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1.
Eur J Pharmacol ; 967: 176385, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38311276

RESUMO

Fibromyalgia is a painful disorder of unknown aetiology that presents activation and recruitment of innate immune cells, including mast cells. Efforts have been made to understand its pathogenesis to manage it better. Thus, we explored the involvement of peripheral mast cells in an experimental model of fibromyalgia induced by reserpine. Reserpine (1 mg/kg) was subcutaneously (s.c.) injected once daily in the back of male Swiss mice for three consecutive days. We analysed mechanical and cold allodynia, muscle fatigue and number of mast cell in plantar tissue. The fibromyalgia induction produced mast cell infiltration (i.e., mastocytosis) in the mice's plantar tissue. The depletion of mast cell mediators with the compound 48/80 (0.5-4 mg/kg, intraperitoneal (i.p.)) or the mast cell membrane stabilizer ketotifen fumarate (10 mg/kg, oral route (p.o.) widely (80-90 %) and extensively (from 1 up to 10 days) prevented reserpine-induced mechanical and cold allodynia and muscle fatigue. Compound 48/80 also prevented the reserpine-induced mastocytosis. Finally, we demonstrated that PAR-2, 5-HT2A, 5-HT3, H1, NK1 and MrgprB2 receptors, expressed in neuronal or mast cells, seem crucial to mediate fibromyalgia-related cardinal symptoms since antagonists or inhibitors of these receptors (gabexate (10 mg/kg, s.c.), ENMD-1068 (10 mg/kg, i.p.), ketanserin (1 mg/kg, i.p.), ondansetron (1 mg/kg, p.o.), promethazine (1 mg/kg, i.p.), and L733,060 (5 mg/kg, s.c.), respectively) transiently reversed the reserpine-induced allodynia and fatigue. The results indicate that mast cells mediate painful and fatigue behaviours in this fibromyalgia model, representing potential therapy targets to treat fibromyalgia syndrome.


Assuntos
Fibromialgia , Mastocitose , Camundongos , Masculino , Animais , Fibromialgia/metabolismo , Mastócitos/metabolismo , Hiperalgesia/metabolismo , Serotonina/metabolismo , Reserpina/efeitos adversos , Mastocitose/metabolismo , Mastocitose/patologia
2.
Brain Behav ; 14(1): e3386, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38376034

RESUMO

INTRODUCTION: Nociplastic pain involves reflexive and nonreflexive pain responses and it is a core symptom of fibromyalgia (FM). The increasing prevalence of this health condition and the low rates of patients' quality of life, combined with the lack of suitable pharmacologic treatments, evidence the demand to research new alternatives. Polyphenols may be potential therapeutic candidates as they have been reported to exert pathological pain modulation in preclinical models. In that context, this work was aimed to study the antinociceptive effects of a polyphenolic extract obtained from decaffeinated ground roasted coffee, in the RIM6 FM-like mouse model. METHODS: To this end, RIM6 adult ICR-CD1 female mice were administered daily once a week with either 10 or 15 mg/kg of extract, and reflexive pain responses were evaluated for up to 3 weeks. At the end, the depressive-like behavior was assessed as a nonreflexive pain response, and spinal cord and serum samples were collected for immunohistochemical and toxicological analyses. RESULTS: These findings showed that the repeated administration of the coffee polyphenolic extract (CE) modulated reflexive pain responses, depressive-like behavior, and spinal cord gliosis in a dose-dependent manner, without signs of systemic toxicity. CONCLUSION: Thus, the CE may be a potential pharmacological treatment suitable to relieve nociplastic pain responses characteristic of FM.


Assuntos
Dor Crônica , Fibromialgia , Humanos , Feminino , Camundongos , Animais , Fibromialgia/tratamento farmacológico , Fibromialgia/induzido quimicamente , Reserpina/efeitos adversos , Hiperalgesia/tratamento farmacológico , Qualidade de Vida , Camundongos Endogâmicos ICR
3.
Viruses ; 16(1)2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38257782

RESUMO

Coagulation disorders are described in COVID-19 and long COVID patients. In particular, SARS-CoV-2 infection in megakaryocytes, which are precursors of platelets involved in thrombotic events in COVID-19, long COVID and, in rare cases, in vaccinated individuals, requires further investigation, particularly with the emergence of new SARS-CoV-2 variants. CD147, involved in the regulation of inflammation and required to fight virus infection, can facilitate SARS-CoV-2 entry into megakaryocytes. MCT4, a co-binding protein of CD147 and a key player in the glycolytic metabolism, could also play a role in SARS-CoV-2 infection. Here, we investigated the susceptibility of megakaryocytes to SARS-CoV-2 infection via CD147 and MCT4. We performed infection of Dami cells and human CD34+ hematopoietic progenitor cells induced to megakaryocytic differentiation with SARS-CoV-2 pseudovirus in the presence of AC-73 and syrosingopine, respective inhibitors of CD147 and MCT4 and inducers of autophagy, a process essential in megakaryocyte differentiation. Both AC-73 and syrosingopine enhance autophagy during differentiation but only AC-73 enhances megakaryocytic maturation. Importantly, we found that AC-73 or syrosingopine significantly inhibits SARS-CoV-2 infection of megakaryocytes. Altogether, our data indicate AC-73 and syrosingopine as inhibitors of SARS-CoV-2 infection via CD147 and MCT4 that can be used to prevent SARS-CoV-2 binding and entry into megakaryocytes, which are precursors of platelets involved in COVID-19-associated coagulopathy.


Assuntos
Megacariócitos , Fenóis , Reserpina , SARS-CoV-2 , Humanos , COVID-19 , Megacariócitos/virologia , Fenóis/farmacologia , Síndrome Pós-COVID-19 Aguda , Reserpina/análogos & derivados , Reserpina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Internalização do Vírus/efeitos dos fármacos
4.
J Biochem Mol Toxicol ; 38(1): e23627, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38229316

RESUMO

The given investigation examined the neuroprotection role of 5-HT1b/1d agonist in reserpine induced Parkinson's disease (PD) in male Wistar rats. PD was induced in rats by reserpine at 5 mg/kg ip for 3 days and thereafter the rats were provided with the following treatments for 4 days, zolmitriptan (ZLM) group (30 mg/kg ip); STD group (levodopa + carbidopa, 200 + 5 mg/kg ip); ZLM + GA group (zolmitriptan, 30 mg/kg ip and glutamic acid, 1.5 mg/kg); ZLM + DX group (zolmitriptan, 30 mg/kg ip and dextromethorphan, 20 mg/kg ip). All the groups were then assessed for cognitive and motor functions at the end of the protocol. Moreover, oxidative stress parameters and histopathological changes were observed in rats of all treatment groups. Deposition of α-synuclein in the brain tissue was observed by silver staining. Data of this investigation revealed that motor and cognitive functions were improved in the ZLM-treated group compared with the negative control group, which was observed to be reversed in ZLM + GA group. Treatment with ZLM ameliorated oxidative stress and histopathological changes in the brain tissue of PD rats. Further, ZLM reduced the deposition of α-synuclein in PD rats, which reversed in ZLM + GA-treated group. This study concludes by stating that 5-HT1b/1d agonist can prevent neurodegeneration and reduce oxidative stress in PD rats. The probable underlying mechanism of such an effect of 5-HT1b/1d agonist could be by regulating the deposition of α-synuclein and reducing the expression of NMDA receptor.


Assuntos
Oxazolidinonas , Doença de Parkinson , Agonistas do Receptor 5-HT1 de Serotonina , Triptaminas , Masculino , Ratos , Animais , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Doença de Parkinson/tratamento farmacológico , alfa-Sinucleína , Ácido Glutâmico , Reserpina , Ratos Wistar
5.
Cell Res ; 34(1): 47-57, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38163846

RESUMO

Monoamine neurotransmitters such as serotonin and dopamine are loaded by vesicular monoamine transporter 2 (VMAT2) into synaptic vesicles for storage and subsequent release in neurons. Impaired VMAT2 function underlies various neuropsychiatric diseases. VMAT2 inhibitors reserpine and tetrabenazine are used to treat hypertension, movement disorders associated with Huntington's Disease and Tardive Dyskinesia. Despite its physiological and pharmacological significance, the structural basis underlying VMAT2 substrate recognition and its inhibition by various inhibitors remains unknown. Here we present cryo-EM structures of human apo VMAT2 in addition to states bound to serotonin, tetrabenazine, and reserpine. These structures collectively capture three states, namely the lumen-facing, occluded, and cytosol-facing conformations. Notably, tetrabenazine induces a substantial rearrangement of TM2 and TM7, extending beyond the typical rocker-switch movement. These functionally dynamic snapshots, complemented by biochemical analysis, unveil the essential components responsible for ligand recognition, elucidate the proton-driven exchange cycle, and provide a framework to design improved pharmaceutics targeting VMAT2.


Assuntos
Tetrabenazina , Proteínas Vesiculares de Transporte de Monoamina , Humanos , Reserpina , Serotonina/metabolismo , Vesículas Sinápticas/metabolismo , Tetrabenazina/farmacologia , Tetrabenazina/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
6.
Neurogastroenterol Motil ; 36(2): e14716, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38031349

RESUMO

BACKGROUND: Colonic motility is regulated by various factors along the gut-brain axis; however, detailed mechanisms are unknown. This study aimed to examine the involvement of the autonomic nervous system in colonic motility. Suncus murinus (suncus) is a small laboratory mammal suitable for gastrointestinal motility studies. METHODS: Colonic motility and concomitant feeding and defecation behaviors in vagotomized and reserpine-administered suncus were recorded simultaneously for 24 h. Furthermore, we performed immunohistochemistry on tyrosine hydroxylase (TH) and in situ hybridization on corticotropin-releasing hormone (CRH) in suncus brain. Additionally, we examined c-Fos expression in the brain using immunohistochemistry in conscious suncus with colorectal distension. KEY RESULTS: In vagotomized suncus, clustered giant migrating contractions (GMCs), consisting of strong contractions occurring in a short time, were observed, and the percentage of GMCs without defecation increased. The frequency of GMCs in the reserpine-administered suncus increased during a light period (ZT0-4, 4-8) and decreased during a dark period (ZT16-20, 20-24) compared to a vehicle group. Additionally, the percentage of GMCs without defecation in the reserpine-administered suncus increased. Suncus TH-immunopositive neurons were found in the locus coeruleus (LC), as shown in rodents. In contrast, CRH mRNA-expressing cells were not observed in a region assumed to be the Barrington's nucleus (Bar). Furthermore, colorectal distension in conscious suncus induced c-Fos expression in LC TH neurons. CONCLUSIONS & INFERENCES: Our results suggest that the vagus and sympathetic nerves are not required for induction of GMCs in vivo. However, they are likely to exert a modulatory role in control of GMC frequency in Suncus murinus.


Assuntos
Neoplasias Colorretais , Reserpina , Animais , Nervo Vago/fisiologia , Motilidade Gastrointestinal/fisiologia , Estado de Consciência , Hormônio Liberador da Corticotropina , Mamíferos
7.
Artigo em Inglês | MEDLINE | ID: mdl-37839537

RESUMO

Reserpine is a drug that is commonly used as an antihypertensive and antipsychotic drug in clinical practice. During our previous research, we found that reserpine treatment in zebrafish larvae can cause depression-like behaviors, but the corresponding mechanisms are still unclear. In this study, we aimed to investigate the molecular mechanism by which reserpine exposure affects locomotor behaviors in larval zebrafish through transcriptome analysis. The gene enrichment results showed that the differentially highly expressed genes of zebrafish are mainly enriched in voltage-gated ion channels, dopaminergic synapses and wnt signaling pathways. Selected genes (apc2, cacna1aa, drd2b, dvl1a, fzd1, wnt1, wnt3a, wnt9a and wnt10a) by transcriptomic results was validated by real-time PCR. Consistently, Wnt signaling pathway inhibitor XAV939 may induce reduced behavioral changes in zebrafish larvae, while the Wnt signaling pathway agonist SB415286 reversed the reserpine-induced depressive effects. Our study provides gene transcriptional profile data for future research on reserpine-induced locomotor behavioral changes.


Assuntos
Transcriptoma , Peixe-Zebra , Animais , Peixe-Zebra/metabolismo , Reserpina/farmacologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Perfilação da Expressão Gênica
8.
Nature ; 626(7998): 427-434, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38081299

RESUMO

Vesicular monoamine transporter 2 (VMAT2) accumulates monoamines in presynaptic vesicles for storage and exocytotic release, and has a vital role in monoaminergic neurotransmission1-3. Dysfunction of monoaminergic systems causes many neurological and psychiatric disorders, including Parkinson's disease, hyperkinetic movement disorders and depression4-6. Suppressing VMAT2 with reserpine and tetrabenazine alleviates symptoms of hypertension and Huntington's disease7,8, respectively. Here we describe cryo-electron microscopy structures of human VMAT2 complexed with serotonin and three clinical drugs at 3.5-2.8 Å, demonstrating the structural basis for transport and inhibition. Reserpine and ketanserin occupy the substrate-binding pocket and lock VMAT2 in cytoplasm-facing and lumen-facing states, respectively, whereas tetrabenazine binds in a VMAT2-specific pocket and traps VMAT2 in an occluded state. The structures in three distinct states also reveal the structural basis of the VMAT2 transport cycle. Our study establishes a structural foundation for the mechanistic understanding of substrate recognition, transport, drug inhibition and pharmacology of VMAT2 while shedding light on the rational design of potential therapeutic agents.


Assuntos
Microscopia Crioeletrônica , Proteínas Vesiculares de Transporte de Monoamina , Humanos , Sítios de Ligação , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Ketanserina/química , Ketanserina/metabolismo , Ketanserina/farmacologia , Reserpina/química , Reserpina/metabolismo , Reserpina/farmacologia , Serotonina/química , Serotonina/metabolismo , Especificidade por Substrato , Tetrabenazina/química , Tetrabenazina/metabolismo , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Monoamina/química , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/ultraestrutura
9.
Brain Res ; 1825: 148723, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38101693

RESUMO

Neuroplasticity and inflammation represent a common final pathway for effective antidepressant treatment. SSRIs are the most commonly prescribed medications for depression and have demonstrated efficacy in reducing depressive symptoms. However, the precise impact of SSRIs on neuroplasticity and inflammation remains unclear. In this study, we aimed to investigate the influence of long-term treatment with SSRIs on hippocampal neuron, inflammation, synaptic function and morphology. Our findings revealed that fluoxetine treatment significantly alleviated behavioral despair, anhedonia, and anxiety in reserpine-treated mice. Moreover, fluoxetine mitigated hippocampal neuron impairment, inhibited inflammatory release, and increased the expression of synaptic proteins markers (SYP and PSD95) in mice. Notably, fluoxetine also suppressed reserpine-induced synapse loss in the hippocampus. Based on these results, fluoxetine has been demonstrated effectively to ameliorate depressive mood and cognitive dysfunction, possibly through the enhancement of synaptic plasticity. Overall, our study contributes to a further understanding of the mechanisms underlying the therapeutic effects of fluoxetine and its potential role in improving depressive symptoms and cognitive impairments.


Assuntos
Fluoxetina , Inibidores Seletivos de Recaptação de Serotonina , Camundongos , Animais , Fluoxetina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Reserpina/metabolismo , Reserpina/farmacologia , Depressão/tratamento farmacológico , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Plasticidade Neuronal , Hipocampo/metabolismo
10.
Nature ; 623(7989): 1086-1092, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37914936

RESUMO

Monoamine neurotransmitters such as dopamine and serotonin control important brain pathways, including movement, sleep, reward and mood1. Dysfunction of monoaminergic circuits has been implicated in various neurodegenerative and neuropsychiatric disorders2. Vesicular monoamine transporters (VMATs) pack monoamines into vesicles for synaptic release and are essential to neurotransmission3-5. VMATs are also therapeutic drug targets for a number of different conditions6-9. Despite the importance of these transporters, the mechanisms of substrate transport and drug inhibition of VMATs have remained elusive. Here we report cryo-electron microscopy structures of the human vesicular monoamine transporter VMAT2 in complex with the antichorea drug tetrabenazine, the antihypertensive drug reserpine or the substrate serotonin. Remarkably, the two drugs use completely distinct inhibition mechanisms. Tetrabenazine binds VMAT2 in a lumen-facing conformation, locking the luminal gating lid in an occluded state to arrest the transport cycle. By contrast, reserpine binds in a cytoplasm-facing conformation, expanding the vestibule and blocking substrate access. Structural analyses of VMAT2 also reveal the conformational changes following transporter isomerization that drive substrate transport into the vesicle. These findings provide a structural framework for understanding the physiology and pharmacology of neurotransmitter packaging by synaptic vesicular transporters.


Assuntos
Neurotransmissores , Reserpina , Serotonina , Tetrabenazina , Proteínas Vesiculares de Transporte de Monoamina , Humanos , Inibidores da Captação Adrenérgica/química , Inibidores da Captação Adrenérgica/farmacologia , Transporte Biológico/efeitos dos fármacos , Microscopia Crioeletrônica , Neurotransmissores/química , Neurotransmissores/farmacologia , Reserpina/química , Reserpina/farmacologia , Serotonina/metabolismo , Transmissão Sináptica , Tetrabenazina/química , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Monoamina/química , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Proteínas Vesiculares de Transporte de Monoamina/ultraestrutura , Especificidade por Substrato/efeitos dos fármacos
11.
Cells ; 12(21)2023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37947607

RESUMO

The pathophysiology of tremor in Parkinson's disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. To this end, we studied the development of tremor in a reserpinized rat model of PD, with or without a selective lesioning of LC-NA innervation with the neurotoxin DSP-4. Eight male rats (Sprague Dawley) received DSP-4 (50 mg/kg) two weeks prior to reserpine injection (10 mg/kg) (DR-group), while seven male animals received only reserpine treatment (R-group). Tremor, rigidity, hypokinesia, postural flexion and postural immobility were scored before and after 20, 40, 60, 80, 120 and 180 min of reserpine injection. Tremor was assessed visually and with accelerometers. The injection of DSP-4 induced a severe reduction in LC-NA terminal axons (DR-group: 0.024 ± 0.01 vs. R-group: 0.27 ± 0.04 axons/um2, p < 0.001) and was associated with significantly less tremor, as compared to the R-group (peak tremor score, DR-group: 0.5 ± 0.8 vs. R-group: 1.6 ± 0.5; p < 0.01). Kinematic measurement confirmed the clinical data (tremor consistency (% of tremor during 180 s recording), DR-group: 37.9 ± 35.8 vs. R-group: 69.3 ± 29.6; p < 0.05). Akinetic-rigid symptoms did not differ between the DR- and R-groups. Our results provide preliminary causal evidence for a critical role of LC-NA innervation in the development of PD tremor and foster the development of targeted therapies for PD patients.


Assuntos
Doença de Parkinson , Tremor , Humanos , Masculino , Animais , Ratos , Ratos Sprague-Dawley , Tremor/induzido quimicamente , Reserpina/farmacologia , Encéfalo , Norepinefrina
12.
Photochem Photobiol Sci ; 22(12): 2891-2904, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37917308

RESUMO

Photobiomodulation (PBM) of deep brain structures through transcranial infrared irradiation might be an effective treatment for Parkinson's disease (PD). However, the mechanisms underlying this intervention should be elucidated to optimize the therapeutic outcome and maximize therapeutic efficacy. The present study aimed at investigating the oxidative stress-related parameters of malondialdehyde (MDA), nitric oxide (NO), and reduced glutathione (GSH) and the enzymatic activities of sodium-potassium-ATPase (Na+, K+-ATPase), Acetylcholinesterase (AChE), and monoamine oxidase (MAO) and monoamine levels (dopamine (DA), norepinephrine (NE) and serotonin (5-HT) in the midbrain and striatum of reserpine-induced PD in an animal model treated with PBM. Furthermore, the locomotor behavior of the animals has been determined by the open field test. Animals were divided into three groups; the control group, the PD-induced model group, and the PD-induced model treated with the PBM group. Non-invasive treatment of animals for 14 days with 100 mW, 830 nm laser has demonstrated successful attainment in the recovery of oxidative stress, and enzymatic activities impairments induced by reserpine (0.2 mg/kg) in both midbrain and striatum of adult male Wistar rats. PBM also improved the decrease in DA, NE, and 5-HT in the investigated brain regions. On a behavioral level, animals showed improvement in their locomotion activity. These findings have shed more light on some mechanisms underlying the treatment potential of PBM and displayed the safety, easiness, and efficacy of PBM treatment as an alternative to pharmacological treatment for PD.


Assuntos
Terapia com Luz de Baixa Intensidade , Transtornos Parkinsonianos , Ratos , Masculino , Animais , Reserpina/farmacologia , Ratos Wistar , Serotonina , Acetilcolinesterase , Mesencéfalo , Dopamina , Adenosina Trifosfatases , Modelos Animais de Doenças
13.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 45(4): 533-540, 2023 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-37654133

RESUMO

Objective To determine the optimal dosage and intervention duration of reserpine to establish a rat model of hypotension.Methods According to the body weight and systolic blood pressure (SBP),60 male Wistar rats were assigned to six groups (n=10),including a control group and five observation groups with different doses.The control group was administrated with 10 ml/kg 0.5% sodium carboxymethyl cellulose solution,and the observation groups with 0.016,0.032,0.064,0.128,and 0.160 mg/kg reserpine suspensions,respectively.All the groups were administrated by gavage twice a day,and the body weights of rats were monitored daily.SBP and heart rate (HR) were measured before modeling and 1-6 weeks after administration.After 6 weeks of administration,the blood samples of inner canthus were collected.The levels of lactate dehydrogenase (LDH),creatine kinase MB isoenzyme (CK-MB),alanine aminotransferase,aspartate aminotransferase (AST),serum creatinine,and blood urea nitrogen (BUN) were measured by an autoanalyzer.Three rats in each group were randomly selected for observation of the changes in SBP after drug withdrawal and the rest rats were sacrificed for measurement of the levels of norepinephrine and dopamine in the brain.Results Compared with the control group,different doses of reserpine lowered the SBP of rats (F=28.492,P<0.001).The decline in SBP increased in a concentration-dependent manner.SBP reached the lowest value after 1 week,rose slightly later,and was stable after 3 weeks of administration.There was no significant difference in SBP between 0.016 mg/kg reserpine group and the control group after the 5th week (P>0.05).The SBP levels of rats in 0.032,0.064,0.128,and 0.160 mg/kg reserpine groups showed no significant difference between each other (P=0.204) and were lower than that in the control group (all P<0.001).One week after drug withdrawal,the SBP of rats in the observation groups rose to the baseline level and remained stable.HR showed similar changes among groups,first increasing and then decreasing.There was no significant difference in HR among different groups at the same time point (F=0.922,P=0.475).Compared with the control group,reserpine of different doses reduced the norepinephrine content in the hippocampus (all P<0.001),and 0.128 mg/kg (P=0.045) and 0.160 mg/kg (P=0.042) reserpine lowered the dopamine level in the striatum,which showed no significant differences between different reserpine groups(P=0.343,P=0.301).The levels of LDH,CK-MB,and BUN in the serum increased with the increase in reserpine concentration,and the levels of LDH (P=0.001),CK-MB (P=0.020),AST (P=0.007),and BUN (P=0.001) in the 0.160 mg/kg reserpine group were significantly different from those in the control group.Conclusions The rat model of hypotension can be induced by gavage with reserpine.The gavage with reserpine at a dose of 0.032 mg/kg,twice a day for three consecutive weeks is the optimal scheme for the modeling.After the model establishment,continuous administration is essential to maintain the hypotension.


Assuntos
Hipotensão , Reserpina , Masculino , Ratos , Animais , Dopamina , Ratos Wistar , Hipotensão/induzido quimicamente , Norepinefrina
14.
Neurogastroenterol Motil ; 35(12): e14675, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37743702

RESUMO

BACKGROUND: Zebrafish larvae are translucent, allowing in vivo analysis of gut development and physiology, including gut motility. While recent progress has been made in measuring gut motility in larvae, challenges remain which can influence results, such as how data are interpreted, opportunities for technical user error, and inconsistencies in methods. METHODS: To overcome these challenges, we noninvasively introduced Nile Red fluorescent dye to fill the intraluminal gut space in zebrafish larvae and collected serial confocal microscopic images of gut fluorescence. We automated the detection of fluorescent-contrasted contraction events against the median-subtracted signal and compared it to manually annotated gut contraction events across anatomically defined gut regions. Supervised machine learning (multiple logistic regression) was then used to discriminate between true contraction events and noise. To demonstrate, we analyzed motility in larvae under control and reserpine-treated conditions. We also used automated event detection analysis to compare unfed and fed larvae. KEY RESULTS: Automated analysis retained event features for proximal midgut-originating retrograde and anterograde contractions and anorectal-originating retrograde contractions. While manual annotation showed reserpine disrupted gut motility, machine learning only achieved equivalent contraction discrimination in controls and failed to accurately identify contractions after reserpine due to insufficient intraluminal fluorescence. Automated analysis also showed feeding had no effect on the frequency of anorectal-originating contractions. CONCLUSIONS & INFERENCES: Automated event detection analysis rapidly and accurately annotated contraction events, including the previously neglected phenomenon of anorectal contractions. However, challenges remain to discriminate contraction events based on intraluminal fluorescence under treatment conditions that disrupt functional motility.


Assuntos
Reserpina , Peixe-Zebra , Animais , Peixe-Zebra/fisiologia , Larva/fisiologia , Algoritmos , Aprendizado de Máquina Supervisionado
15.
Brain Res ; 1819: 148541, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37619854

RESUMO

Depression remains a significant public health concern, and current animal models of depression are limited in their ability to accurately mimic human depression. However, studying the new development of antidepressants requires the use of progressive animal models. In this study, the mice were exposed to a low dose of reserpine (0.5 mg/kg) once daily for 14 days, followed by a 14-day period to allow for the development of spontaneous depression. We have successfully established a repeated reserpine-induced depressive animal model, which was characterized by emotional symptoms (anhedonia), cognitive symptoms, and psychomotor agitation or retardation. Our study demonstrated that repeated treatment with low-dose reserpine increased immobility time in the TST and FST. It also decreased the sucrose consumption ratio and induced anxiety-like behaviors. These anxiety-like behaviors were evidenced by decreased time spent in the center zone, longer first latency to center zone, and fewer entries into the center zone in the open field test. These findings support the utility of the low-dose reserpine repeated injection animal model for studying the pathogenesis of depression and the development of novel antidepressant treatments. Additionally, this study provides valuable insights into the potential of low-dose reserpine as a tool for modeling chronic depression in animals. Furthermore, our findings suggest that prolonged low-dose reserpine treatment could result in chronic depression. These findings have significant implications for the use of reserpine as a therapeutic agent for various conditions and emphasize the importance of closely monitoring patients' mental health.


Assuntos
Depressão , Reserpina , Humanos , Camundongos , Animais , Modelos Animais de Doenças , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Hipocampo , Comportamento Animal
16.
J Psychopharmacol ; 37(11): 1132-1148, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37593958

RESUMO

BACKGROUND: Nicotine cessation leads to anxiety and depression. AIMS: The suitability of the zebrafish model of anhedonia using reserpine and fluoxetine was evaluated. Fluoxetine was also used to reduce nicotine withdrawal-induced anhedonic state. METHODS: Zebrafish were exposed to reserpine (40 mg/l) and then to fluoxetine (0.1 mg/l) for 1 week. Anhedonia was evaluated in the Novel Tank Diving and Compartment Preference tests. Another group was exposed to nicotine (1 mg/l/2 weeks) and then exposed to fluoxetine. Anxiety and anhedonia were evaluated 2-60 days after. Tyrosine hydroxylase (TH) immunoreactivity and microglial morphology (labelled by 4C4 monoclonal antibody) in the parvocellular pretectal nucleus (PPN), dorsal part, and of calcitonin gene-related peptide (CGRP) in the hypothalamus were also analysed. RESULTS: Less time in the top and increased latency to the top in reserpine compared to a drug-free group was found. Fluoxetine rescued reserpine-induced the reduced time in the top. Seven and 30 days after nicotine withdrawal more time in the bottom and similar time in the Compartment Preference test, rescued by fluoxetine, were shown. In the PPN, 30-day withdrawal induced an increase in TH immunoreactivity, but fluoxetine induced a further significant increase. No changes in PPN microglia morphology and hypothalamic CGRP were detected. CONCLUSIONS: Our findings validate the suitability of the zebrafish model of anhedonia using the reserpine-induced depression-like behaviour and the predictivity using fluoxetine. Fluoxetine rescued nicotine withdrawal-induced anhedonic state, opening the possibility to screen new drugs to alleviate anxiety and depression in smokers during abstinence.


Assuntos
Nicotina , Síndrome de Abstinência a Substâncias , Animais , Nicotina/farmacologia , Fluoxetina/farmacologia , Peixe-Zebra , Reserpina/farmacologia , Tirosina 3-Mono-Oxigenase , Anedonia , Peptídeo Relacionado com Gene de Calcitonina , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/psicologia
17.
Eur J Pharmacol ; 957: 175996, 2023 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-37597646

RESUMO

BACKGROUND: Frizzled 6 (Fzd6) is involved in the development of various disorders; however, its role in the etiology of depression remains unclear. We aimed to determine the potential regulatory mechanisms of Fzd6 as a Wnt receptor in depression. METHODS: Mice were divided into four groups: wild-type control (Fzd6WT-control), Fzd6 mutant control (Fzd6Q152E-control), wild-type reserpine (Fzd6WT-reserpine), and Fzd6 mutant reserpine (Fzd6Q152E-reserpine). Reserpine (0.5 mg/kg) was injected intraperitoneally for 10 days. Four behavioral experiments were performed to assess the effects of Fzd6Q152E on depression-like behaviors in the reserpine-treated mice. Blood samples were collected for an enzyme-linked immunosorbent assay (ELISA). Gene expression in the hippocampus was quantified using quantitative real-time polymerase chain reaction (qRT-PCR), and protein expression levels in the hippocampus were identified using western blotting. RESULTS: The Fzd6 mutation affected reserpine-induced depression-like behavioral changes in mice. ELISA revealed significantly reduced serum levels of 5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF), and norepinephrine in both Fzd6Q152E-reserpine and Fzd6WT-reserpine mice, with a more pronounced decrease in Fzd6Q152E-reserpine mice, especially in norepinephrine expression. The qRT-PCR results showed significantly decreased Fzd6 expression in Fzd6Q152E-reserpine mice and altered expression of Dkk2, Gsk-3ß, Lrp6, Wnt2, Wnt3, and Wnt3a in the Wnt pathway. Western blotting revealed decreased Fzd6 protein expression in Fzd6Q152E-control mice compared to Fzd6WT-control mice, whereas Fzd6 protein expression was restored in Fzd6Q152E-reserpine mice, and Gsk-3ß expression was significantly changed. CONCLUSION: Fzd6 potentially influences reserpine-induced depressive behavioral changes and serum depressive factor alterations and modulates the expression of the Wnt signaling pathway in the hippocampus of depressed mice.


Assuntos
Depressão , Via de Sinalização Wnt , Animais , Camundongos , Depressão/induzido quimicamente , Depressão/genética , Glicogênio Sintase Quinase 3 beta , Reserpina , Mutação , Norepinefrina , Serotonina
18.
Neuroscience ; 528: 37-53, 2023 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-37532013

RESUMO

Fibromyalgia (FM) is a syndrome characterized by chronic pain with depression as a frequent comorbidity. However, efficient management of the pain and depressive symptoms of FM is lacking. Given that endogenous oxytocin (OXT) contributes to the regulation of pain and depressive disorders, herein, we investigated the role of OXT in an experimental reserpine-induced FM model. In FM model, OXT-monomeric red fluorescent protein 1 (OXT-mRFP1) transgenic rats exhibited increased depressive behavior and sensitivity in a mechanical nociceptive test, suggesting reduced pain tolerance. Additionally, the development of the FM-like phenotype in OXT-mRFP1 FM model rats was accompanied by a significant reduction in OXT mRNA expression in the magnocellular neurons of the paraventricular nucleus. OXT-mRFP1 FM model rats also had significantly fewer tryptophan hydroxylase (TPH)- and tyrosine hydroxylase (TH)-immunoreactive (ir) neurons as well as reduced serotonin and norepinephrine levels in the dorsal raphe and locus coeruleus. To investigate the effects of stimulating the endogenous OXT pathway, rats expressing OXT-human muscarinic acetylcholine receptor (hM3Dq)-mCherry designer receptors exclusively activated by designer drugs (DREADDs) were also assessed in the FM model. Treatment of these rats with clozapine-N-oxide (CNO), an hM3Dq-activating drug, significantly improved characteristic FM model-induced pathophysiological pain, but did not alter depressive-like behavior. The chemogenetically induced effects were reversed by pre-treatment with an OXT receptor antagonist, confirming the specificity of action via the OXT pathway. These results indicate that endogenous OXT may have analgesic effects in FM, and could be a potential target for effective pain management strategies for this disorder.


Assuntos
Fibromialgia , Ocitocina , Ratos , Humanos , Animais , Ocitocina/farmacologia , Ocitocina/metabolismo , Reserpina/farmacologia , Reserpina/metabolismo , Fibromialgia/induzido quimicamente , Fibromialgia/metabolismo , Proteínas Luminescentes/genética , Dor/metabolismo , Ratos Transgênicos , Neurônios/metabolismo , Receptores de Ocitocina/metabolismo
19.
Biochim Biophys Acta Biomembr ; 1865(7): 184197, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37394027

RESUMO

Neurotransmitter release from sympathetic terminals is a key avenue for heart regulation. Herein, presynaptic exocytotic activity was monitored in mice atrial tissue using a false fluorescent neurotransmitter FFN511, a substrate for monoamine transporters. FFN511 labeling had similarity with tyrosine hydroxylase immunostaining. High [K+]o depolarization caused FFN511 release, which was augmented by reserpine, an inhibitor of neurotransmitter uptake. However, reserpine lost the ability to increase depolarization-induced FFN511 unloading after depletion of ready releasable pool with hyperosmotic sucrose. Cholesterol oxidase and sphingomyelinase modified atrial membranes, changing in opposite manner fluorescence of lipid ordering-sensitive probe. Plasmalemmal cholesterol oxidation increased FFN511 release upon K+-depolarization and more markedly potentiated FFN511 unloading in the presence of reserpine. Hydrolysis of plasmalemmal sphingomyelin profoundly enhanced the rate of FFN511 loss due to K+-depolarization, but completely prevented potentiating action of reserpine on FFN511 unloading. If cholesterol oxidase or sphingomyelinase got access to membranes of recycling synaptic vesicles, then the enzyme effects were suppressed. Hence, a fast neurotransmitter reuptake dependent on exocytosis of vesicles from ready releasable pool occurs during presynaptic activity. This reuptake can be enhanced or inhibited by plasmalemmal cholesterol oxidation or sphingomyelin hydrolysis, respectively. These modifications of plasmalemmal (but not vesicular) lipids increase the evoked neurotransmitter release.


Assuntos
Fibrilação Atrial , Reserpina , Camundongos , Animais , Reserpina/farmacologia , Esfingomielina Fosfodiesterase , Colesterol Oxidase/farmacologia , Esfingomielinas/farmacologia , Terminações Nervosas , Neurotransmissores/farmacologia , Colesterol/farmacologia
20.
Psychiatry Res Neuroimaging ; 334: 111682, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37506423

RESUMO

The aim of this study was to construct an animal model of depression that reproduces the human clinical manifestation, to evaluate the possible benefits of curcumin (CUR) in the treatment of depression and to compare its effect with the effect of a classic antidepressant, escitalopram (ESC). The behavior of depressive-like animals induced by administration of 1.5 mg/kg i. p. reserpine (R), during 10 days (n = 24) was evaluated via the open field test (OFT) and elevated plus maze (EPM) compared to control animals (n = 24) treated with carboxymethylcellulose (CMC) used as a vehicle. On the 11th day, each group was divided into 3 subgroups (n = 8): control (CMC), CMC+CUR, CMC+ESC for group without depression and CMC+R, CMC+R+CUR, CMC+R+ESC for group with depression. CUR (150 mg/kg i.p.) and ESC (20 mg/kg i.p.) were intraperitoneally administrated for 21 days. The improvement in depressive behaviour was assessed by OFT, EPM and biochemical analysis on the 32nd day. The results demonstrated that R induced hypomotility and increased oxidative stress in the brain, but also in the serum of rats. CUR had an antioxidant effect in the brain without significant effect on depressive-like behaviour while ESC improved the hypomotility of the depressive rats.


Assuntos
Curcumina , Ratos , Humanos , Animais , Curcumina/farmacologia , Curcumina/uso terapêutico , Depressão/induzido quimicamente , Depressão/tratamento farmacológico , Reserpina/farmacologia , Encéfalo , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico
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