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1.
Molecules ; 26(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34443679

RESUMO

Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a "two-bottle" as well as a "drinking in the dark" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.


Assuntos
Consumo de Bebidas Alcoólicas/patologia , Antagonistas de Receptores de Canabinoides/farmacologia , Endotoxemia/patologia , Etanol/efeitos adversos , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Receptor CB1 de Canabinoide/antagonistas & inibidores , Consumo de Bebidas Alcoólicas/sangue , Animais , Ansiedade/sangue , Ansiedade/complicações , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/complicações , Cicloexanóis/administração & dosagem , Teste de Labirinto em Cruz Elevado , Endotoxemia/sangue , Endotoxemia/complicações , Endotoxinas/sangue , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/metabolismo , Hipotermia Induzida , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Pirazóis/administração & dosagem , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto/administração & dosagem , Rimonabanto/farmacologia , Estereoisomerismo , Sulfonamidas/administração & dosagem
2.
Psychopharmacology (Berl) ; 238(9): 2471-2483, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34002247

RESUMO

RATIONALE: Recently, it was found that cyclosomatostatin-induced catalepsy in middle-aged rats is accompanied by neuronal hypoactivation in the lateral entorhinal cortex (LEntCx); this hypoactivation was reversed by systemic administration of nicotine combined with diphenhydramine. These findings suggest the ability of nicotine to regulate catalepsy and the involvement of the LEntCx in this nicotine effect. OBJECTIVES: The study was aimed to assess whether nicotine alone influences catalepsy when injected into the LEntCx and some other neuroanatomical structures. METHODS: Experiments were conducted with male Wistar rats of 540-560 days of age. Catalepsy was induced by intracerebroventricular injection of cyclosomatostatin and assessed by the standard bar test. Nicotine was injected into the LEntCx, prelimbic cortex (PrCx), or basolateral amygdala (BLA). The tissue levels of tyrosine hydroxylase, dopamine, and DOPAC in the substantia nigra pars compacta and dorsal striatum were measured with use of HPLC and ELISA. RESULTS: Injections of nicotine into the LEntCx but not into the PrCx and BLA produced anticataleptic effect; the nicotine effect was significantly reversed by intra-LEntCx administration of NMDA and non-NMDA glutamate receptor antagonists. Nicotine also attenuated cataleptogen-induced changes in nigrostriatal dopamine metabolism. CONCLUSIONS: This may be the first demonstration of anticataleptic activity of nicotine. The results show that the effect is mediated by nicotine receptors in the LEntCx, via a glutamatergic mechanism. These findings may help advance the development of novel treatments for extrapyramidal disorders, including parkinsonism.


Assuntos
Córtex Entorrinal , Nicotina , Animais , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Antagonistas de Dopamina , Masculino , Nicotina/farmacologia , Ratos , Ratos Wistar
3.
Eur J Pharmacol ; 903: 174112, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33901458

RESUMO

In the present study, we investigated the anti-Parkinson's effect of vanillic acid (VA) (12 mg/kg, 25 mg/kg, 50 mg/kg p.o.) against rotenone (2 mg/kg s.c.) induced Parkinson's disease (PD) in rats. The continuous administration of rotenone for 35 days resulted in rigidity in muscles, catalepsy, and decrease in locomotor activity, body weight, and rearing behaviour along with the generation of oxidative stress in the brain (rise in the TBARS, and SAG level and reduced CAT, and GSH levels). Co-treatment of VA and levodopa-carbidopa (100 mg/kg + 25 mg/kg p.o.) lead to a significant (P < 0.001) reduction in the muscle rigidity and catalepsy along with a significant (P < 0.001) increase in body weight, rearing behaviour, locomotion and muscle activity as compared to the rotenone-treated group in the dose dependent manner, showing maximum effect at the 50 mg/kg. It also showed reversal of levels of oxidative stress parameters thus, reducing the neuronal oxidative stress. The level of DA was also estimated which showed an increase in the level of DA in the VA plus standard drug treated animals as compared to rotenone treated group. Histopathological evaluation showed a high number of eosinophilic lesions in the rotenone group which were found to be very less in the VA co-treated group. The study thus proved that co-treatment of VA and levodopa-carbidopa, significantly protected the brain from neuronal damage due to oxidative stress and attenuated the motor defects indicating the possible therapeutic potential of VA as a neuroprotective in PD.


Assuntos
Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Ácido Vanílico/farmacologia , Ácido Vanílico/uso terapêutico , Animais , Antiparkinsonianos/farmacologia , Antiparkinsonianos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Carbidopa/farmacologia , Carbidopa/uso terapêutico , Catalase/metabolismo , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Dopamina/metabolismo , Combinação de Medicamentos , Feminino , Glutationa/metabolismo , Levodopa/farmacologia , Levodopa/uso terapêutico , Locomoção/efeitos dos fármacos , Masculino , Mesencéfalo/efeitos dos fármacos , Mesencéfalo/metabolismo , Mesencéfalo/patologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson/etiologia , Equilíbrio Postural/efeitos dos fármacos , Ratos Sprague-Dawley , Rotenona/toxicidade , Superóxidos/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
4.
Eur J Neurosci ; 53(11): 3743-3767, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33818841

RESUMO

Several useful animal models for parkinsonism have been developed so far. Haloperidol-induced catalepsy is often used as a rodent model for the study of motor impairments observed in Parkinson's disease and related disorders and for the screening of potential antiparkinsonian compounds. The objective of this systematic review is to identify publications that used the haloperidol-induced catalepsy model for parkinsonism and to explore the methodological characteristics and the main questions addressed in these studies. A careful systematic search of the literature was carried out by accessing articles in three different databases: Web of Science, PubMed and SCOPUS. The selection and inclusion of studies were performed based on the abstract and, subsequently, on full-text analysis. Data extraction included the objective of the study, study design and outcome of interest. Two hundred and fifty-five articles were included in the review. Publication years ranged from 1981 to 2020. Most studies used the model to explore the effects of potential treatments for parkinsonism. Although the methodological characteristics used are quite varied, most studies used Wistar rats as experimental subjects. The most frequent dose of haloperidol used was 1.0 mg/kg, and the horizontal bar test was the most used to assess catalepsy. The data presented here provide a framework for an evidence-based approach to the design of preclinical research on parkinsonism using the haloperidol-induced catalepsy model. This model has been used routinely and successfully and is likely to continue to play a critical role in the ongoing search for the next generation of therapeutic interventions for parkinsonism.


Assuntos
Catalepsia , Transtornos Parkinsonianos , Animais , Catalepsia/induzido quimicamente , Modelos Animais de Doenças , Haloperidol/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/tratamento farmacológico , Ratos , Ratos Wistar
5.
Biochem Biophys Res Commun ; 555: 154-159, 2021 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-33819745

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. Oxidative stress-induced neuronal death has been identified as one of the major causes of nigrostriatal degeneration in PD. The fruit of Actinidia arguta (A. arguta), known as sarunashi in Japan, has been reported to show beneficial health effects such as antioxidant, anti-inflammatory, anti-mutagenic, and anticholinergic effects. In this study, we investigated the neuroprotective effects of A. arguta in 1-methyl-4-phenyl-1,2,3,6-tetrahydropypridine (MPTP)-induced PD model mice. A. arguta juice was administered to 7-week-old C57BL/6J mice continuously for 10 days before the first MPTP injection. The degeneration of dopaminergic neurons in the substantia nigra was induced by MPTP (30 mg/kg, i. p.) once daily for five consecutive days. We found that the administration of A. arguta ameliorated MPTP-induced motor impairment and suppressed the MPTP-induced reductions of tyrosine hydroxylase-positive neurons and tyrosine hydroxylase protein expression in the substantia nigra. Our findings suggest that taking A. arguta could provide neuroprotection that delays or prevents the neurodegenerative process of PD.


Assuntos
Actinidia/química , Neurônios Dopaminérgicos/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Animais , Western Blotting , Catalepsia/induzido quimicamente , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Sucos de Frutas e Vegetais , Intoxicação por MPTP/complicações , Masculino , Camundongos Endogâmicos C57BL , Doença de Parkinson/etiologia , Doença de Parkinson Secundária/tratamento farmacológico , Tirosina 3-Mono-Oxigenase/metabolismo
6.
Biol Pharm Bull ; 44(3): 442-447, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33642553

RESUMO

The dopamine system plays an important role in regulating many brain functions, including the motor function. The blockade of dopamine receptors results in a serious motor dysfunction, such as catalepsy and Parkinsonism. However, the neuronal mechanism underlying the drug-induced motor dysfunction is not well understood. Here, we examine brain-wide activation patterns in Fos-enhanced green fluorescent protein reporter mice that exhibit cataleptic behavior induced by SCH39166, a dopamine D1-like receptor antagonist, and raclopride, a dopamine D2-like receptor antagonist. Support vector classifications showed that the orbital cortex (ORB) and striatum including the caudoputamen (CP) and nucleus accumbens (ACB), prominently contribute to the discrimination between brains of the vehicle-treated and both SCH39166- and raclopride-treated mice. Interregional correlations indicated that the increased functional connectivity of functional networks, including the ORB, CP, and ACB, is the common mechanism underlying SCH39166- and raclopride-induced cataleptic behavior. Moreover, the distinct mechanisms in the SCH39166- and raclopride-induced cataleptic behaviors are the decreased functional connectivity between three areas above and the cortical amygdala, and between three areas above and the anterior cingulate cortex, respectively. Thus, the alterations of functional connectivity in diverse brain regions, including the ORB, provide new insights on the mechanism underlying drug-induced movement disorders.


Assuntos
Benzazepinas/farmacologia , Catalepsia/induzido quimicamente , Corpo Estriado/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Racloprida/farmacologia , Animais , Catalepsia/fisiopatologia , Corpo Estriado/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia
7.
Neuron ; 109(9): 1513-1526.e11, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33770505

RESUMO

Recent advances in neuroscience have positioned brain circuits as key units in controlling behavior, implying that their positive or negative modulation necessarily leads to specific behavioral outcomes. However, emerging evidence suggests that the activation or inhibition of specific brain circuits can actually produce multimodal behavioral outcomes. This study shows that activation of a receptor at different subcellular locations in the same neuronal circuit can determine distinct behaviors. Pharmacological activation of type 1 cannabinoid (CB1) receptors in the striatonigral circuit elicits both antinociception and catalepsy in mice. The decrease in nociception depends on the activation of plasma membrane-residing CB1 receptors (pmCB1), leading to the inhibition of cytosolic PKA activity and substance P release. By contrast, mitochondrial-associated CB1 receptors (mtCB1) located at the same terminals mediate cannabinoid-induced catalepsy through the decrease in intra-mitochondrial PKA-dependent cellular respiration and synaptic transmission. Thus, subcellular-specific CB1 receptor signaling within striatonigral circuits determines multimodal control of behavior.


Assuntos
Encéfalo/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais/fisiologia , Transmissão Sináptica/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Catalepsia/induzido quimicamente , Membrana Celular/metabolismo , Células HEK293 , Células HeLa , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos
8.
Bioorg Med Chem Lett ; 37: 127838, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33556572

RESUMO

A high throughput screen (HTS) identified a novel, but weak (EC50 = 6.2 µM, 97% Glu Max) mGlu4 PAM chemotype based on a 1,4-thiazepane core, VU0544412. Reaction development and chemical optimization delivered a potent mGlu4 PAM VU6022296 (EC50 = 32.8 nM, 108% Glu Max) with good CNS penetration (Kp = 0.45, Kp,uu = 0.70) and enantiopreference. Finally, VU6022296 displayed robust, dose-dependent efficacy in reversing Haloperidol-Induced Catalepsy (HIC), a rodent preclinical Parkinson's disease model.


Assuntos
Catalepsia/tratamento farmacológico , Modelos Animais de Doenças , Descoberta de Drogas , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Animais , Catalepsia/induzido quimicamente , Relação Dose-Resposta a Droga , Haloperidol , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-Atividade
9.
Behav Brain Res ; 396: 112919, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956773

RESUMO

In the suited rat-models, we focused on the stable pentadecapeptide BPC 157, L-NAME, NOS-inhibitor, and L-arginine, NOS-substrate, relation, the effect on schizophrenia-like symptoms. Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), BPC 157 (0.01), given alone and/or together, at 5 min before the challenge for the acutely disturbed motor activity (dopamine-indirect/direct agonists (amphetamine (3.0), apomorphine (2.5)), NMDA-receptor non-competitive antagonist (MK-801 (0.2)), or catalepsy, (dopamine-receptor antagonist haloperidol (2.0)). Alternatively, BPC 157 10 µg/kg was given immediately after L-NAME 40 mg/kg intraperitoneally. To induce or prevent sensitization, we used chronic methamphetamine administration, alternating 3 days during the first 3 weeks, and challenge after next 4 weeks, and described medication (L-NAME, L-arginine, BPC 157) at 5 min before the methamphetamine at the second and third week. Given alone, BPC 157 or L-arginine counteracted the amphetamine-, apomorphine-, and MK-801-induced effect, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization. L-NAME did not affect the apomorphine-, and MK-801-induced effects, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization, but counteracted the acute amphetamine-induced effect. In combinations (L-NAME + L-arginine), as NO-specific counteraction, L-NAME counteracts L-arginine-induced counteractions in the apomorphine-, MK-801-, haloperidol- and methamphetamine-rats, but not in amphetamine-rats. Unlike L-arginine, BPC 157 maintains its counteracting effect in the presence of the NOS-blockade (L-NAME + BPC 157) or NO-system-over-stimulation (L-arginine + BPC 157). Illustrating the BPC 157-L-arginine relationships, BPC 157 restored the antagonization (L-NAME + L-arginine + BPC 157) when it had been abolished by the co-administration of L-NAME with L-arginine (L-NAME + L-arginine). Finally, BPC 157 directly inhibits the L-NAME high dose-induced catalepsy. Further studies would determine precise BPC 157/dopamine/glutamate/NO-system relationships and clinical application.


Assuntos
Anfetamina/farmacologia , Apomorfina/farmacologia , Arginina/farmacologia , Catalepsia , Maleato de Dizocilpina/farmacologia , Dopaminérgicos/farmacologia , Inibidores Enzimáticos/farmacologia , Haloperidol/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase , Fragmentos de Peptídeos/farmacologia , Proteínas/farmacologia , Esquizofrenia , Anfetamina/administração & dosagem , Animais , Apomorfina/administração & dosagem , Arginina/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Catalepsia/fisiopatologia , Modelos Animais de Doenças , Maleato de Dizocilpina/administração & dosagem , Dopaminérgicos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Haloperidol/administração & dosagem , Masculino , NG-Nitroarginina Metil Éster/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Fragmentos de Peptídeos/administração & dosagem , Proteínas/administração & dosagem , Ratos , Ratos Wistar , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia
10.
PLoS One ; 15(12): e0243438, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33275614

RESUMO

Deep brain stimulation (DBS) of the colliculus inferior (IC) improves haloperidol-induced catalepsy and induces paradoxal kinesia in rats. Since the IC is part of the brain aversive system, DBS of this structure has long been related to aversive behavior in rats limiting its clinical use. This study aimed to improve intracollicular DBS parameters in order to avoid anxiogenic side effects while preserving motor improvements in rats. Catalepsy was induced by systemic haloperidol (0.5mg/kg) and after 60 min the bar test was performed during which a given rat received continuous (5 min, with or without pre-stimulation) or intermittent (5 x 1 min) DBS (30Hz, 200-600µA, pulse width 100µs). Only continuous DBS with pre-stimulation reduced catalepsy time. The rats were also submitted to the elevated plus maze (EPM) test and received either continuous stimulation with or without pre-stimulation, or sham treatment. Only rats receiving continuous DBS with pre-stimulation increased the time spent and the number of entries into the open arms of the EPM suggesting an anxiolytic effect. The present intracollicular DBS parameters induced motor improvements without any evidence of aversive behavior, pointing to the IC as an alternative DBS target to induce paradoxical kinesia improving motor deficits in parkinsonian patients.


Assuntos
Ansiedade/terapia , Catalepsia/terapia , Estimulação Encefálica Profunda/métodos , Animais , Ansiedade/induzido quimicamente , Ansiedade/fisiopatologia , Catalepsia/induzido quimicamente , Catalepsia/fisiopatologia , Modelos Animais de Doenças , Haloperidol/toxicidade , Masculino , Ratos , Ratos Wistar
11.
Transl Psychiatry ; 10(1): 336, 2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33009372

RESUMO

The mammalian target of rapamycin (mTOR) is a ubiquitously expressed serine/threonine kinase protein complex (mTORC1 or mTORC2) that orchestrates diverse functions ranging from embryonic development to aging. However, its brain tissue-specific roles remain less explored. Here, we have identified that the depletion of the mTOR gene in the mice striatum completely prevented the extrapyramidal motor side effects (catalepsy) induced by the dopamine 2 receptor (D2R) antagonist haloperidol, which is the most widely used typical antipsychotic drug. Conversely, a lack of striatal mTOR in mice did not affect catalepsy triggered by the dopamine 1 receptor (D1R) antagonist SCH23390. Along with the lack of cataleptic effects, the administration of haloperidol in mTOR mutants failed to increase striatal phosphorylation levels of ribosomal protein pS6 (S235/236) as seen in control animals. To confirm the observations of the genetic approach, we used a pharmacological method and determined that the mTORC1 inhibitor rapamycin has a profound influence upon post-synaptic D2R-dependent functions. We consistently found that pretreatment with rapamycin entirely prevented (in a time-dependent manner) the haloperidol-induced catalepsy, and pS6K (T389) and pS6 (S235/236) signaling upregulation, in wild-type mice. Collectively, our data indicate that striatal mTORC1 blockade may offer therapeutic benefits with regard to the prevention of D2R-dependent extrapyramidal motor side effects of haloperidol in psychiatric illness.


Assuntos
Antipsicóticos , Haloperidol , Animais , Antipsicóticos/toxicidade , Catalepsia/induzido quimicamente , Antagonistas de Dopamina , Haloperidol/toxicidade , Camundongos , Serina-Treonina Quinases TOR
12.
Neurochem Res ; 45(11): 2786-2799, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32939670

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder of dopaminergic, noradrenergic, and serotonergic systems, in which dopamine, noradrenaline, and serotonin levels are depleted and lead to the development of motor and non-motor symptoms such as tremor, bradykinesia, weight changes, fatigue, depression, and visual hallucinations. Therapeutic strategies place much focus on dopamine replacement and the inhibition of dopamine metabolism. The present study was based on the known abilities of chalcones to act as molecular scaffolds that selectively inhibit MAO-B with the added advantage of binding reversibly. Recently, we synthesized a series of 26 chalcone compounds, amongst which (2E)-1-(2H-1,3-benzodioxol-5-yl)-3-(4-fluorophenyl)prop-2-en-1-one (O10) and (2E)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(4-fluorophenyl)prop-2-en-1-one (O23) most inhibited MAO-B. Hence, the present study was performed to explore the molecular mechanisms responsible for the neuroprotective effect of O10 and O23 at varying doses such as 10, 20, and 30 mg/kg each in a haloperidol-induced murine model of PD. Both compounds were effective (though O23 was the more effective) at ameliorating extrapyramidal and non-motor symptoms in the model and improved locomotory and exploratory behaviors, reduced oxidative stress markers, and enhanced antioxidant marker and neurotransmitter levels. Furthermore, histopathological studies showed O10 and O23 both reduced neurofibrillary tangles and plaques to almost normal control levels.


Assuntos
Catalepsia/tratamento farmacológico , Chalconas/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson Secundária/tratamento farmacológico , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Catalepsia/induzido quimicamente , Dopamina/metabolismo , Haloperidol , Camundongos , Norepinefrina/metabolismo , Teste de Campo Aberto/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Doença de Parkinson Secundária/induzido quimicamente , Serotonina/metabolismo
13.
Neuropharmacology ; 179: 108287, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32860777

RESUMO

Δ9-tetrahydrocannabinol (THC), the major psychoactive ingredient of Cannabis sativa, exerts its actions through the endocannabinoid system by stimulation of the cannabinoid type 1 (CB1) receptor. The widespread distribution of this receptor in different neuronal cell types and the plethora of functions that is modulated by the endocannabinoid system explain the versatility of the effects of THC. However, the cell types involved in the different THC effects are still not fully known. Conditional CB1 receptor knock-out mice were previously used to identify CB1 receptor subpopulations that are "necessary" for the tetrad effects of a high dose of THC: hypothermia, hypolocomotion, catalepsy and analgesia. Here, we used mouse models for conditional CB1 receptor "rescue" in dorsal telencephalic glutamatergic and forebrain GABAergic neurons to determine which CB1 receptor subpopulations are "sufficient" for these tetrad effects. Glutamatergic CB1 receptor was not only necessary but also sufficient for THC-induced hypothermia and hypolocomotion. Analgesic and cataleptic effects of THC are largely independent of glutamatergic and GABAergic CB1 receptors, since no sufficiency was found, in agreement with the previously reported lack of necessity. We also revealed a novel aspect of GABAergic CB1 receptor signaling. In animals with CB1 receptors exclusively in forebrain GABAergic neurons, THC stimulated rather than reduced locomotion. This cell-type selective and hitherto unsuspected hyperlocomotive effect may be occluded in wild-types and conditional knockouts and only be exposed when CB1 signaling is absent in all other cell types, thus underlining the importance of investigating both necessary and sufficient functions to unequivocally unravel cell-type specific actions.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/farmacologia , Receptor CB1 de Canabinoide/agonistas , Receptores de GABA , Receptores de Glutamato , Analgesia/métodos , Animais , Agonistas de Receptores de Canabinoides/metabolismo , Catalepsia/induzido quimicamente , Catalepsia/metabolismo , Dronabinol/metabolismo , Agonistas de Aminoácidos Excitatórios/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Agonistas GABAérgicos/metabolismo , Agonistas GABAérgicos/farmacologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Camundongos , Camundongos Knockout , Receptor CB1 de Canabinoide/metabolismo , Receptores de GABA/metabolismo , Receptores de Glutamato/metabolismo
14.
Neuropsychopharmacol Rep ; 40(2): 190-195, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32351052

RESUMO

AIM: Phosphodiesterase 10A (PDE10A) inhibitors not only have antipsychotic-like effects but also cause cognitive enhancement without affecting extrapyramidal side effects in rodents, suggesting that PDE10A may be a novel approach for the treatment of schizophrenia. However, how a combination of PDE10A inhibitor with a currently available antipsychotic drug, risperidone contributes to the effect of each compound in rats remains unclear. The purpose of the present study was to examine the combination effects of MR1916 with a currently available antipsychotic drug, risperidone, in rats. METHODS: We examined the combination effects of the PDE10A inhibitor, MR1916 with risperidone on conditioned avoidance response (CAR) to assess antipsychotic-like effects in rats. We also examined them on catalepsy as extrapyramidal side effects and novel object recognition test in cognitive functions in rats. RESULTS: MR1916 (0.025-0.2 mg/kg, p.o.) and risperidone (0.75-6 mg/kg, p.o.) alone attenuated the CAR in a dose-dependent manner. The combination of MR1916 (0.025 mg/kg, p.o.) with risperidone (0.75 mg/kg, p.o.) significantly enhanced the attenuation of CAR without increasing the escape failure response. At the same dosage, the cataleptic effects were not enhanced by combined treatment of MR1916 with risperidone. Furthermore, the enhancement of object recognition memory induced by MR1916 (0.3 mg/kg, p.o.) was not affected by the combination with risperidone (0.75 mg/kg, p.o.). CONCLUSION: The combination of MR1916 with risperidone may have additive antipsychotic-like effects without affecting extrapyramidal side effects, and the cognitive-enhancing effect of MR1916 may not be interfered with the addition of risperidone.


Assuntos
Antipsicóticos/administração & dosagem , Nootrópicos/administração & dosagem , Compostos Orgânicos/administração & dosagem , Inibidores de Fosfodiesterase/administração & dosagem , Diester Fosfórico Hidrolases , Risperidona/administração & dosagem , Animais , Antipsicóticos/efeitos adversos , Catalepsia/induzido quimicamente , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Nootrópicos/efeitos adversos , Compostos Orgânicos/efeitos adversos , Inibidores de Fosfodiesterase/efeitos adversos , Diester Fosfórico Hidrolases/metabolismo , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Risperidona/efeitos adversos
15.
Int J Mol Sci ; 21(10)2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32408504

RESUMO

Dual target ligands are a promising concept for the treatment of Parkinson's disease (PD). A combination of monoamine oxidase B (MAO B) inhibition with histamine H3 receptor (H3R) antagonism could have positive effects on dopamine regulation. Thus, a series of twenty-seven 4-tert-butylphenoxyalkoxyamines were designed as potential dual-target ligands for PD based on the structure of 1-(3-(4-tert-butylphenoxy)propyl)piperidine (DL76). Probed modifications included the introduction of different cyclic amines and elongation of the alkyl chain. Synthesized compounds were investigated for human H3R (hH3R) affinity and human MAO B (hMAO B) inhibitory activity. Most compounds showed good hH3R affinities with Ki values below 400 nM, and some of them showed potent inhibitory activity for hMAO B with IC50 values below 50 nM. However, the most balanced activity against both biological targets showed DL76 (hH3R: Ki = 38 nM and hMAO B: IC50 = 48 nM). Thus, DL76 was chosen for further studies, revealing the nontoxic nature of DL76 in HEK293 and neuroblastoma SH-SY5Ycells. However, no neuroprotective effect was observed for DL76 in hydrogen peroxide-treated neuroblastoma SH-SY5Y cells. Furthermore, in vivo studies showed antiparkinsonian activity of DL76 in haloperidol-induced catalepsy (Cross Leg Position Test) at a dose of 50 mg/kg body weight.


Assuntos
Aminas/farmacologia , Antagonistas dos Receptores Histamínicos H3/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Aminas/química , Animais , Catalepsia/induzido quimicamente , Catalepsia/fisiopatologia , Catalepsia/prevenção & controle , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Células HEK293 , Haloperidol , Antagonistas dos Receptores Histamínicos H3/química , Humanos , Cinética , Ligantes , Masculino , Estrutura Molecular , Inibidores da Monoaminoxidase/química , Doença de Parkinson/fisiopatologia , Doença de Parkinson/prevenção & controle , Ratos Wistar , Relação Estrutura-Atividade
16.
Brain Res Bull ; 159: 79-86, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32224159

RESUMO

Aging represents the largest risk factor for developing Parkinson's disease (PD); another salient feature of this disorder is a decreased brain levels of somatostatin. Recently, in aged Wistar rats, we simulated the central somatostatinergic deficiency by intracerebroventricular injections of a somatostatin antagonist, cyclosomatostatin (cSST). The treated animals displayed catalepsy, a state that resembles the extrapyramidal signs of Parkinson's disease; young animals were insensitive to cSST. The neuroanatomical substrates responsible for the increased cataleptogenic activity of cSST in aged animals, are currently unknown. To study this issue, we assessed the cSST effect on brain c-Fos-protein expression in aged and young rats; thirty three brain regions were examined. cSST was employed at the dose cataleptogenic for aged animals and non-cataleptogenic for young ones. c-Fos expression patterns in the 'cataleptic' and 'non-cataleptic' animals were very similar, with the only distinction being a decrease in the c-Fos expression in the aged lateral entorhinal cortex (LEntCx). This decrease was not observed when the cSST-induced cataleptic response was inhibited by administration of diphenhydramine and nicotine. Thus, the development of catalepsy in the aged Wistar rats appeared to be associated with a hypoactivation of the LEntCx; possibly, there exists a mechanistic link between the LEntCx hypoactivation and increased susceptibility of aged rats to catalepsy. Apparently, these findings may provide novel insight into the link between mechanisms of parkinsonian motor disorders and aging.


Assuntos
Envelhecimento/metabolismo , Catalepsia/induzido quimicamente , Catalepsia/metabolismo , Córtex Entorrinal/metabolismo , Peptídeos Cíclicos/toxicidade , Proteínas Proto-Oncogênicas c-fos/biossíntese , Envelhecimento/efeitos dos fármacos , Animais , Córtex Entorrinal/efeitos dos fármacos , Expressão Gênica , Masculino , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Wistar
17.
eNeuro ; 7(3)2020.
Artigo em Inglês | MEDLINE | ID: mdl-32198157

RESUMO

Catalepsy bar tests are widely used to measure the failure to correct an imposed posture resulting from muscular rigidity. Procedures for measuring catalepsy vary greatly in the published literature, but one commonly used test measures the time it takes for a rodent to remove one or both of its forelimbs from a bar. The following paper describes an affordable, adjustable, open-source bar test that automatically measures and logs the time it takes for a rat to remove itself from a bar. While commercially available automated bar tests are prohibitively expensive, requiring proprietary software and hardware to operate, the proposed apparatus runs on an Arduino-based microcontroller making it low-cost and customizable. This 3D-printed design costs less than 65 United States dollars to build and is simple to assemble and operate. The beam-break sensor design also eliminates many of the pitfalls of the "complete-the-circuit"-based approach to recording catalepsy. The paper further describes the successful validation of the design using adult male rats injected with different doses of haloperidol to demonstrate a dose-dependent cataleptic effect. This design provides a versatile, low-cost solution to standardizing and automating measurement of catalepsy in rodents.


Assuntos
Catalepsia , Haloperidol , Animais , Catalepsia/induzido quimicamente , Catalepsia/diagnóstico , Masculino , Postura , Ratos
18.
Yakugaku Zasshi ; 140(2): 193-204, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32009043

RESUMO

Cannabis contains over 700 known cannabinoids, terpenoids, flavonoids, and so on; however, the roles and importance of these components have yet to be fully understood. Δ9-Tetrahydrocannabinol (THC) is believed the most psychoactive component in cannabis, whereas cannabidiol (CBD), cannabinol, and cannabigerol are the most well-known non-psychoactive components. THC, but not CBD, has been shown to produce abnormal behavior in animals; these effects are caused, at least in part, by binding to cannabinoid receptor type 1 (CB1) in the brain. Regarding the risks associated with cannabis use, acute effects of THC, such as a "high", cognitive deficits, and irritability, are considered more important than potential dependence. On the other hand, CBD has shown anticonvulsant, anti-inflammatory, immunosuppressive, analgesic, and anticancer effects. However, CBD has very low affinity (in the micromolar range) for the CB1 receptor, as well as for the CB2 receptor, and its underlying mechanism remains obscure. In this review, we demonstrate that THC induces abnormal behavior such as catalepsy-like immobilization, spatial memory impairment, and high and low sensitivity to ultrasonic vocalization after an aversive air-puff stimulus. Moreover, we demonstrate that THC and CBD improve brain injury in middle cerebral artery occlusion in a mouse model through different mechanisms. These findings suggest the need to discuss the recent development of "THC and CBD pharmacology" in animal studies, as well as the utility and risk of various cannabis components in humans.


Assuntos
Cannabis/efeitos adversos , Animais , Lesões Encefálicas/tratamento farmacológico , Canabinoides/efeitos adversos , Canabinoides/uso terapêutico , Cannabis/química , Catalepsia/induzido quimicamente , Modelos Animais de Doenças , Humanos , Transtornos da Memória/induzido quimicamente , Camundongos , Risco , Memória Espacial/efeitos dos fármacos
19.
Pharmacol Biochem Behav ; 189: 172853, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31945381

RESUMO

Antipsychotic drugs (APDs) are essential for the treatment of schizophrenia and other neuropsychiatric illnesses such as bipolar disease. However, they are also extensively prescribed off-label for many other conditions, a practice that is controversial given their potential for long-term side effects. There is clinical and preclinical evidence that chronic treatment with some APDs may lead to impairments in cognition and decreases in brain volume, although the molecular mechanisms of these effects are unknown. The purpose of the rodent studies described here was to evaluate a commonly prescribed APD, risperidone, for chronic effects on recognition memory, brain-derived neurotrophic factor (BDNF), its precursor proBDNF, as well as relevant downstream signaling molecules that are known to influence neuronal plasticity and cognition. Multiple cohorts of adult rats were treated with risperidone (2.5 mg/kg/day) or vehicle (dilute acetic acid solution) in their drinking water for 30 or 90 days. Subjects were then evaluated for drug effects on recognition memory in a spontaneous novel object recognition task and protein levels of BDNF-related signaling molecules in the hippocampus and prefrontal cortex. The results indicated that depending on the treatment period, a therapeutically relevant daily dose of risperidone impaired recognition memory and increased the proBDNF/BDNF ratio in the hippocampus and prefrontal cortex. Risperidone treatment also led to a decrease in Akt and CREB phosphorylation in the prefrontal cortex. These results indicate that chronic treatment with a commonly prescribed APD, risperidone, has the potential to adversely affect recognition memory and neurotrophin-related signaling molecules that support synaptic plasticity and cognitive function.


Assuntos
Antipsicóticos/administração & dosagem , Antipsicóticos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Risperidona/administração & dosagem , Risperidona/farmacologia , Transdução de Sinais/efeitos dos fármacos , Administração Oral , Animais , Antipsicóticos/sangue , Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/diagnóstico , Cognição/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/metabolismo , Masculino , Fatores de Crescimento Neural/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Risperidona/sangue
20.
Pak J Pharm Sci ; 33(5): 1945-1953, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33824100

RESUMO

We determined anti-Parkinson's activity of M. chamomilla L. tea in chlorpromazine (CPZ) developed investigational animal model. In this research, effects of M. chamomilla L. tea 2.14ml/ kg P.O were studied on cataleptic behavior and its effect on brain histopathological changes and immunohistochemistry (IHC) in rats. The experimental design was developed by administering CPZ (3mg/kg, I/P) for twenty-one days to produce Parkinson's disease-like symptoms to 4 animal groups. We observed that chlorpromazine significantly produced motor dysfunctions (catalepsy) in a time period of twenty-one days. The M. chamomilla L. significantly (P<0.005) minimized/shorten/taper down catalepsy in rats just like standard group (Levodopa/carbidopa treated group). The maximum reduction was observed from both treated and standard groups on the 21st day. M. chamomilla L. treated rats mid brain sections showed presence of proliferative blood vessels, increase cellularity with reactive glial cells as compared to CPZ group. Furthermore, immunostaining CD68 & CD21 of M. chamomilla L. treated rats mid brain region showed few CD68 cells & no polymorphs neutrophils after CD21 staining. Thus, this research work disclosed the neuroprotective effect of M. chamomilla L. tea against Parkinson's disease-like symptoms or anti-Parkinson's activity induced by CPZ.


Assuntos
Antiparkinsonianos/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Catalepsia/prevenção & controle , Matricaria , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transtornos Parkinsonianos/prevenção & controle , Extratos Vegetais/farmacologia , Animais , Antiparkinsonianos/isolamento & purificação , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Catalepsia/induzido quimicamente , Catalepsia/patologia , Catalepsia/fisiopatologia , Clorpromazina , Modelos Animais de Doenças , Masculino , Matricaria/química , Fármacos Neuroprotetores/isolamento & purificação , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/fisiopatologia , Extratos Vegetais/isolamento & purificação , Ratos Wistar
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