RESUMEN
BACKGROUND: Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the nigrostriatal pathway. Even with scientific and technological advances, the therapeutic approaches used for the treatment of PD have shown to be largely ineffective in controlling the progression of symptoms in the long term. There is a growing demand for the development of novel therapeutic strategies for PD treatment. Different herbs and supplements have been considered as adjuvant to treat the symptoms of Parkinsonism. The carrot is one of the most consumed vegetable species worldwide, and its root is known for its content of anthocyanins, which possess antioxidant and antiinflammatory properties. This study evaluated the neuroprotective effect of purple carrot extract (CAR) in rats on the reserpine (RES)-induced progressive parkinsonism model. METHODS: Male rats (6-month-old) received orally the CAR (400 mg/kg) or vehicle and subcutaneously RES (0.01 mg/kg) or vehicle for 28 days (Preventive Phase). From the 29th day, rats received CAR or vehicle daily and RES (0.1 mg/kg) or vehicle every other day (for 23 days, Protective phase). Behavioral tests were conducted throughout the treatment. Upon completion, the animals' brain were processed for tyrosine hydroxylase (TH) immunohistochemical assessment. RESULTS: Our results showed that the chronic treatment of CAR protected against motor disabilities, reducing the time of catalepsy behavior and decreasing the frequency of oral movements, possibly by preserving TH levels in the Ventral Tegmental Area (VTA) and SNpc. CONCLUSION: CAR extract is effective to attenuate motor symptoms in rats associated with increased TH+ levels in the Ventral Tegmental Area (VTA) and SNpc, indicating the potential nutraceutical benefits of CAR extract in a progressive parkinsonism model induced by RES.
Asunto(s)
Daucus carota , Fármacos Neuroprotectores , Extractos Vegetales , Reserpina , Tirosina 3-Monooxigenasa , Animales , Reserpina/toxicidad , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratas , Daucus carota/química , Tirosina 3-Monooxigenasa/metabolismo , Ratas Wistar , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/patología , Modelos Animales de Enfermedad , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patologíaRESUMEN
OBJECTIVE AND METHODS: We investigated the locomotor, emotional, physiological, and neurobiological effects induced by low-dose reserpine repeated treatment (0.1 mg/kg; 14 injections) in males from the Lewis (LEW), Spontaneously Hypertensive Rats (SHR), and SHR.LEW-(D4Rat76-D4Mgh11) (SLA16) isogenic rat strains, which have different genetic backgrounds on chromosome 4. Behavioral responses in the catalepsy, open-field, and oral movements' tests were coupled with blood pressure, body weight, and striatal tyrosine hydroxylase (TH) level assessments to establish neurobiological comparisons between reserpine-induced impairments and genetic backgrounds RESULTS: Results revealed the SHR strain was more sensitive in the catalepsy test and exhibited higher TH immunoreactivity in the dorsal striatum. The SLA16 strain presented more oral movements, suggesting increased susceptibility to develop oral dyskinesia. CONCLUSIONS: Our results showed the efficacy of repeated treatment with a low dose of reserpine and demonstrated, for the first time, the genetic influence of a specific region of chromosome 4 on the expression of these effects.
Asunto(s)
Trastornos Parkinsonianos , Reserpina , Masculino , Ratas , Animales , Reserpina/toxicidad , Catalepsia , Conducta Animal , Ratas Endogámicas Lew , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/metabolismo , Ratas Endogámicas SHRRESUMEN
Progressive neurodegenerative disorders such as Parkinson Disease (PD) lack curative or long-term treatments. At the same time, the increase of the worldwide elderly population and, consequently, the extension in the prevalence of age-related diseases have promoted research interest in neurodegenerative disorders. Caenorhabditis elegans is a free-living nematode widely used as an animal model in studies of human diseases. Here we evaluated cannabidiol (CBD) as a possible neuroprotective compound in PD using the C. elegans models exposed to reserpine. Our results demonstrated that CBD reversed the reserpine-induced locomotor alterations and this response was independent of the NPR-19 receptors, an orthologous receptor for central cannabinoid receptor type 1. Morphological alterations of cephalic sensilla (CEP) dopaminergic neurons indicated that CBD also protects neurons from reserpine-induced degeneration. That is, CBD attenuates the reserpine-induced increase of worms with shrunken soma and dendrites loss, increasing the number of worms with intact CEP neurons. Finally, we found that CBD also reduced ROS formation and α-syn protein accumulation in mutant worms. Our findings collectively provide new evidence that CBD acts as neuroprotector in dopaminergic neurons, reducing neurotoxicity and α-syn accumulation highlighting its potential in the treatment of PD.
Asunto(s)
Proteínas de Caenorhabditis elegans , Cannabidiol , Enfermedades Neurodegenerativas , Fármacos Neuroprotectores , Enfermedad de Parkinson , Anciano , Animales , Humanos , Caenorhabditis elegans/metabolismo , alfa-Sinucleína/metabolismo , Animales Modificados Genéticamente , Cannabidiol/farmacología , Reserpina/toxicidad , Reserpina/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Neuronas Dopaminérgicas/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/metabolismo , Enfermedad de Parkinson/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Modelos Animales de Enfermedad , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by progressive dopaminergic neuron loss. Animal models have been used to develop a better understanding of the pathophysiologic mechanisms of PD. However, these models are usually conducted with young animals diverging of the age of PD patients, suggesting a bias in translational science. Thus, the aim of the study was to evaluate the effect of the age on rats in a progressive parkinsonism model induced by reserpine (RES). Adult (6 - 8 month-old) or elderly (18 - 24 month-old) male rats were assigned to six groups: control-elderly (CTL-ELDERLY), reserpine-elderly (RES-ELDERLY), reserpine-elderly withdrawal (RES-ELDERLY WITHDRAWAL), control-adult (CTL-ADULT), reserpine-adult (RES-ADULT), and reserpine-adult withdrawal (RES-ADULT WITHDRAWAL). Animals received 15 injections every other day of RES (0.1 mg / kg) or vehicle during 30 days. Throughout treatment, animals were evaluated in the catalepsy test (every 48 h) and open field test (24 h after the second injection), and weight assessment (every 4 days) was also made. Upon completion of behavioral tests, rat brains were collected for tyrosine hydroxylase (TH) immunohistochemical analysis. Main results demonstrated that RES-treated animals spent more time in the catalepsy bar compared with control groups, moreover the RES-elderly group showed a longer catalepsy time compared with the RES-ADULT group. A shorter time from RES treatment to the development of symptoms was observed in the RES-ADULT group, compared with the RES-ELDERLY group. In addition, RES-induced weight loss in both RES-ELDERLY and RES-ADULT when compared with their corresponding controls. Cessation of RES treatment was followed by weight gain only in the RES-ADULT group. A significant decrease in TH-immunoreactive cells was observed in the substantia nigra pars compacta (SNpc) and dorsal striatum (STR) in the rats in both the RES-ADULT and RES-ELDERLY groups and in the ventral tegmental area in rats in the RES-ADULT group. Furthermore, TH immunoreactivity decrease was not reversible in SNpc and STR in the RES-ELDERLY. These results show that RES has an age-dependent effect in rats, suggesting a greater sensitivity of the dopaminergic pathway to RES with advancing age. These suggest that the RES rat model of parkinsonism can be useful in improving our knowledge on the effect of aging on neurodegeneration.
Asunto(s)
Trastornos Motores , Enfermedad de Parkinson , Trastornos Parkinsonianos , Animales , Masculino , Ratas , Tirosina 3-Monooxigenasa/metabolismo , Reserpina/toxicidad , Catalepsia , Actividad Motora , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/metabolismo , Dopamina/metabolismo , Envejecimiento , Sustancia Negra/metabolismo , Modelos Animales de EnfermedadRESUMEN
Chronic pain and depression often coexist sharing common pathological mechanisms, and available analgesics and antidepressants have demonstrated limited clinical efficacy. Evidence has demonstrated that neuronal oxidative stress, apoptosis, and also glucocorticoid receptor dysregulation facilitate the occurrence and development of both chronic pain and depression. This study evaluated the effect of the organoselenium compound m-trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] in the pain-depression comorbidity induced by reserpine. Mice were treated with reserpine 0.5 mg/kg for 3 days (intraperitoneal, once a day), and in the next 2 days, they were treated with (m-CF3-PhSe)2 10 mg/kg (intragastric, once a day). Thirty minutes after the last administration of (m-CF3-PhSe)2, mice were subjected to the behavioral testing. (m-CF3-PhSe)2 treatment reverted the reserpine-increased thermal hyperalgesia and depressive-like behavior observed in the hot-plate test and forced swimming test, respectively. Reserpine provoked a decrease of crossings and rearings in the open-field test, while (m-CF3-PhSe)2 presented a tendency to normalize these parameters. Reserpine and/or (m-CF3-PhSe)2 treatments did not alter the locomotor activity of mice observed in the rota-rod test. These effects could be related to modulation of oxidative stress, apoptotic pathway, and glucocorticoid receptors, once (m-CF3-PhSe)2 normalized thiobarbituric acid reactive substances and 4-hydroxynonenal modified protein levels, markers of lipoperoxidation, poly(ADP-ribose) polymerase cleaved/total ratio, and glucocorticoid receptor levels increased by reserpine in the hippocampus. Considering that pain-depression dyad is a complex state of difficult treatment, this organoselenium compound could raise as an interesting alternative to treat pain-depression condition.
Asunto(s)
Dolor Crónico/tratamiento farmacológico , Depresión/tratamiento farmacológico , Compuestos de Organosilicio/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Receptores de Glucocorticoides , Reserpina/toxicidad , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Dolor Crónico/inducido químicamente , Dolor Crónico/metabolismo , Depresión/inducido químicamente , Depresión/metabolismo , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratones , Compuestos de Organosilicio/farmacología , Estrés Oxidativo/fisiología , Receptores de Glucocorticoides/metabolismo , Resultado del TratamientoRESUMEN
OBJECTIVE: The literature has shown that synthetic antipsychotic drugs induce reproductive toxicity, while psychiatric patients treated with traditionally used antipsychotic herbs (Rauwolfia vomitoria) showed no traces of reproductive toxicity. Thus, this study aimed to investigate the expression of CREM, PRM I and II genes in the testes of Wistar rats treated with antipsychotic drugs: chlorpromazine, Rauwolfia vomitoria (RV) and co-administration of reserpine, zinc and ascorbate (RAZ). METHODS: Forty-five adult male Wistar rats with rats with average weight of 180±4.67g were divided into nine groups (A-I) (n=5). Group A was administered saline (control) while rats in Groups B and C received 10 and 20mg/kg body weight (bwt) of chlorpromazine respectively. Groups D and E received 2.5 and 5mg/kg bwt of reserpine, respectively; while Groups F and G received 150 and 300mg/kg bwt of RV leaf extract. Groups H and I received (2.5+5+100) mg/kg bwt and (5+10+200) mg/kg of combination of RAZ, respectively for 56 days. RESULTS: The CREM, PRM I and II genes were significantly downregulated while significant decreased in serum FSH and testosterone concentration were found in the Chlorpromazine- and Reserpine-treated groups. Groups H and I showed a highly significant upregulation of the CREM, PRM I and II genes, and a highly significant increase in serum FSH and testosterone concentrations. CONCLUSION: The study concluded that the HPT-Axis was impaired by chlorpromazine and reserpine, while RV and a combination of RAZ administration enhanced the axis in an animal model. The study recommended that synthetic antipsychotic drugs should be taken with Zinc and Ascorbate in order to help prevent reproductive toxicity associated with antipsychotic drugs. We need further studies in humans to confirm these findings.
Asunto(s)
Antipsicóticos , Rauwolfia , Animales , Ácido Ascórbico , Clorpromazina/toxicidad , Modulador del Elemento de Respuesta al AMP Cíclico , Expresión Génica , Humanos , Extractos Vegetales/uso terapéutico , Ratas , Ratas Wistar , Rauwolfia/genética , Reserpina/toxicidad , Testículo , ZincRESUMEN
This study evaluated the effect of (+)-catechin, a polyphenolic compound, on orofacial dyskinesia (OD) induced by reserpine in mice. The potential modulation of monoaminoxidase (MAO) activity, tyrosine hydroxylase (TH) and glutamic acid decarboxylase (GAD67) immunoreactivity by catechin were used as biochemical endpoints. The interaction of catechin with MAO-A and MAO-B was determined in vitro and in silico. The effects of catechin on OD induced by reserpine (1 mg/kg for 4 days, subcutaneously) in male Swiss mice were examined. After, catechin (10, 50 or 100 mg/kg, intraperitoneally) or its vehicle were given for another 20 days. On the 6th, 8th, 15th and 26th day, vacuous chewing movements (VCMs) and locomotor activity were quantified. Biochemical markers (MAO activity, TH and GAD67 immunoreactivity) were evaluated in brain structures. In vitro, catechin inhibited both MAO isoforms at concentrations of 0.34 and 1.03 mM being completely reversible for MAO-A and partially reversible for MAO-B. Molecular docking indicated that the catechin bound in the active site of MAO-A, while in the MAO-B it interacted with the surface of the enzyme in an allosteric site. In vivo, reserpine increased the VCMs and decreased the locomotor activity. Catechin (10 mg/kg), decreased the number of VCMs in the 8th day in mice pre-treated with reserpine without altering other behavioral response. Ex vivo, the MAO activity and TH and GAD67 immunoreactivity were not altered by the treatments. Catechin demonstrated a modest and transitory protective effect in a model of OD in mice.
Asunto(s)
Catequina/uso terapéutico , Discinesias/tratamiento farmacológico , Discinesias/metabolismo , Masticación/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Reserpina/toxicidad , Animales , Antipsicóticos/toxicidad , Catequina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Masticación/fisiología , Ratones , Simulación del Acoplamiento Molecular/métodos , Inhibidores de la Monoaminooxidasa/farmacología , Inhibidores de la Monoaminooxidasa/uso terapéutico , Actividad Motora/fisiología , Estructura Secundaria de Proteína , Resultado del TratamientoRESUMEN
Parkinson's disease (PD) is mainly characterized by a dopamine deficiency accompanied by structural and functional changes in striatal neuronal projections. However, studies have considered PD as a multi-systemic disease in which the neurodegenerative process extends beyond the dopaminergic system. Therefore, the purpose of the present study was to investigate the time-course of serotonergic neuron damage in a progressive model of parkinsonism induced by a low dose of reserpine. Thus, male Wistar rats received 4 (ST, short-treatment of reserpine) or 10 (MT, middle-term treatment of reserpine) subcutaneous injections of vehicle or reserpine (0.1 mg/kg) at a volume of 1 mL/kg body weight, on alternate days. Animals were euthanized 48 h after the last injection for immunohistochemical analysis. After ST, 5-HT immunoreactivity decreased in hippocampal subareas (CA1 and CA3) and medial prefrontal cortex (mPFC) compared to vehicle. Furthermore, animals MT-treated also showed progressive decrease of 5-HT immunoreactivity in CA1 and CA3 subareas. Conversely, a significant increase of 5-HT immunoreactivity was found in mPFC and dorsal raphe nucleus (DRN) in animals submitted to MT when compared to ST exposure. The results showed that, in the repeated low-dose reserpine rat model, variations in the immunoreactivity of 5-HT start early in the course of progressive parkinsonism.
Asunto(s)
Inhibidores de Captación Adrenérgica/toxicidad , Encéfalo/metabolismo , Trastornos Parkinsonianos/metabolismo , Reserpina/toxicidad , Serotonina/metabolismo , Animales , Encéfalo/efectos de los fármacos , Masculino , Ratas , Ratas WistarRESUMEN
Parkinson's disease (PD) is a neurodegenerative disease characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra pars compact (SNpc), with consequent depletion of dopamine in the striatum, which gives rise to the characteristic motor symptoms of PD. Although its etiology is unknown, several studies have suggested that oxidative stress plays a critical function in the pathophysiology of PD, and antioxidant agents could be helpful to slown down the dopaminergic neurodegeneration. Carvacrol (CA) is a phenolic monoterpene found in essential oils of many aromatic plants that presents antioxidant and neuroprotective effects. This study aimed to assess the effect of CA in a reserpine (RES)-induced rat model of PD. Male Wistar rats received 15â¯s.c. injections of 0.1â¯mg/kg RES or vehicle, every other day, concomitantly to daily i.p. injections of CA (12.5 or 25â¯mg/kg) or vehicle. Across the treatment, the animals were submitted to behavioral evaluation in the catalepsy test (performed daily), open field test (7th day) and assessment of vacuous chewing movements (12th, 20th and 30th days). Upon completion of behavioral tests, rats were perfused and their brains underwent tyrosine hydroxylase (TH) immunohistochemical analysis. Our results showed that CA (12.5 e 25â¯mg/kg) prevented the increase in catalepsy behavior and number of vacuous chewing movements, but failed to revert the decreased open-field locomotor activity induced by RES. In addition, CA in both doses prevented the decrease in TH immunostaining induced by RES in the SNpc and dorsal striatum. Taken together, our results suggest that CA shows a protective effect in a rat model of PD, preventing motor and neurochemical impairments induced by RES. Thus, the use of CA as a promising new strategy for the prevention and/or treatment of PD may be considered.
Asunto(s)
Antiparasitarios/uso terapéutico , Antipsicóticos/toxicidad , Monoterpenos/uso terapéutico , Trastornos Parkinsonianos/inducido químicamente , Reserpina/toxicidad , Tirosina 3-Monooxigenasa/metabolismo , Análisis de Varianza , Animales , Catalepsia/diagnóstico , Catalepsia/etiología , Cimenos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Masticación/efectos de los fármacos , Trastornos Parkinsonianos/fisiopatología , Ratas , Ratas Wistar , Proteínas de Transporte Vesicular de Monoaminas/metabolismoRESUMEN
Dyskinesia consists in a series of trunk, limbs and orofacial involuntary movements that can be observed following long-term pharmacological treatment in some psychotic and neurological disorders such as schizophrenia and Parkinson's disease, respectively. Agmatine is an endogenous arginine metabolite that emerges as neuromodulator and a promising agent to manage diverse central nervous system disorders by modulating nitric oxide (NO) pathway, glutamate NMDA receptors and oxidative stress. Herein, we investigated the effects of a single intraperitoneal (i.p.) administration of different agmatine doses (10, 30 or 100mg/kg) against the orofacial dyskinesia induced by reserpine (1mg/kg,s.c.) in mice by measuring the vacuous chewing movements and tongue protusion frequencies, and the duration of facial twitching. The results showed an orofacial antidyskinetic effect of agmatine (30mg/kg, i.p.) or the combined administration of sub-effective doses of agmatine (10mg/kg, i.p.) with the NMDA receptor antagonists amantadine (1mg/kg, i.p.) and MK801 (0.01mg/kg, i.p.) or the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole (7-NI; 0.1mg/kg, i.p.). Reserpine-treated mice displayed locomotor activity deficits in the open field and agmatine had no effect on this response. Reserpine increased nitrite and nitrate levels in cerebral cortex, but agmatine did not reverse it. Remarkably, agmatine reversed the decrease of dopamine and non-protein thiols (NPSH) levels caused by reserpine in the striatum. However, no changes were observed in striatal immunocontent of proteins related to the dopaminergic system including tyrosine hydroxylase, dopamine transporter, vesicular monoamine transporter type 2, pDARPP-32[Thr75], dopamine D1 and D2 receptors. These results indicate that the blockade of NO pathway, NMDAR and oxidative stress are possible mechanisms associated with the protective effects of agmatine against the orofacial dyskinesia induced by reserpine in mice.
Asunto(s)
Agmatina/administración & dosificación , Discinesias/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo/efectos de los fármacos , Receptores de N-Metil-D-Aspartato/metabolismo , Reserpina/toxicidad , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Discinesia Inducida por Medicamentos/metabolismo , Discinesias/prevención & control , Antagonistas de Aminoácidos Excitadores/farmacología , Locomoción/efectos de los fármacos , Masculino , Ratones , Óxido Nítrico Sintasa/metabolismo , Receptores Dopaminérgicos/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Reserpine is used as an animal model of parkinsonism. We hypothesized that the involuntary movements induced by reserpine in rodents are induced by dopaminergic toxicity caused by extracellular dopamine accumulation. The present study tested the effects of reserpine on the dopaminergic system in Caenorhabditis elegans. Reserpine was toxic to worms (decreased the survival, food intake, development and changed egg laying and defecation cycles). In addition, reserpine increased the worms' locomotor rate on food and decreased dopamine levels. Morphological evaluations of dopaminergic CEP neurons confirmed neurodegeneration characterized by decreased fluorescence intensity and the number of worms with intact CEP neurons, and increased number of shrunken somas per worm. These effects were unrelated to reserpine's effect on decreased expression of the dopamine transporter, dat-1. Interestingly, the locomotor rate on food and the neurodegenerative parameters fully recovered to basal conditions upon reserpine withdrawal. Furthermore, reserpine decreased survival in vesicular monoamine transporter and dat-1 loss-of-function mutant worms. In addition, worms pre-exposed to dopamine followed by exposure to reserpine had decreased survival. Reserpine activated gst-4, which controls a phase II detoxification enzymes downstream of nuclear factor (erythroid-derived-2)-like 2. Our findings establish that the dopamine transporter, dat-1, plays an important role in reserpine toxicity, likely by increasing extracellular dopamine concentrations.
Asunto(s)
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/efectos de los fármacos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Dopamina/metabolismo , Reserpina/toxicidad , Animales , Animales Modificados Genéticamente , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Defecación/efectos de los fármacos , Modelos Animales de Enfermedad , Dopamina/farmacología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Óvulo/efectos de los fármacos , Enfermedad de Parkinson/fisiopatologíaRESUMEN
The administration of reserpine to rodents was one of the first models used to investigate the pathophysiology and screening for potential treatments of Parkinson's disease (PD). The reserpine model was critical to the understanding of the role of monoamine system in the regulation of motor and affective disorders, as well as the efficacy of current PD treatments, such as L-DOPA and dopamine agonists. Nevertheless, with the introduction of toxin-induced and genetic models of PD, reserpine became underused. The main rationale to this drawback was the supposed absence of reserpine construct validity with PD. Here, we highlight classical and recent experimental findings that support the face, pharmacological, and construct validity of reserpine PD model and reason against the current rationale for its underuse. We also aim to shed a new perspective upon the model by discussing the main challenges and potentials for the reserpine model of PD.
Asunto(s)
Antipsicóticos/toxicidad , Modelos Animales de Enfermedad , Enfermedad de Parkinson , Reserpina/toxicidad , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Trastornos Mentales/inducido químicamente , Enfermedad de Parkinson/etiología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatologíaRESUMEN
Reserpine administration results in a predictable animal model of orofacial dyskinesia (OD) that has been largely used to access movement disturbances related to extrapyramidal oxidative damage. Here, OD was acutely induced by reserpine (two doses of 0.7 mg/kg subcutaneous (s.c.)), every other day for 3 days), which was administered after (experiment 1) and before (experiment 2) magnesium (Mg) supplementation (40 mg/kg/mL, peroral (p.o.)). In experiment 1, Mg was administered for 28 days before reserpine treatment, while in experiment 2, it was initiated 24 h after the last reserpine administration and was maintained for 10 consecutive days. Experiment 1 (prevention) showed that Mg supplementation was able to prevent reserpine-induced OD and catalepsy development. Mg was also able to prevent reactive species (RS) generation, thus preventing increase of protein carbonyl (PC) levels in both cortex and substantia nigra, but not in striatum. Experiment 2 (reversion) showed that Mg was able to decrease OD and catalepsy at all times assessed. In addition, Mg was able to decrease RS generation, with lower levels of PC in both cortex and striatum, but not in substantia nigra. These outcomes indicate that Mg is an important metal that should be present in the diet, since its intake is able to prevent and minimize the development of movement disorders closely related to oxidative damage in the extrapyramidal brain areas, such as OD.
Asunto(s)
Encéfalo/metabolismo , Magnesio/farmacología , Magnesio/uso terapéutico , Trastornos del Movimiento/tratamiento farmacológico , Animales , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Trastornos del Movimiento/etiología , Ratas , Ratas Wistar , Reserpina/toxicidadRESUMEN
The effects of Hypericum perforatum, a plant with antidepressant action, were evaluated in models of abnormal movements in rats, brought about by administration of fluphenazine or reserpine. The number of vacuous chewing movements (VCMs) and locomotor activity (the number of crossings and rears in the open field test) were measured. In experiment 1, rats received a single administration of fluphenazine enanthate (25 mg/kg, intramuscular) and/or daily treatment with H. perforatum (300 mg/kg, in place of drinking water) for 7 days. Fluphenazine increased VCMs and decreased locomotor activity. H. perforatum had no effect on either the number of VCMs or the locomotor activity. In experiment 2, rats received reserpine every 2 days for 6 days (0.5 mg/kg, subcutaneous) and/or H. perforatum (300 mg/kg, in place of drinking water) daily for 16 days beginning 10 days before the first administration of reserpine. Reserpine treatment increased VCMs and decreased locomotor activity. H. perforatum had no effect on either the number of VCMs or the number of rears but did prevent the effect of reserpine on the number of crossings. In conclusion, H. perforatum failed to protect against orofacial movements induced by fluphenazine or reserpine in rats.
Asunto(s)
Hypericum/química , Trastornos del Movimiento/tratamiento farmacológico , Extractos Vegetales/farmacología , Animales , Modelos Animales de Enfermedad , Flufenazina/análogos & derivados , Flufenazina/toxicidad , Masculino , Masticación/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Reserpina/toxicidadRESUMEN
Involuntary oral movements are present in several diseases and pharmacological conditions; however, their etiology and efficient treatments remain unclear. Gallic acid is a natural polyphenolic acid found in gall nuts, sumac, oak bark, tea leaves, grapes and wine, with potent antioxidant and antiapoptotic activity. Thus, the present study investigated the effects of gallic acid on vacuous chewing movements (VCMs) in an animal model induced by reserpine. Rats received either vehicle or reserpine (1mg/kg/day, s.c.) during three days, followed by treatment with water or different doses of gallic acid (4.5, 13.5 or 40.5mg/kg/day, p.o.) for three more days. As result, reserpine increased the number of VCMs in rats, and this effect was maintained for at least three days after its withdrawal. Gallic acid at two different doses (13.5 and 40.5mg/kg/day) has reduced VCMs in rats previously treated with reserpine. Furthermore, we investigated oxidative stress parameters (DCFH-DA oxidation, TBARS and thiol levels) and Na(+),K(+)-ATPase activity in striatum and cerebral cortex, however, no changes were observed. These findings show that gallic acid may have promissory use in the treatment of involuntary oral movements.
Asunto(s)
Discinesia Inducida por Medicamentos/tratamiento farmacológico , Ácido Gálico/farmacología , Masticación/efectos de los fármacos , Reserpina/toxicidad , Inhibidores de Captación Adrenérgica/toxicidad , Animales , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Antipsicóticos/toxicidad , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/fisiopatología , Ácido Gálico/administración & dosificación , Masculino , Masticación/fisiología , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
Oral movements are associated with important neuropathologies as Parkinson's disease and tardive dyskinesia. However, until this time, there has been no known efficacious treatment, without side effects, for these disorders. Thus, the aim of the present study was to investigate the possible preventive effects of V. officinalis, a phytotherapic that has GABAergic and antioxidant properties, in vacuous chewing movements (VCMs) induced by reserpine in rats. Adult male rats were treated with reserpine (1 mg/kg, s.c.) and/or with V. officinalis (in the drinking water, starting 15 days before the administration of the reserpine). VCMs, locomotor activity and oxidative stress measurements were evaluated. Furthermore, we carried out the identification of valeric acid and gallic acid by HPLC in the V. officinalis tincture. Our findings demonstrated that reserpine caused a marked increase on VCMs and the co-treatment with V. officinalis was able to reduce the intensity of VCM. Reserpine did not induce oxidative stress in cerebral structures (cortex, hippocampus, striatum and substantia nigra). However, a significant positive correlation between DCF-oxidation (an estimation of oxidative stress) in the cortex and VCMs (p < 0.05) was observed. Moreover, a negative correlation between Na(+)K(+)-ATPase activity in substantia nigra and the number of VCMs was observed (p < 0.05). In conclusion, V. officinalis had behavioral protective effect against reserpine-induced VCMs in rats; however, the exact mechanisms that contributed to this effect have not been completely understood.
Asunto(s)
Discinesia Inducida por Medicamentos/tratamiento farmacológico , Masticación/efectos de los fármacos , Fitoterapia/métodos , Preparaciones de Plantas/farmacología , Reserpina/toxicidad , Valeriana/química , Inhibidores de Captación Adrenérgica/toxicidad , Animales , Modelos Animales de Enfermedad , Discinesia Inducida por Medicamentos/fisiopatología , Discinesia Inducida por Medicamentos/prevención & control , Masculino , Masticación/fisiología , Preparaciones de Plantas/uso terapéutico , Ratas , Ratas WistarRESUMEN
Fish oil (FO) supplementation could cause an increase in the concentration of plasmatic free fatty acids and, consequently, could compete with pro-inflammatory arachidonic acid (ARA) derived from brain biomembranes metabolism in the cerebrospinal fluid. Essential fatty acids (EFA) (n-3) have been reported by their antioxidant and neuroprotective properties, and therefore the influence of the FO supplementation on the reserpine-induced motor disorders was studied. Wistar rats were orally treated with FO solution for 5 days, and co-treated with reserpine (R; 1 mg/kg/mL) or its vehicle for 3 days (every other day). Reserpine-induced orofacial dyskinesia and catalepsy (P < 0.05) were prevented by FO (P < 0.05). Biochemical evaluations showed that reserpine treatment increased the lipid peroxidation in the cortex and striatum (P < 0.05), while the FO supplementation prevented this oxidative effect in both brain regions (P < 0.05). Our results showed the protective role of FO in the brain lipid membranes, reinforcing the beneficial effect of n-3 fatty acids in the prevention of degenerative and motor disorders.
Asunto(s)
Catalepsia/prevención & control , Suplementos Dietéticos , Aceites de Pescado/uso terapéutico , Trastornos del Movimiento/prevención & control , Trastornos Parkinsonianos/prevención & control , Sustancias Protectoras/uso terapéutico , Animales , Catalepsia/inducido químicamente , Catalepsia/fisiopatología , Modelos Animales de Enfermedad , Aceites de Pescado/administración & dosificación , Masculino , Trastornos del Movimiento/etiología , Trastornos del Movimiento/fisiopatología , Trastornos Parkinsonianos/inducido químicamente , Sustancias Protectoras/administración & dosificación , Ratas , Ratas Wistar , Reserpina/toxicidadRESUMEN
We have recently verified that the monoamine-depleting drug reserpine--at doses that do not modify motor function--impairs memory in a rodent model of aversive discrimination. In this study, the effects of reserpine (0.1-0.5 mg/kg) on the performance of rats in object recognition, spatial working memory (spontaneous alternation) and emotional memory (contextual freezing conditioning) tasks were investigated. While object recognition and spontaneous alternation behavior were not affected by reserpine treatment, contextual fear conditioning was impaired. Together with previous studies, these results suggest that low doses of reserpine would preferentially induce deficits in tasks involved with emotional contexts. Possible relationships with cognitive and emotional processing deficits in Parkinson disease are discussed.
Asunto(s)
Antipsicóticos/toxicidad , Emociones/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/psicología , Enfermedad de Parkinson/psicología , Reserpina/toxicidad , Percepción Social , Animales , Interpretación Estadística de Datos , Miedo/efectos de los fármacos , Miedo/psicología , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratas , Ratas Wistar , Reconocimiento en Psicología/efectos de los fármacos , Percepción Espacial/efectos de los fármacosRESUMEN
Several neurological diseases are related to oxidative stress (OS) and neurotoxicity. Considering that physical exercise may exert beneficial effects on antioxidant defenses, our objective was to evaluate the influence of a swimming exercise on an OS animal model (reserpine-induced orofacial dyskinesia). In this model, the increased dopamine metabolism can generate OS and neuronal degeneration, causing involuntary movements. The increase in vacuous chewing movements and facial twitching caused by reserpine (1 mg/kg s.c.) was partially prevented by exercise. An increase in catalase activity and a decrease in GSH levels were observed in the striatum. Physical training did not change the effects of reserpine on catalase, however it partially recovered GSH. Exercise per se caused a significant GSH decrease. There was a positive correlation between catalase and OD (r=0.41; r=0.47, P<0.05) and a negative correlation between GSH and OD (r=0.61; r=0.71, P<0.05). These results reveal the benefit of exercise in attenuating the motor disorder related to OS.
Asunto(s)
Antioxidantes/metabolismo , Antipsicóticos/farmacología , Estrés Oxidativo/efectos de los fármacos , Condicionamiento Físico Animal/fisiología , Reserpina/farmacología , Animales , Antipsicóticos/toxicidad , Química Encefálica/efectos de los fármacos , Catalasa/sangre , Discinesia Inducida por Medicamentos/psicología , Glutatión/sangre , Masculino , Ratas , Ratas Wistar , Análisis de Regresión , Reserpina/toxicidadRESUMEN
Ilex paraguariensis St Hilaire (Aquifoliaceae) is a plant widely cultivated in South America and with various reputed medicinal properties that can be attributed to phenolic constituents of the leaves: caffeine, theophylline and theobromine, besides the flavonoids, quercetin and rutin. This study examined the antiparkinsonian activity of the hydroalcohol extract of Ilex paraguariensis in models of protection against cerebral injury induced by MPTP and reversal of the catatonia induced by reserpine in mice. The hydroalcohol extract prevented MPTP-induced hypolocomotion at doses of 250 and 500 mg/kg at the all time points observed and also prevented the reserpine-induced catalepsy at the same doses. The extract potentiated the effect of apomorphine in preventing catatonia, suggesting a non-dopaminergic activity, probably through antagonism of adenosine. In biochemical studies the hydroalcohol extract caused a significant decrease in the NO levels, exhibited a DPPH-scavenging ability and was effective in preventing the oxidation of deoxyribose. The results obtained suggest that the hydroalcohol extract of Ilex paraguariensis may have an antiparkinsonian profile in animal models, probably through its antioxidant activity and antagonist action on adenosine A(2A) receptors.