effects of intracerebroventricular (i.c.v.) injection of cinanserin (5-HT2 receptor antagonist) on Harmaline-induced responses on depression- and anxiety-like behaviors in the ARS mice. For i.c.v. infusion, guide cannula was surgically implanted in the left lateral ventricle of mice. The ARS model was conducted via movement restraint at a period of 4 h. Depression- and anxiety-related behaviors were evaluated by forced swim test (FST) and elevated plus maze (EPM), respectively. The results displayed that the ARS mice showed depressive- and anxiety-like responses. I.p. administration of different doses of Harmaline (0.31, 0.625 and 1.25 mg/kg) or i.c.v. microinjection of cinanserin (1, 2.5, and 5 μg/mouse) blocked depression- and anxiogenic-like behaviors in the ARS mice. Furthermore, co-administration of Harmaline (1.25 mg/kg; i.p.) and cinanserin (5 μg/mouse; i.c.v.) prevented the depression- and anxiogenic-like effects in the ARS mice. We found a synergistic antidepressant- and anxiolytic-like effects of Harmaline and cinanserin in the ARS mice. These results propose an interaction between Harmaline and cinanserin to prevent depressive- and anxiogenic-like behaviors in the ARS mice.
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potentiation of morphine induced antinociception by Harmaline involvement of μ opioid and ventral tegmental area nmda receptors
Psychopharmacology, 2020Co-Authors: Sakineh Alijanpour, Mohammadreza ZarrindastAbstract:Morphine is one of the most well-known and potent analgesic agents; however, it can also induce various side effects. Thus, finding drugs and mechanisms which can potentiate the analgesic effects of low doses of morphine will be a good strategy for pain management. The involvement of μ-opioid receptors and ventral tegmental area (VTA) glutamatergic system in Harmaline and morphine combination on the nociceptive response were investigated. Also, we examined reward efficacy and tolerance expression following the drugs. Animals were bilaterally cannulated in the VTA by stereotaxic instrument. A tail-flick (TF) apparatus and conditioned place preference (CPP) paradigm were used to measure nociceptive response and rewarding effects in male NMRI mice respectively. Morphine (2 mg/kg, i.p.) had no effect in TF test. Also, Harmaline (1.25 and 5 mg/kg, i.p.) could not change pain threshold. Combination of a non-effective dose of Harmaline (5 mg/kg) and morphine (2 mg/kg) produced antinociception and also prevented morphine tolerance but had no effect on the acquisition of CPP. Systemic administration of naloxone (0.5 and 1 mg/kg) and intra-VTA microinjection of NMDA (0.06 and 0.1 μg/mouse) before Harmaline (5 mg/kg) plus morphine (2 mg/kg) prevented antinociception induced by the drugs. D-AP5 (0.5 and 1 μg/mouse, intra-VTA) potentiated the effect of low-dose Harmaline (1.25 mg/kg) and morphine (2 mg/kg) and induced antinociception. Microinjection of the same doses of NMDA or D-AP5 into the VTA alone had no effect on pain threshold. The findings showed that Harmaline potentiated the analgesic effect of morphine and reduced morphine tolerance. Glutamatergic and μ-opioidergic system interactions in the VTA seem to have a modulatory role in Harmaline plus morphine-induced analgesia.
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anxiolytic and antidepressant effects of acpa and Harmaline co treatment
Behavioural Brain Research, 2019Co-Authors: Mohaddeseh Ebrahimighiri, Mohammad Nasehi, Mohammadreza ZarrindastAbstract:Abstract Depression and anxiety disorders are among the most common illnesses and a close relationship between them has been found. Because the psychotropic effects and abuse liability of cannabis prevent its therapeutic application in depression and anxiety states, we decided to investigate the effects of the combination of ineffective doses of cannabinoid CB1 receptor agonist arachidonylcyclopropylamide (ACPA) and β-carbolines on anxiety- and depression-related behaviors in male NMRI mice. Anxiety- and depression-related behaviors were assesses using elevated plus maze (EPM) and forced swim test (FST), respectively. Intraperitoneal administration of ACPA (1 mg/kg) decreased the percentage of time spent in the open-arms (%OAT) and the number of entries to the open-arms (OAE) in the EPM, indicating an anxiogenic-like effect. ACPA also decreased immobility time in the FST compared to the control group, suggesting an antidepressant-like effect. β-carbolines including harmane (5 and 10 mg/kg), norharmane (5 mg/kg) and Harmaline (2.5 and 5 mg/kg) produced an anxiogenic-like response, while the highest dose of harmane or Harmaline and the middle dose of norharmane induced an antidepressant-like behavior. Furthermore, co-administration of a subthreshold dose of ACPA (0.5 mg/kg) and Harmaline (1.25 mg/kg), but not harmane or norharmane (both at the dose of 2.5 mg/kg), caused anxiolytic- and antidepressant-like behaviors and decreased locomotor activity. Our findings suggest a therapeutic potential for combined ineffective doses of ACPA and Harmaline on anxiety- and depression-related processes.
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possible involvement of the ca1 gabaergic system on Harmaline induced memory consolidation deficit
Brain Research Bulletin, 2017Co-Authors: Mohammad Nasehi, Fatemeh Khakpai, Naghmeh Saadati, Mohammadreza ZarrindastAbstract:Abstract Activation of the GABAB receptors inhibit learning and memory processes. The current research was designed to examine the role of dorsal hippocampal (CA1) GABAB receptors on Harmaline induced memory consolidation deficit in mice. For this purpose, the effects induced by the GABAB antagonist phaclofen and the GABAB agonist baclofen on memory consolidation were assessed by using the step-down inhibitory avoidance task. Furthermore, the possible involvement of Harmaline on GABAB receptor’s effects was also assessed through using the same behavioral procedure. In a first dose response experiments, post-training intra-CA1 injections of phaclofen did not change while baclofen (0.1 μg/mouse) impaired animals’ performance in this task, suggesting a modulation of storage of information. Moreover, Post-training intra-peritoneal (i.p.) infusion of Harmaline (2 and 5 mg/kg) also decreased memory consolidation. Interestingly, phaclofen at the sub-threshold dose (0.001 μg/mouse, intra-CA1), successfully antagonized the deficits on memory consolidation induced by the highest doses of Harmaline (2 and 4 mg/kg, i.p.). On the other hand, non significant dose of baclofenc (0.001 μg/mouse, intra-CA1) potentiated impairment of memory consolidation induced by Harmaline (2 mg/kg, i.p.). In addition in all experiments, locomotor activity did not alter significantly. These results indicate a) that the CA1 GABAB receptors are involved in memory consolidation b) that Harmaline interact with the CA1 GABAB receptors in modulation of memory consolidation.
Jadwiga Wardas - One of the best experts on this subject based on the ideXlab platform.
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Pramipexole Reduces zif-268 mRNA Expression in Brain Structures involved in the Generation of Harmaline-Induced Tremor
Neurochemical Research, 2020Co-Authors: Barbara Kosmowska, Krystyna Ossowska, Jadwiga WardasAbstract:Essential tremor is one of the most common neurological disorders, however, it is not sufficiently controlled with currently available pharmacotherapy. Our recent study has shown that pramipexole, a drug efficient in inhibiting parkinsonian tremor, reduced the Harmaline-induced tremor in rats, generally accepted to be a model of essential tremor. The aim of the present study was to investigate brain targets for the tremorolytic effect of pramipexole by determination of the early activity-dependent gene zif-268 mRNA expression. Tremor in rats was induced by Harmaline administered at a dose of 15 mg/kg ip . Pramipexole was administered at a low dose of 0.1 mg/kg sc . Tremor was measured by Force Plate Actimeters where four force transducers located below the corners of the plate tracked the animal’s position on a Cartesian plane. The zif-268 mRNA expression was analyzed by in situ hybridization in brain slices. Harmaline induced tremor and increased zif-268 mRNA levels in the inferior olive, cerebellar cortex, ventroanterior/ventrolateral thalamic nuclei and motor cortex. Pramipexole reversed both the Harmaline-induced tremor and the increase in zif-268 mRNA expression in the inferior olive, cerebellar cortex and motor cortex. Moreover, the tremor intensity correlated positively with zif-268 mRNA expression in the above structures. The present results seem to suggest that the tremorolytic effect of pramipexole is related to the modulation of the Harmaline-increased neuronal activity in the tremor network which includes the inferior olive, cerebellar cortex and motor cortex. Potential mechanisms underlying the above pramipexole action are discussed.
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inhibition of excessive glutamatergic transmission in the ventral thalamic nuclei by a selective adenosine a1 receptor agonist 5 chloro 5 deoxy enba underlies its tremorolytic effect in the Harmaline induced model of essential tremor
Neuroscience, 2020Co-Authors: Barbara Kosmowska, Krystyna Ossowska, J Konieczny, Tomasz Lenda, Klemencja Berghauzenmaciejewska, Jadwiga WardasAbstract:Abstract The primary cause of Harmaline tremor, which is a model of essential tremor (ET) in animals, is excessive activation of olivocerebellar glutamatergic climbing fibers. Our recent study indicated that 5′-chloro-5′-deoxy-(±)-N6-(±)-(endo-norborn-2-yl)adenosine (5′Cl5′d-(±)-ENBA), a potent and selective adenosine A1 receptor (A1) agonist, inhibited Harmaline tremor. The present study was aimed to evaluate the role of glutamatergic transmission system in 5′Cl5′d-(±)-ENBA tremorolytic action in the Harmaline model in rats, by analyzing glutamate release in the motor nuclei of the thalamus and mRNA expression of glutamatergic neuron markers (vGlut1/2) in reference to the general neuronal activity marker (zif-268) in different brain structures. The extracellular glutamate level in the motor thalamus was evaluated by in vivo microdialysis and the vGlut1/vGlut2 and zif-268 mRNA expression was analyzed by in situ hybridization. The intensity of tremor was measured automatically using Force Plate Actimeters (FPAs). 5′Cl5′d-(±)-ENBA (0.5 mg/kg) given 30 min before Harmaline (30 mg/kg) decreased the Harmaline-induced excessive glutamate release in the motor thalamus and reversed Harmaline - induced molecular effects, such as elevation of the vGlut1 mRNA expression in the inferior olive (IO) and decrease in the motor cortex, as well as an increase of the zif-268 mRNA expression in the IO, motor thalamus and motor cortex. Moreover, 5′Cl5′d-(±)-ENBA reduced Harmaline tremor by lowering its power in 9–15 Hz frequency band. Our findings show that A1 stimulation decreases glutamate release in the motor thalamic nuclei in the Harmaline model of ET, suggesting that A1 receptors, especially in this structure, may be a potential therapeutic target in this disorder.
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tremorolytic effect of 5 chloro 5 deoxy enba a potent and selective adenosine a1 receptor agonist evaluated in the Harmaline induced model in rats
CNS Neuroscience & Therapeutics, 2017Co-Authors: Barbara Kosmowska, K Ossowska, Urszula Glowacka, Jadwiga WardasAbstract:AIM The aim of this study was to examine the role of adenosine A1 receptors in the Harmaline-induced tremor in rats using 5'-chloro-5'-deoxy-(±)-ENBA (5'Cl5'd-(±)-ENBA), a brain-penetrant, potent, and selective adenosine A1 receptor agonist. METHODS Harmaline was injected at a dose of 15 mg/kg ip and tremor was measured automatically in force-plate actimeters by an increased averaged power in the frequency band of 9-15 Hz (AP2) and by tremor index (a difference in power between AP2 and averaged power in the frequency band of 0-8 Hz). The zif-268 mRNA expression was additionally analyzed by in situ hybridization in several brain structures. RESULTS 5'Cl5'd-(±)-ENBA (0.05-0.5 mg/kg ip) dose dependently reduced the Harmaline-induced tremor and this effect was reversed by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective antagonist of adenosine A1 receptors (1 mg/kg ip). Harmaline increased the zif-268 mRNA expression in the inferior olive, cerebellar cortex, ventroanterior/ventrolateral thalamic nuclei, and motor cortex. 5'Cl5'd-(±)-ENBA reversed these increases in all the above structures. DPCPX reduced the effect of 5'Cl5'd-(±)-ENBA on zif-268 mRNA in the motor cortex. CONCLUSION This study suggests that adenosine A1 receptors may be a potential target for the treatment of essential tremor.
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pramipexole at a low dose induces beneficial effect in the Harmaline induced model of essential tremor in rats
CNS Neuroscience & Therapeutics, 2016Co-Authors: Barbara Kosmowska, Jadwiga Wardas, Urszula Glowacka, Subramaniam Ananthan, K OssowskaAbstract:Summary Aims The aim of the study was to examine the effects of preferential agonists of dopamine D3 receptors: pramipexole and 7-OH-DPAT on the Harmaline-induced tremor in rats (a model of essential tremor, ET). To study receptor mechanisms of these drugs, rats were pretreated with dopamine D3 receptor antagonists—SB-277011-A and SR-21502, an antagonist of presynaptic D2/D3 receptors—amisulpride, or a nonselective antagonist of D2-like receptors, haloperidol, at a postsynaptic dose. Methods For tremor measurement, fully automated force plate actimeters were used and data were analyzed using fast Fourier transform. Results Harmaline (15 mg/kg ip)-triggered tremor was manifested by an increase in the power within 9–15 Hz band (AP2). Pramipexole administered at a low (0.1 mg/kg sc), but not higher doses (0.3 and 1 mg/kg sc), and 7-OH-DPAT (0.1, 0.3, and 1 mg/kg sc) reversed the Harmaline-increased AP2. None of the examined dopamine antagonists: SB-277011-A (10 mg/kg ip), SR-21502 (15 mg/kg ip), haloperidol (0.5 mg/kg ip), or amisulpride (1 mg/kg ip) influenced the above effect of dopamine agonists. Conclusion The present study indicates that pramipexole reduces the Harmaline-induced tremor, which may suggest its beneficial effects in ET patients. However, mechanisms underlying its action are still unclear and need further examination.
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Apomorphine enhances Harmaline-induced tremor in rats
Pharmacological Reports, 2015Co-Authors: Krystyna Ossowska, Barbara Kosmowska, Urszula Głowacka, Jadwiga WardasAbstract:Background Harmaline-induced tremor is a well-known model of essential tremor in humans. The aim of the present study was to examine the influence of apomorphine, a non-selective dopamine receptor agonist, on the tremor induced by Harmaline in rats. Propranolol (a first-line drug in essential tremor) was used as a reference compound. Methods Tremor, locomotor activity and focused stereotypy were measured objectively using force plate actimeters. Tremor was analyzed using a Fourier transform to generate power spectra for rhythmic behavior. Results The tremor induced by Harmaline administered at a dose of 15 mg/kg ip was associated with an increase in power in the 9–15 Hz band (AP2) and in the tremor index, calculated as a difference between AP2 and power in the 0–8 Hz band (AP1). Propranolol injected at a dose of 20 mg/kg ip reversed both of these effects of Harmaline. Apomorphine administered at the doses of 0.5 and 1 mg/kg sc further enhanced AP2 and at the lower dose also the tremor index elevated by Harmaline. This increase in AP2 was stronger than enhancement of locomotor activity induced by apomorphine in the Harmaline-treated animals. Conclusions The present study suggests that the dopamine agonist apomorphine enhances the tremor induced by Harmaline, and this effect is at least partly independent of hyperactivity.
Mohammad Shabani - One of the best experts on this subject based on the ideXlab platform.
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functional antagonism of sphingosine 1 phosphate receptor 1 prevents Harmaline induced ultrastructural alterations and caspase 3 mediated apoptosis
The Malaysian journal of medical sciences, 2019Co-Authors: Narjes Dahmardeh, Tajpari Kalantaripour, Mohsen Basiri, Mohammad Shabani, Majid AsadishekaariAbstract:Background There is a meaningful necessity for a targeted therapy of essential tremor (ET), as medications have not been developed specifically for ET. For nearly a century, many drugs have been applied in the treatment of tremor but the drug treatment of ET remains still unknown. Some potential therapeutic factors such fingolimod (FTY720) can be effectively used to treat ET in animals. In the present research, the effect of FTY720, the immunomodulatory sphingosine 1-phosphate (S1P) analog, on degeneration of cerebellar and olivary neurons induced by Harmaline in male rats was investigated. Methods The animals were allotted into control dimethyl sulfoxide (DMSO), saline + Harmaline [30 mg/kg, intraperitoneally, (i.p.)], Harmaline + FTY720 (1 mg/kg, i.p, 1 h and 24 h before Harmaline injection) groups (n = 10). The cerebellum and inferior olive nucleus (ION) were studied for neuronal degeneration using immunohistochemistry (IHC) and ultrastructural study by transmission electron microscopy (TEM) techniques. Results Harmaline caused neuronal cell loss, caspase-3 mediated apoptosis, astrocytosis and ultrastructural changes in cerebellar Purkinje cells and inferior olive neurons. FTY720 exhibited neuroprotective effects on cerebellar Purkinje cells and inferior olivary neurons. Conclusion These results suggest that FTY720 has potential efficacy for prevention of ET neurodegeneration and astrocytosis induced by Harmaline in male rats.
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erythropoietin ameliorates Harmaline induced essential tremor and cognition disturbances
Neuroscience Letters, 2019Co-Authors: Fatemeh Mohammadi, Mohsen Abedini Esfahlani, Mohammad ShabaniAbstract:Abstract There are conflicting reports concerning the association of motor disabilities with increased risk of mental disorders. This investigation will provide a good understanding about defining the possible association between tremor and risk of anxiety and cognitive alterations. Beside, a secondary objective of the current study was to determine the effect of erythropoietin (EPO) on Harmaline-induced motor and cognitive impairments. Male Wistar rats were used for the present study. The animal model of Esential tremor (ET) was established by the intraperitoneal injection of Harmaline. EPO (5000 U/kg, i.p.) administered to the animals 1 h prior to Harmaline injection. Exploratory, balance, anxiety related behaviors and cognitive function were assessed using footprint, open field, wire grip, rotarod and shuttle box tests. Findings demonstrated EPO ameliorated tremor scores that was induced by Harmaline. Harmaline impaired cognitive functions of the treated rats, whereas EPO showed a promising effect against the cognitive impairments induced by Harmaline. EPO can be offered as a potential neuroprotective agent in the treatment of patients with ET that manifest locomotor and cognitive impairments; however, further studies are needed to clarify the exact mechanisms.
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peroxisome proliferator activated receptor γ activation attenuates Harmaline induced cognitive impairments in rats
Journal of Clinical Neuroscience, 2019Co-Authors: Iraj Aghaei, Zohreh Vaziri, Vahid Hajali, M Haghani, Mahmmod Moosazadeh, Mohammad ShabaniAbstract:Abstract Cognitive and motor disturbances are serious concerns of the tremors induced by motor disorders. Despite the lack of effective clinical treatment, some potential therapeutic agents have been used to alleviate the cognitive symptoms in the animal models of tremor. Recent studies have shown that PPAR-γ agonists have neuroprotective effects. In the current study, the effects of pioglitazone (PIO), a peroxisome proliferator-activated receptor gamma agonist, on Harmaline-induced motor and cognitive impairment were studied. Male Wistar rats were divided into vehicle (normal saline), PIO (20 mg/kg i.p.), Harmaline (10 mg/kg, i.p.) and PIO + Harmaline (PIO injected 2 h before Harmaline) groups. Open field, rotarod, wire grip, foot print and Morris water maze tests were used to evaluate the motor and cognitive performance. The results indicated that administration of PIO attenuated Harmaline-induced locomotor, anxiety-like behaviors, and spatial learning and memory impairments, but it partially decreased the tremor score. The neuroprotective and anxiolytic effects of PIO demonstrated in the current study can offer the PPAR-γ receptor agonism as a potential therapeutic agent in the treatment of patients with tremor that manifest mental dysfunction.
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Modulation of sphingosine-1-phosphate receptor ameliorates Harmaline-induced essential tremor in rat
Neuroscience letters, 2017Co-Authors: Narjes Dahmardeh, Majid Asadi-shekaari, Shokouh Arjmand, Tajpari Kalantaripour, Mohsen Basiri, Mohammad ShabaniAbstract:Abstract 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.
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cannabinoid type 1 receptor antagonism ameliorates Harmaline induced essential tremor in rat
British Journal of Pharmacology, 2016Co-Authors: Hassan Abbassian, Vahid Sheibani, Benjamin J Whalley, Mohammad ShabaniAbstract:Background and purpose Essential tremor (ET) is a neurological disorder with unknown etiology. Its symptoms include cerebellar motor disturbances, cognitive and personality changes, hearing and olfactory deficits. Excitotoxic cerebellar climbing fibre hyperactivity may underlie essential tremor and has been emulated in rodents by systemic Harmaline administration. Cannabinoid receptor agonists can cause motor disturbances although there are also anecdotal reports of therapeutic benefits of cannabis in motor disorders. We set out to establish the effects of cannabinoid type 1 receptor agonism and antagonism in an established rodent model of ET using a battery of accepted behaviour assays in order to determine risk and therapeutic potential of endocannabinoid system modulation in ET. Experimental Approach The behavioural effects of systemic cannabinoid (CB) receptor agonist (0.1, 0.5 and 1 mg kg-1 WIN55, 212-2) and antagonist (1 mg kg-1 AM251 and 10 mg kg-1 rimonabant) treatment on Harmaline-induced (30 mg kg-1) tremor in rats was assessed using tremor scoring, open field, rotarod, grip and gait tests. Key Results Overall, Harmaline induced robust tremor that was typically worsened across the measured behavioural domains by CB type 1 (CB1) receptor agonism but ameliorated by cannabinoid type 1 receptor antagonism. Conclusions and Implications These results provide the first evidence of effects of endocannabinoid system modulation on motor function in the Harmaline model of essential tremor and suggest that CB1 receptor manipulation warrants clinical investigation as a therapeutic approach to protection against behavioural disturbances associated with essential tremor.
Barbara Kosmowska - One of the best experts on this subject based on the ideXlab platform.
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Pramipexole Reduces zif-268 mRNA Expression in Brain Structures involved in the Generation of Harmaline-Induced Tremor
Neurochemical Research, 2020Co-Authors: Barbara Kosmowska, Krystyna Ossowska, Jadwiga WardasAbstract:Essential tremor is one of the most common neurological disorders, however, it is not sufficiently controlled with currently available pharmacotherapy. Our recent study has shown that pramipexole, a drug efficient in inhibiting parkinsonian tremor, reduced the Harmaline-induced tremor in rats, generally accepted to be a model of essential tremor. The aim of the present study was to investigate brain targets for the tremorolytic effect of pramipexole by determination of the early activity-dependent gene zif-268 mRNA expression. Tremor in rats was induced by Harmaline administered at a dose of 15 mg/kg ip . Pramipexole was administered at a low dose of 0.1 mg/kg sc . Tremor was measured by Force Plate Actimeters where four force transducers located below the corners of the plate tracked the animal’s position on a Cartesian plane. The zif-268 mRNA expression was analyzed by in situ hybridization in brain slices. Harmaline induced tremor and increased zif-268 mRNA levels in the inferior olive, cerebellar cortex, ventroanterior/ventrolateral thalamic nuclei and motor cortex. Pramipexole reversed both the Harmaline-induced tremor and the increase in zif-268 mRNA expression in the inferior olive, cerebellar cortex and motor cortex. Moreover, the tremor intensity correlated positively with zif-268 mRNA expression in the above structures. The present results seem to suggest that the tremorolytic effect of pramipexole is related to the modulation of the Harmaline-increased neuronal activity in the tremor network which includes the inferior olive, cerebellar cortex and motor cortex. Potential mechanisms underlying the above pramipexole action are discussed.
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inhibition of excessive glutamatergic transmission in the ventral thalamic nuclei by a selective adenosine a1 receptor agonist 5 chloro 5 deoxy enba underlies its tremorolytic effect in the Harmaline induced model of essential tremor
Neuroscience, 2020Co-Authors: Barbara Kosmowska, Krystyna Ossowska, J Konieczny, Tomasz Lenda, Klemencja Berghauzenmaciejewska, Jadwiga WardasAbstract:Abstract The primary cause of Harmaline tremor, which is a model of essential tremor (ET) in animals, is excessive activation of olivocerebellar glutamatergic climbing fibers. Our recent study indicated that 5′-chloro-5′-deoxy-(±)-N6-(±)-(endo-norborn-2-yl)adenosine (5′Cl5′d-(±)-ENBA), a potent and selective adenosine A1 receptor (A1) agonist, inhibited Harmaline tremor. The present study was aimed to evaluate the role of glutamatergic transmission system in 5′Cl5′d-(±)-ENBA tremorolytic action in the Harmaline model in rats, by analyzing glutamate release in the motor nuclei of the thalamus and mRNA expression of glutamatergic neuron markers (vGlut1/2) in reference to the general neuronal activity marker (zif-268) in different brain structures. The extracellular glutamate level in the motor thalamus was evaluated by in vivo microdialysis and the vGlut1/vGlut2 and zif-268 mRNA expression was analyzed by in situ hybridization. The intensity of tremor was measured automatically using Force Plate Actimeters (FPAs). 5′Cl5′d-(±)-ENBA (0.5 mg/kg) given 30 min before Harmaline (30 mg/kg) decreased the Harmaline-induced excessive glutamate release in the motor thalamus and reversed Harmaline - induced molecular effects, such as elevation of the vGlut1 mRNA expression in the inferior olive (IO) and decrease in the motor cortex, as well as an increase of the zif-268 mRNA expression in the IO, motor thalamus and motor cortex. Moreover, 5′Cl5′d-(±)-ENBA reduced Harmaline tremor by lowering its power in 9–15 Hz frequency band. Our findings show that A1 stimulation decreases glutamate release in the motor thalamic nuclei in the Harmaline model of ET, suggesting that A1 receptors, especially in this structure, may be a potential therapeutic target in this disorder.
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tremorolytic effect of 5 chloro 5 deoxy enba a potent and selective adenosine a1 receptor agonist evaluated in the Harmaline induced model in rats
CNS Neuroscience & Therapeutics, 2017Co-Authors: Barbara Kosmowska, K Ossowska, Urszula Glowacka, Jadwiga WardasAbstract:AIM The aim of this study was to examine the role of adenosine A1 receptors in the Harmaline-induced tremor in rats using 5'-chloro-5'-deoxy-(±)-ENBA (5'Cl5'd-(±)-ENBA), a brain-penetrant, potent, and selective adenosine A1 receptor agonist. METHODS Harmaline was injected at a dose of 15 mg/kg ip and tremor was measured automatically in force-plate actimeters by an increased averaged power in the frequency band of 9-15 Hz (AP2) and by tremor index (a difference in power between AP2 and averaged power in the frequency band of 0-8 Hz). The zif-268 mRNA expression was additionally analyzed by in situ hybridization in several brain structures. RESULTS 5'Cl5'd-(±)-ENBA (0.05-0.5 mg/kg ip) dose dependently reduced the Harmaline-induced tremor and this effect was reversed by 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective antagonist of adenosine A1 receptors (1 mg/kg ip). Harmaline increased the zif-268 mRNA expression in the inferior olive, cerebellar cortex, ventroanterior/ventrolateral thalamic nuclei, and motor cortex. 5'Cl5'd-(±)-ENBA reversed these increases in all the above structures. DPCPX reduced the effect of 5'Cl5'd-(±)-ENBA on zif-268 mRNA in the motor cortex. CONCLUSION This study suggests that adenosine A1 receptors may be a potential target for the treatment of essential tremor.
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pramipexole at a low dose induces beneficial effect in the Harmaline induced model of essential tremor in rats
CNS Neuroscience & Therapeutics, 2016Co-Authors: Barbara Kosmowska, Jadwiga Wardas, Urszula Glowacka, Subramaniam Ananthan, K OssowskaAbstract:Summary Aims The aim of the study was to examine the effects of preferential agonists of dopamine D3 receptors: pramipexole and 7-OH-DPAT on the Harmaline-induced tremor in rats (a model of essential tremor, ET). To study receptor mechanisms of these drugs, rats were pretreated with dopamine D3 receptor antagonists—SB-277011-A and SR-21502, an antagonist of presynaptic D2/D3 receptors—amisulpride, or a nonselective antagonist of D2-like receptors, haloperidol, at a postsynaptic dose. Methods For tremor measurement, fully automated force plate actimeters were used and data were analyzed using fast Fourier transform. Results Harmaline (15 mg/kg ip)-triggered tremor was manifested by an increase in the power within 9–15 Hz band (AP2). Pramipexole administered at a low (0.1 mg/kg sc), but not higher doses (0.3 and 1 mg/kg sc), and 7-OH-DPAT (0.1, 0.3, and 1 mg/kg sc) reversed the Harmaline-increased AP2. None of the examined dopamine antagonists: SB-277011-A (10 mg/kg ip), SR-21502 (15 mg/kg ip), haloperidol (0.5 mg/kg ip), or amisulpride (1 mg/kg ip) influenced the above effect of dopamine agonists. Conclusion The present study indicates that pramipexole reduces the Harmaline-induced tremor, which may suggest its beneficial effects in ET patients. However, mechanisms underlying its action are still unclear and need further examination.
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Apomorphine enhances Harmaline-induced tremor in rats
Pharmacological Reports, 2015Co-Authors: Krystyna Ossowska, Barbara Kosmowska, Urszula Głowacka, Jadwiga WardasAbstract:Background Harmaline-induced tremor is a well-known model of essential tremor in humans. The aim of the present study was to examine the influence of apomorphine, a non-selective dopamine receptor agonist, on the tremor induced by Harmaline in rats. Propranolol (a first-line drug in essential tremor) was used as a reference compound. Methods Tremor, locomotor activity and focused stereotypy were measured objectively using force plate actimeters. Tremor was analyzed using a Fourier transform to generate power spectra for rhythmic behavior. Results The tremor induced by Harmaline administered at a dose of 15 mg/kg ip was associated with an increase in power in the 9–15 Hz band (AP2) and in the tremor index, calculated as a difference between AP2 and power in the 0–8 Hz band (AP1). Propranolol injected at a dose of 20 mg/kg ip reversed both of these effects of Harmaline. Apomorphine administered at the doses of 0.5 and 1 mg/kg sc further enhanced AP2 and at the lower dose also the tremor index elevated by Harmaline. This increase in AP2 was stronger than enhancement of locomotor activity induced by apomorphine in the Harmaline-treated animals. Conclusions The present study suggests that the dopamine agonist apomorphine enhances the tremor induced by Harmaline, and this effect is at least partly independent of hyperactivity.
Hong Wu Shen - One of the best experts on this subject based on the ideXlab platform.
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development of a mechanism based pharmacokinetic pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice
Acta Pharmaceutica Sinica B, 2016Co-Authors: Xi Ling Jiang, Hong Wu Shen, Donald E. Mager, Stephan SchmidtAbstract:We have shown recently that concurrent Harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT-elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1A receptor and thermogenesis via the stimulation of 5-HT2A receptor, respectively. Thus serotonergic 5-MeO-DMT-induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and Harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SC50 value (1.88-0.496 µmol/L) for 5-MeO-DMT when Harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI Harmaline on 5-MeO-DMT-induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of Harmaline and 5-MeO-DMT were linked to the increased systemic exposure to Harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.
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Modification of 5-methoxy-N, N-dimethyltryptamine-induced hyperactivity by monoamine oxidase A inhibitor Harmaline in mice and the underlying serotonergic mechanisms
Pharmacological Reports, 2016Co-Authors: Xi Ling Jiang, Hong Wu ShenAbstract:Background 5-Methoxy- N,N -dimethyltryptamine (5-MeO-DMT) and Harmaline are indolealkylamine (IAA) drugs often abused together. Our recent studies have revealed the significant effects of co-administered Harmaline, a monoamine oxidase inhibitor (MAOI), on 5-MeO-DMT pharmacokinetics and thermoregulation. This study was to delineate the impact of Harmaline and 5-MeO-DMT on home-cage activity in mouse models, as well as the contribution of serotonin (5-HT) receptors. Methods Home-cage activities of individual animals were monitored automatically in the home cages following implantation of telemetry transmitters and administration of various doses of IAA drugs and 5-HT receptor antagonists. Area under the effect curve (AUEC) of mouse activity values were calculated by trapezoidal rule. Results High dose of Harmaline (15 mg/kg, ip ) alone caused an early-phase (0–45 min) hypoactivity in mice that was fully attenuated by 5-HT_1A receptor antagonist WAY-100635, whereas a late-phase (45–180 min) hyperactivity that was reduced by 5-HT_2A receptor antagonist MDL-100907. 5-MeO-DMT (10 and 20 mg/kg, ip ) alone induced biphasic effects, an early-phase (0–45 min) hypoactivity that was completely attenuated by WAY-100635, and a late-phase (45–180 min) hyperactivity that was fully suppressed by MDL-100907. Interestingly, co-administration of MAOI Harmaline (2–15 mg/kg) with a subthreshold dose of 5-MeO-DMT (2 mg/kg) induced excessive hyperactivities at late phase (45–180 min) that could be abolished by either WAY-100635 or MDL-100907. Conclusions Co-administration of MAOI with 5-MeO-DMT provokes excessive late-phase hyperactivity, which involves the activation of both 5-HT_1A and 5-HT_2A receptors.
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Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced hyperthermia by Harmaline and the involvement of activation of 5-HT1A and 5-HT2A receptors.
Neuropharmacology, 2015Co-Authors: Xi Ling Jiang, Hong Wu ShenAbstract:5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and Harmaline are serotonin (5-HT) analogs often abused together, which alters thermoregulation that may indicate the severity of serotonin toxicity. Our recent studies have revealed that co-administration of monoamine oxidase inhibitor Harmaline leads to greater and prolonged exposure to 5-HT agonist 5-MeO-DMT that might be influenced by cytochrome P450 2D6 (CYP2D6) status. This study was to define the effects of Harmaline and 5-MeO-DMT on thermoregulation in wild-type and CYP2D6-humanized (Tg-CYP2D6) mice, as well as the involvement of 5-HT receptors. Animal core body temperatures were monitored noninvasively in the home cages after implantation of telemetry transmitters and administration of drugs. Harmaline (5 and 15 mg/kg, i.p.) alone was shown to induce hypothermia that was significantly affected by CYP2D6 status. In contrast, higher doses of 5-MeO-DMT (10 and 20 mg/kg) alone caused hyperthermia. Co-administration of Harmaline (2, 5 or 15 mg/kg) remarkably potentiated the hyperthermia elicited by 5-MeO-DMT (2 or 10 mg/kg), which might be influenced by CYP2D6 status at certain dose combination. Interestingly, Harmaline-induced hypothermia was only attenuated by 5-HT1A receptor antagonist WAY-100635, whereas 5-MeO-DMT- and Harmaline-5-MeO-DMT-induced hyperthermia could be suppressed by either WAY-100635 or 5-HT2A receptor antagonists (MDL-100907 and ketanserin). Moreover, stress-induced hyperthermia under home cage conditions was not affected by WAY-100635 but surprisingly attenuated by MDL-100907 and ketanserin. Our results indicate that co-administration of monoamine oxidase inhibitor largely potentiates 5-MeO-DMT-induced hyperthermia that involves the activation of both 5-HT1A and 5-HT2A receptors. These findings shall provide insights into development of anxiolytic drugs and new strategies to relieve the lethal hyperthermia in serotonin toxicity.
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Pharmacokinetic Interactions between Monoamine Oxidase A Inhibitor Harmaline and 5-Methoxy-N,N-Dimethyltryptamine, and the Impact of CYP2D6 Status
Drug metabolism and disposition: the biological fate of chemicals, 2013Co-Authors: Xi Ling Jiang, Hong Wu Shen, Donald E. MagerAbstract:5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT or street name “5-MEO”) is a newer designer drug belonging to a group of naturally occurring indolealkylamines. Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor Harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite bufotenine. This study is aimed at delineating Harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of CYP2D6 that affects Harmaline PK and determines 5-MeO-DMT O-demethylation to produce bufotenine. Our data revealed that inhibition of MAO-A–mediated metabolic elimination by Harmaline (2, 5, and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations. A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to Harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice. Harmaline (5 mg/kg) also increased blood and brain bufotenine concentrations that were generally higher in Tg-CYP2D6 mice. Surprisingly, greater Harmaline dose (15 mg/kg) reduced bufotenine levels. The in vivo inhibitory effect of Harmaline on CYP2D6-catalyzed bufotenine formation was confirmed by in vitro study using purified CYP2D6. Given these findings, a unified PK model including the inhibition of MAO-A- and CYP2D6-catalyzed 5-MeO-DMT metabolism by Harmaline was developed to describe blood Harmaline, 5-MeO-DMT, and bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models. This PK model may be further employed to predict Harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive Harmaline–5-MeO-DMT pharmacodynamics.
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effects of cyp2d6 status on Harmaline metabolism pharmacokinetics and pharmacodynamics and a pharmacogenetics based pharmacokinetic model
Biochemical Pharmacology, 2009Co-Authors: Xi Ling Jiang, Hong Wu ShenAbstract:Harmaline is a beta-carboline alkaloid showing neuroprotective and neurotoxic properties. Our recent studies have revealed an important role for cytochrome P450 2D6 (CYP2D6) in Harmaline O-demethylation. This study, therefore, aimed to delineate the effects of CYP2D6 phenotype/genotype on Harmaline metabolism, pharmacokinetics (PK) and pharmacodynamics (PD), and to develop a pharmacogenetics mechanism-based compartmental PK model. In vitro kinetic studies on metabolite formation in human CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) hepatocytes indicated that Harmaline O-demethylase activity (V(max)/K(m)) was about 9-fold higher in EM hepatocytes. Substrate depletion showed mono-exponential decay trait, and estimated in vitro Harmaline clearance (CL(int), microL/min/10(6)cells) was significantly lower in PM hepatocytes (28.5) than EM hepatocytes (71.1). In vivo studies in CYP2D6-humanized and wild-type mouse models showed that wild-type mice were subjected to higher and longer exposure to Harmaline (5 and 15mg/kg; i.v. and i.p.), and more severe hypothermic responses. The PK/PD data were nicely described by our pharmacogenetics-based PK model involving the clearance of drug by CYP2D6 (CL(CYP2D6)) and other mechanisms (CL(other)), and an indirect response PD model, respectively. Wild-type mice were also more sensitive to Harmaline in marble-burying tests, as manifested by significantly lower ED(50) and steeper Hill slope. These findings suggest that distinct CYP2D6 status may cause considerable variations in Harmaline metabolism, PK and PD. In addition, the pharmacogenetics-based PK model may be extended to define PK difference caused by other polymorphic drug-metabolizing enzyme in different populations.
