Publications by authors named "Elaine Del Bel"

103 Publications

Cannabidiol prevents disruptions in sensorimotor gating induced by psychotomimetic drugs that last for 24-h with probable involvement of epigenetic changes in the ventral striatum.

Prog Neuropsychopharmacol Biol Psychiatry 2021 May 17;111:110352. Epub 2021 May 17.

Department of Morphology, Physiology, and Basic Pathology, School of Dentistry of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. Electronic address:

Cannabidiol (CBD), a major non-psychotomimetic component of the Cannabis sativa plant, shows therapeutic potential in several psychiatric disorders, including schizophrenia. The molecular mechanisms underlying the antipsychotic-like effects of CBD are not fully understood. Schizophrenia and antipsychotic treatment can modulate DNA methylation in the blood and brain, resulting in altered expression of diverse genes associated with this complex disorder. However, to date, the possible involvement of DNA methylation in the antipsychotic-like effects of CBD has not been investigated. Therefore, this study aimed at evaluating in mice submitted to the prepulse inhibition (PPI) model: i) the effects of a single injection of CBD or clozapine followed by AMPH or MK-801 on PPI and global DNA methylation changes in the ventral striatum and prefrontal cortex (PFC); and ii). if the acute antipsychotic-like effects of CBD would last for 24-h. AMPH (5 mg/kg) and MK-801 (0.5 mg/kg) impaired PPI. CBD (30 and 60 mg/kg), similar to clozapine (5 mg/kg), attenuated AMPH- and MK801-induced PPI disruption. AMPH, but not MK-801, increased global DNA methylation in the ventral striatum, an effect prevented by CBD. CBD and clozapine increased, by themselves, DNA methylation in the prefrontal cortex. The acute effects of CBD (30 or 60 mg/kg) on the PPI impairment induced by AMPH or MK-801 was also detectable 24 h later. Altogether, the results show that CBD induces acute antipsychotic-like effects that last for 24-h. It also modulates DNA methylation in the ventral striatum, suggesting a new potential mechanism for its antipsychotic-like effects.
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http://dx.doi.org/10.1016/j.pnpbp.2021.110352DOI Listing
May 2021

Doxycycline Interferes With Tau Aggregation and Reduces Its Neuronal Toxicity.

Front Aging Neurosci 2021 22;13:635760. Epub 2021 Mar 22.

Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (UNT-CONICET-SIPROSA), Tucumán, Argentina.

Tauopathies are neurodegenerative disorders with increasing incidence and still without cure. The extensive time required for development and approval of novel therapeutics highlights the need for testing and repurposing known safe molecules. Since doxycycline impacts α-synuclein aggregation and toxicity, herein we tested its effect on tau. We found that doxycycline reduces amyloid aggregation of the 2N4R and K18 isoforms of tau protein in a dose-dependent manner. Furthermore, in a cell free system doxycycline also prevents tau seeding and in cell culture reduces toxicity of tau aggregates. Overall, our results expand the spectrum of action of doxycycline against aggregation-prone proteins, opening novel perspectives for its repurposing as a disease-modifying drug for tauopathies.
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http://dx.doi.org/10.3389/fnagi.2021.635760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020845PMC
March 2021

The antibiotic doxycycline mimics the NGF signaling in PC12 cells: A relevant mechanism for neuroprotection.

Chem Biol Interact 2021 May 30;341:109454. Epub 2021 Mar 30.

Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto - USP, Av Do Café S/n, 14040-903, Ribeirão Preto, SP, Brazil. Electronic address:

Doxycycline has been used as antibiotic since the 1960s. Recently, studies have shown that doxycycline is neuroprotective in models of neurodegenerative diseases and brain injuries, mainly due to anti-inflammatory and anti-apoptotic effects. However, it is not known if doxycycline has neurotrophic potential, which is relevant, considering the role of axonal degeneration at the early stages of neurodegeneration in Alzheimer's disease, Amyotrophic Lateral Sclerosis and Parkinson's disease as well as in normal aging. Axons are preceded by the formation of neurites, the hallmark of the neuronal differentiation induced by neurotrophins like NGF. Therefore, the modulation of neurotrophin receptors aimed at formation and regeneration of axons has been proposed as a strategy to delay the progression of neurodegeneration and has gained relevance as new techniques for early diagnosis arise. Based on these premises, we investigated the potential of doxycycline to mimic the effects of Nerve Growth Factor (NGF) with focus on the signaling pathways and neuronal modulators of neurite initiation, growth and branching. We used PC12 cells, a neuronal model widely employed to study the neurotrophic pathways and mechanisms induced by NGF. Results showed that doxycycline induced neurite outgrowth via activation of the trkA receptor and the downstream signaling pathways, PI3K/Akt and MAPK/ERK, without inducing the expression of NGF. Doxycycline also increased the expression of GAP-43, synapsin I and NF200, proteins involved in axonal and synaptic plasticity. Altogether, these data demonstrate, for the first time, the neurotrophic potential of doxycycline, which might be useful to restore the neuronal connectivity lost at the initial phase of neurodegeneration.
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http://dx.doi.org/10.1016/j.cbi.2021.109454DOI Listing
May 2021

Doxycycline and its derivative, COL-3, decrease dyskinesia induced by l-DOPA in hemiparkinsonian rats.

Br J Pharmacol 2021 Jul 21;178(13):2595-2616. Epub 2021 Apr 21.

Dental School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.

Background And Purpose: l-DOPA-induced dyskinesia is a debilitating effect of treating Parkinson's disease with this drug. New therapeutic approaches that prevent or attenuate this side effect are needed.

Experimental Approach: Wistar adult male rats submitted to 6-hydroxydopamine-induced unilateral medial forebrain bundle lesion were treated with l-DOPA (p.o. 20 mg·kg or s.c. 10 mg·kg ) once a day for 14 days. After this period, we tested if doxycycline (40 mg·kg , i.p.) and COL-3 (50 and 100 nmol, i.c.v.) could reverse l-DOPA-induced dyskinesia. In an additional experiment, doxycycline was administered together with l-DOPA to verify if it would prevent l-DOPA-induced dyskinesia development.

Key Results: A single injection of doxycycline or COL-3 attenuated l-DOPA-induced dyskinesia. Co-treatment with doxycycline from the first day of l-DOPA suppressed the onset of dyskinesia. The improved motor response after l-DOPA was not affected by doxycycline or COL-3. Doxycycline treatment was associated with decreased immunoreactivity of FosB, COX-2, the astroglial protein GFAP and the microglial protein OX-42, which were elevated in the basal ganglia of rats exhibiting dyskinesia. Doxycycline decreased metalloproteinase-2/-9 activity, metalloproteinase-3 expression and ROS production. Metalloproteinase-2/-9 activity and production of ROS in the basal ganglia of dyskinetic rats showed a significant correlation with the intensity of dyskinesia.

Conclusion And Implications: The present study demonstrates the anti-dyskinetic potential of doxycycline and its analogue compound COL-3 in hemiparkinsonian rats. Given the long-established and safe clinical use of doxycycline, this study suggests that these drugs might be tested to reduce or prevent l-DOPA-induced dyskinesia in Parkinson's patients.
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http://dx.doi.org/10.1111/bph.15439DOI Listing
July 2021

Astrocyte Intracellular Caand TrkB Signaling in the Hippocampus Could Be Involved in the Beneficial Behavioral Effects of Antidepressant Treatment.

Neurotox Res 2021 Jun 22;39(3):860-871. Epub 2021 Feb 22.

Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto-SP, Brazil.

Although monoaminergic-based antidepressant drugs are largely used to treat major depressive disorder (MDD), their mechanisms are still incompletely understood. Intracellular Ca (iCa) and Calmodulin 1(CaM-1) homeostasis have been proposed to participate in the therapeutic effects of these compounds. We investigated whether intra-hippocampal inhibition of CaM-1 would modulate the behavioral responses to chronic treatment with imipramine (IMI) or 7-nitroindazole (7-NI), a selective inhibitor of the neuronal nitric oxide synthase 1 (NOS1) enzyme that shows antidepressant-like effects. We also investigated the interactions of IMI and CaM-1 on transient astrocyte iCa evoked by glutamate stimuli. Intra-hippocampal microinjection of the lentiviral delivered (LV) short hairpin iRNA-driven against the CaM-1 mRNA (LV-shRNA-CaM-1) or the CaM-1 inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide (W-7) blocked the antidepressant-like effect of chronic treatment with IMI or 7-NI. The shRNA also inhibited the mRNA expression of the tropomyosin receptor kinase B (TrkB) in the microinjection region. The iCa in ex vivo hippocampus slices stained with fluorescent Caindicator Oregon Green 488 BAPTA-1 revealed that IMI increased the intensity and duration of iCa oscillation and reduced the number of events evoked by glutamate stimuli, evaluated by using CCD imaging and the % ΔF/Fo parameters. The pre-treatment with W-7 fully antagonized this effect. The present results indicate that the behavioral benefits of chronic antidepressant treatment might be associated with astrocyte intracellular Cadynamics and TrkB mRNA expression in the hippocampus.
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http://dx.doi.org/10.1007/s12640-021-00334-0DOI Listing
June 2021

Contributive Role of TNF-α to L-DOPA-Induced Dyskinesia in a Unilateral 6-OHDA Lesion Model of Parkinson's Disease.

Front Pharmacol 2020 11;11:617085. Epub 2021 Jan 11.

Department of Basic and Oral Biology, FORP, Campus USP, University of São Paulo, Ribeirão Preto, Brazil.

Our present objective was to better characterize the mechanisms that regulate striatal neuroinflammation in mice developing L-DOPA-induced dyskinesia (LID). For that, we used 6-hydroxydopamine (6-OHDA)-lesioned mice rendered dyskinetic by repeated intraperitoneal injections of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) and quantified ensuing neuroinflammatory changes in the dopamine-denervated dorsal striatum. LID development was associated with a prominent astrocytic response, and a more moderate microglial cell reaction restricted to this striatal area. The glial response was associated with elevations in two pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-1β. Treatment with the phytocannabinoid cannabidiol and the transient receptor potential vanilloid-1 (TRPV-1) channel antagonist capsazepine diminished LID intensity and decreased TNF-α levels without impacting other inflammation markers. To possibly reproduce the neuroinflammatory component of LID, we exposed astrocyte and microglial cells in culture to candidate molecules that might operate as inflammatory cues during LID development, i.e., L-DOPA, dopamine, or glutamate. Neither L-DOPA nor dopamine produced an inflammatory response in glial cell cultures. However, glutamate enhanced TNF-α secretion and GFAP expression in astrocyte cultures and promoted Iba-1 expression in microglial cultures. Of interest, the antidyskinetic treatment with cannabidiol + capsazepine reduced TNF-α release in glutamate-activated astrocytes. TNF-α, on its own, promoted the synaptic release of glutamate in cortical neuronal cultures, whereas cannabidiol + capsazepine prevented this effect. Therefore, we may assume that the release of TNF-α by glutamate-activated astrocytes may contribute to LID by exacerbating corticostriatal glutamatergic inputs excitability and maintaining astrocytes in an activated state through a self-reinforcing mechanism.
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http://dx.doi.org/10.3389/fphar.2020.617085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836015PMC
January 2021

Doxycycline inhibits α-synuclein-associated pathologies in vitro and in vivo.

Neurobiol Dis 2021 Apr 8;151:105256. Epub 2021 Jan 8.

Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany; Max Planck Institute for Experimental Medicine, Goettingen, Germany; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne NE2 4HH, UK. Electronic address:

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn). Doxycycline, a tetracyclic antibiotic shows neuroprotective effects, initially proposed to be due to its anti-inflammatory properties. More recently, an additional mechanism by which doxycycline may exert its neuroprotective effects has been proposed as it has been shown that it inhibits amyloid aggregation. Here, we studied the effects of doxycycline on aSyn aggregation in vivo, in vitro and in a cell free system using real-time quaking induced conversion (RT-QuiC). Using H4, SH-SY5Y and HEK293 cells, we found that doxycycline decreases the number and size of aSyn aggregates in cells. In addition, doxycycline inhibits the aggregation and seeding of recombinant aSyn, and attenuates the production of mitochondrial-derived reactive oxygen species. Finally, we found that doxycycline induces a cellular redistribution of aggregates in a C.elegans animal model of PD, an effect that is associated with a recovery of dopaminergic function. In summary, we provide strong evidence that doxycycline treatment may be an effective strategy against synucleinopathies.
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http://dx.doi.org/10.1016/j.nbd.2021.105256DOI Listing
April 2021

Effects of JL13, a pyridobenzoxazepine compound, in dopaminergic and glutamatergic models of antipsychotic activity.

Behav Pharmacol 2021 02;32(1):2-8

Department of Pharmacology, Institute of Biological Sciences.

The pyridobenzoxazepine compound, 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13), has been developed as a potential antipsychotic drug. We tested the hypothesis that JL13 is efficacious in both dopaminergic and glutamatergic animal models of schizophrenia. We investigated JL13 for its efficacy to prevent cocaine- and ketamine-induced hyperlocomotion and MK-801-induced deficits in prepulse inhibition (PPI) of the startle reflex. Male Swiss mice received injections of JL13 (0.1-10 mg/kg) and were tested in the open field for basal locomotion. In separate experiments, the animals received injections of JL13 (0.1-3 mg/kg) followed by cocaine (10 mg/kg), ketamine (60 mg/kg), or MK-801 (0.5 mg/kg) and were tested in the open field for hyperlocomotion. In addition, it was also tested if JL13 prevented MK-801-induced disruption of PPI. Only the highest dose of JL13 impaired spontaneous locomotion, suggesting its favorable profile regarding motor side effects. At doses that did not impair basal motor activity, JL13 prevented cocaine-, ketamine-, and MK-801-induced hyperlocomotion. Moreover, JL13 prevented MK-801-induced disruption of PPI. Extending previous findings, this study shows that JL13 exerts antipsychotic-like activity in both dopaminergic and glutamatergic models. This compound has a favorable pharmacological profile, similar to second-generation antipsychotics.
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http://dx.doi.org/10.1097/FBP.0000000000000595DOI Listing
February 2021

In-tube solid-phase microextraction directly coupled to tandem mass spectrometry for anandamide and 2-arachidonoylglycerol determination in rat brain samples from an animal model of Parkinson's disease.

J Chromatogr A 2021 Jan 5;1636:461766. Epub 2020 Dec 5.

Universidade de São Paulo (USP), Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Departamento de Química, Avenida Bandeirantes, 3900, CEP 14040-901. Electronic address:

To evaluate the endocannabinoid system in an animal model of Parkinson's disease, in-tube solid-phase microextraction (in-tube SPME) was directly coupled to a tandem mass spectrometry (MS/MS) system for determination of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in rat brain samples. In-tube SPME-which consisted of a microtube of restricted access material (RAM) with a hydrophilic diol external surface and a hydrophobic octyl inner surface-efficiently excluded (up to 95%) macromolecules from the biological samples and selectively pre-concentrated the analytes. In-tube SPME parameters, such as sample volume, mobile phases, flow rate, and pre-concentration time, were evaluated to improve the extraction efficiency and throughput performance. The selectivity of the in-tube SPME and MS/MS (MRM mode) techniques allowed them to be directly coupled online, which dismissed the need for the chromatographic separation step. The in-tube SPME-MS/MS method was validated and shown to be linear from 6.0 to 30.0 ng mL for AEA and from 10.0 to 100.0 ng mL for 2-AG; the intra- and inter-assay accuracy and precision were lower than 15%. Parallelism between the calibration curves constructed in the matrix and aqueous solution confirmed that there was no matrix effect. The method allowed endogenous concentrations of AEA and 2-AG to be determined in rat brain striatum from unilaterally 6-hydroxydopamine-lesioned animals. The concentrations of these endocannabinoids in striatum ipsilateral and contralateral to the lesion differed significantly (p<0.001).
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http://dx.doi.org/10.1016/j.chroma.2020.461766DOI Listing
January 2021

CMT-3 targets different α-synuclein aggregates mitigating their toxic and inflammogenic effects.

Sci Rep 2020 11 20;10(1):20258. Epub 2020 Nov 20.

Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA), Pasaje Dorrego 1080, 4000, San Miguel de Tucumán, Argentina.

Parkinson's disease (PD) is a neurodegenerative disorder for which only symptomatic treatments are available. Repurposing drugs that target α-synuclein aggregation, considered one of the main drivers of PD progression, could accelerate the development of disease-modifying therapies. In this work, we focused on chemically modified tetracycline 3 (CMT-3), a derivative with reduced antibiotic activity that crosses the blood-brain barrier and is pharmacologically safe. We found that CMT-3 inhibited α-synuclein amyloid aggregation and led to the formation of non-toxic molecular species, unlike minocycline. Furthermore, CMT-3 disassembled preformed α-synuclein amyloid fibrils into smaller fragments that were unable to seed in subsequent aggregation reactions. Most interestingly, disaggregated species were non-toxic and less inflammogenic on brain microglial cells. Finally, we modelled the interactions between CMT-3 and α-synuclein aggregates by molecular simulations. In this way, we propose a mechanism for fibril disassembly. Our results place CMT-3 as a potential disease modifier for PD and possibly other synucleinopathies.
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http://dx.doi.org/10.1038/s41598-020-76927-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679368PMC
November 2020

Effects of Doxycycline in Swiss Mice Predictive Models of Schizophrenia.

Neurotox Res 2020 Dec 15;38(4):1049-1060. Epub 2020 Sep 15.

Dental School of Ribeirão Preto, Department of Basic and Oral Biology, University of São Paulo (USP), Ribeirão Preto, SP, Brazil.

Schizophrenia patients show very complex symptoms in several psychopathological domains. Some of these symptoms remain poorly treated. Therefore, continued effort is needed to find novel pharmacological strategies for improving schizophrenia symptoms. Recently, minocycline, a second-generation tetracycline, has been suggested as an adjunctive treatment for schizophrenia. The antipsychotic-like effect of doxycycline, a minocycline analog, was investigated here. We found that both minocycline and doxycycline prevented amphetamine-induced prepulse inhibition (PPI) disruption. However, neither of them blocked MK801-induced effects, albeit doxycycline had a modest impact against ketamine-induced effects. Neither c-Fos nor nNOS expression, which was evaluated in limbic regions, were modified after acute or sub-chronic treatment with doxycycline. Therefore, apomorphine inducing either PPI disruption and climbing behavior was not prevented by doxycycline. This result discards a direct blockade of D2-like receptors, also suggested by the lack of doxycycline cataleptic-induced effect. Contrasting, doxycycline prevented SKF 38393-induced effects, suggesting a preferential doxycycline action at D1-like rather than D2-like receptors. However, doxycycline did not bind to the orthosteric sites of D1, D2, D3, D4, 5-HT2A, 5-HT1A, and A2A receptors suggesting no direct modulation of these receptors. Our data corroborate the antipsychotic-like effect of doxycycline. However, these effects are probably not mediated by doxycycline direct interaction with classical receptors enrolled in the antipsychotic effect.
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http://dx.doi.org/10.1007/s12640-020-00268-zDOI Listing
December 2020

Beneficial effects of benzodiazepine on masticatory muscle dysfunction induced by chronic stress and occlusal instability in an experimental animal study.

Sci Rep 2020 05 29;10(1):8787. Epub 2020 May 29.

Department of Integral Dentistry, Research Centre for Dental Sciences (CICO), Dental School, Universidad de La Frontera, Temuco, Chile.

Psychological stress and occlusal alteration are important etiologic factors for temporomandibular/masticatory muscular disorders. In particular, the exact physiologic mechanism underlying the relation by occlusal alteration and temporomandibular disorders remains unclear. Our purpose was to test the hypothesis that benzodiazepine therapy is able to prevent metabolic and vascular changes in the medial pterygoid muscle of rats under chronic stress after 14 days of unilateral exodontia. Adult Wistar rats were submitted to unpredictable chronic mild stress (10 days) and/or unilateral exodontia and their plasma and medial pterygoid muscles were removed for analysis. A pre-treatment with diazepam was used to verify its effect on stress. The parameters evaluated included anxiety behavior, plasma levels of corticosterone, metabolic activity by succinate dehydrogenase, capillary density by laminin staining and ultrastructural findings by transmission electron microscopy. Occlusal instability induced anxiety-like behavior on elevated plus-maze test and diazepam administration blocked the appearance of this behavior. Unilateral exodontia promoted in the contralateral muscle an increase of oxidative fibers and capillaries and modification of sarcoplasmic reticulum. Chronic stress caused increased glycolytic metabolism, reduced capillary density and morphological changes in mitochondria on both sides. Association of both factors induced a glycolytic pattern in muscle and hemodynamic changes. Pharmacological manipulation with diazepam inhibited the changes in the medial pterygoid muscle after stress. Our results reveal a preventive benzodiazepine treatment for stress and occlusal instability conditions affecting masticatory muscle disorders. In addition, provide insights into the mechanisms by which chronic stress and exodontia might be involved in the pathophysiology of masticatory muscular dysfunctions.
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http://dx.doi.org/10.1038/s41598-020-65524-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260241PMC
May 2020

One-Week High-Intensity Interval Training Increases Hippocampal Plasticity and Mitochondrial Content without Changes in Redox State.

Antioxidants (Basel) 2020 May 21;9(5). Epub 2020 May 21.

Departamento de Ciências BioMoleculares, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo 14040-903, Brasil.

Evidence suggests that physical exercise has effects on neuronal plasticity as well as overall brain health. This effect has been linked to exercise capacity in modulating the antioxidant status, when the oxidative stress is usually linked to the neuronal damage. Although high-intensity interval training (HIIT) is the training-trend worldwide, its effect on brain function is still unclear. Thus, we aimed to assess the neuroplasticity, mitochondrial, and redox status after one-week HIIT training. Male (C57Bl/6) mice were assigned to non-trained or HIIT groups. The HIIT protocol consisted of three days with short bouts at 130% of maximum speed (Vmax), intercalated with moderate-intensity continuous exercise sessions of 30 min at 60% Vmax. The mass spectrometry analyses showed that one-week of HIIT increased minichromosome maintenance complex component 2 (MCM2), brain derived neutrophic factor (BDNF), doublecortin (DCX) and voltage-dependent anion-selective channel protein 2 (VDAC), and decreased mitochondrial superoxide dismutase 2 (SOD 2) in the hippocampus. In addition, one-week of HIIT promoted no changes in HO production and carbonylated protein concentration in the hippocampus as well as in superoxide anion production in the dentate gyrus. In conclusion, our one-week HIIT protocol increased neuroplasticity and mitochondrial content regardless of changes in redox status, adding new insights into the neuronal modulation induced by new training models.
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http://dx.doi.org/10.3390/antiox9050445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278594PMC
May 2020

Cannabidiol increases the nociceptive threshold in a preclinical model of Parkinson's disease.

Neuropharmacology 2020 02 7;163:107808. Epub 2019 Nov 7.

Department of Basic and Oral Biology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, 14040-904, Brazil. Electronic address:

Medications that improve pain threshold can be useful in the pharmacotherapy of Parkinson's disease (PD). Pain is a prevalent PD's non-motor symptom with a higher prevalence of analgesic drugs prescription for patients. However, specific therapy for PD-related pain are not available. Since the endocannabinoid system is expressed extensively in different levels of pain pathway, drugs designed to target this system have promising therapeutic potential in the modulation of pain. Thus, we examined the effects of the 6-hydroxydopamine- induced PD on nociceptive responses of mice and the influence of cannabidiol (CBD) on 6-hydroxydopamine-induced nociception. Further, we investigated the pathway involved in the analgesic effect of the CBD through the co-administration with a fatty acid amide hydrolase (FAAH) inhibitor, increasing the endogenous anandamide levels, and possible targets from anandamide, i.e., the cannabinoid receptors subtype 1 and 2 (CB1 and CB2) and the transient receptor potential vanilloid type 1 (TRPV1). We report that 6-hydroxydopamine- induced parkinsonism decreases the thermal and mechanical nociceptive threshold, whereas CBD (acute and chronic treatment) reduces this hyperalgesia and allodynia evoked by 6-hydroxydopamine. Moreover, ineffective doses of either FAAH inhibitor or TRPV1 receptor antagonist potentialized the CBD-evoked antinociception while an inverse agonist of the CB1 and CB2 receptor prevented the antinociceptive effect of the CBD. Altogether, these results indicate that CBD can be a useful drug to prevent the parkinsonism-induced nociceptive threshold reduction. They also suggest that CB1 and TRPV1 receptors are important for CBD-induced analgesia and that CBD could produce these analgesic effects increasing endogenous anandamide levels.
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http://dx.doi.org/10.1016/j.neuropharm.2019.107808DOI Listing
February 2020

Cannabidiol prevents LPS-induced microglial inflammation by inhibiting ROS/NF-κB-dependent signaling and glucose consumption.

Glia 2020 03 24;68(3):561-573. Epub 2019 Oct 24.

Sorbonne Université, Institut du Cerveau et de la Moelle épinière (ICM), Inserm U 1127, CNRS UMR 7225, Paris, France.

We used mouse microglial cells in culture activated by lipopolysaccharide (LPS, 10 ng/ml) to study the anti-inflammatory potential of cannabidiol (CBD), the major nonpsychoactive component of cannabis. Under LPS stimulation, CBD (1-10 μM) potently inhibited the release of prototypical proinflammatory cytokines (TNF-α and IL-1β) and that of glutamate, a noncytokine mediator of inflammation. The effects of CBD were predominantly receptor-independent and only marginally blunted by blockade of CB2 receptors. We established that CBD inhibited a mechanism involving, sequentially, NADPH oxidase-mediated ROS production and NF-κB-dependent signaling events. In line with these observations, active concentrations of CBD demonstrated an intrinsic free-radical scavenging capacity in the cell-free DPPH assay. Of interest, CBD also prevented the rise in glucose uptake observed in microglial cells challenged with LPS, as did the inhibitor of NADPH oxidase apocynin and the inhibitor of IκB kinase-2, TPCA-1. This indicated that the capacity of CBD to prevent glucose uptake also contributed to its anti-inflammatory activity. Supporting this view, the glycolytic inhibitor 2-deoxy-d-glucose (2-DG) mimicked the antioxidant/immunosuppressive effects of CBD. Interestingly, CBD and 2-DG, as well as apocynin and TPCA-1 caused a reduction in glucose-derived NADPH, a cofactor required for NADPH oxidase activation and ROS generation. These different observations suggest that CBD exerts its anti-inflammatory effects towards microglia through an intrinsic antioxidant effect, which is amplified through inhibition of glucose-dependent NADPH synthesis. These results also further confirm that CBD may have therapeutic utility in conditions where neuroinflammatory processes are prominent.
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http://dx.doi.org/10.1002/glia.23738DOI Listing
March 2020

Cannabidiol and Cannabinoid Compounds as Potential Strategies for Treating Parkinson's Disease and L-DOPA-Induced Dyskinesia.

Neurotox Res 2020 Jan 22;37(1):12-29. Epub 2019 Oct 22.

Department of Pharmacology, FMRP, Campus USP, University of São Paulo, Av. Bandeirantes 13400, Ribeirão Preto, SP, 14049-900, Brazil.

Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID) are motor disorders with significant impact on the patient's quality of life. Unfortunately, pharmacological treatments that improve these disorders without causing severe side effects are not yet available. Delay in initiating L-DOPA is no longer recommended as LID development is a function of disease duration rather than cumulative L-DOPA exposure. Manipulation of the endocannabinoid system could be a promising therapy to control PD and LID symptoms. In this way, phytocannabinoids and synthetic cannabinoids, such as cannabidiol (CBD), the principal non-psychotomimetic constituent of the Cannabis sativa plant, have received considerable attention in the last decade. In this review, we present clinical and preclinical evidence suggesting CBD and other cannabinoids have therapeutic effects in PD and LID. Here, we discuss CBD pharmacology, as well as its neuroprotective effects and those of other cannabinoids. Finally, we discuss the modulation of several pro- or anti-inflammatory factors as possible mechanisms responsible for the therapeutic/neuroprotective potential of Cannabis-derived/cannabinoid synthetic compounds in motor disorders.
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http://dx.doi.org/10.1007/s12640-019-00109-8DOI Listing
January 2020

Rifampicin and Its Derivative Rifampicin Quinone Reduce Microglial Inflammatory Responses and Neurodegeneration Induced In Vitro by α-Synuclein Fibrillary Aggregates.

Cells 2019 07 25;8(8). Epub 2019 Jul 25.

Institut du Cerveau et de la Moelle épinière (ICM), Inserm U 1127, CNRS UMR 7225, Sorbonne Université, F-75013 Paris, France.

Aggregated forms of the synaptic protein α-synuclein (αS) have been proposed to operate as a molecular trigger for microglial inflammatory processes and neurodegeneration in Parkinson´s disease. Here, we used brain microglial cell cultures activated by fibrillary forms of recombinant human αS to assess the anti-inflammatory and neuroprotective activities of the antibiotic rifampicin (Rif) and its autoxidation product rifampicin quinone (RifQ). Pretreatments with Rif and RifQ reduced the secretion of prototypical inflammatory cytokines (TNF-, IL-6) and the burst of oxidative stress in microglial cells activated with αS fibrillary aggregates. Note, however, that RifQ was constantly more efficacious than its parent compound in reducing microglial activation. We also established that the suppressive effects of Rif and RifQ on cytokine release was probably due to inhibition of both PI3K- and non-PI3K-dependent signaling events. The control of oxidative stress appeared, however, essentially dependent on PI3K inhibition. Of interest, we also showed that RifQ was more efficient than Rif in protecting neuronal cells from toxic factors secreted by microglia activated by αS fibrils. Overall, data with RifQ are promising enough to justify further studies to confirm the potential of this compound as an anti-parkinsionian drug.
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http://dx.doi.org/10.3390/cells8080776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721546PMC
July 2019

Biological bases for a possible effect of cannabidiol in Parkinson's disease.

Braz J Psychiatry 2020 Apr 15;42(2):218-224. Epub 2019 Jul 15.

Departamento de Neurociências e Ciências do Comportamento, FMRP, USP, Ribeirão Preto, SP, Brazil.

Current pharmacotherapy of Parkinson's disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients' quality of life with fewer side effects are needed, but not yet available. Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD. We searched MEDLINE (via PubMed) for indexed articles published in English from inception to 2019. The following keywords were used: cannabis; cannabidiol and neuroprotection; endocannabinoids and basal ganglia; Parkinson's animal models; Parkinson's history; Parkinson's and cannabidiol. Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms. Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.
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http://dx.doi.org/10.1590/1516-4446-2019-0460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115443PMC
April 2020

Paradoxical Effect of LTB on the Regulation of Stress-Induced Corticosterone Production.

Front Behav Neurosci 2019 16;13:73. Epub 2019 Apr 16.

Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil.

Depression is a mental illness with a complex and multifactorial etiology, which has been associated with stress and inflammation. Infections, autoimmune diseases, envenomation, and trauma induce an inflammatory response that is characterized by increasing levels of circulating cytokines (e.g., IL-1β) and lipid mediators [e.g., PGE and leukotrienes B (LTB)]. Recently, we showed that LTB production by the 5-lipoxygenase (5-LO) pathway regulates IL-1β and PGE release, reducing tissue damage in a model of sterile inflammation. Since IL-1β and PGE increase in serum of stressed patients and potentially trigger depression, we used an animal model of chronic unpredictable stress (CUS) to investigate the potential impact of LTB over depression-like symptoms. At basal conditions, 5-LO deficiency () reduces the preference for sucrose, while inducing a higher immobilization time on the tail suspension test when compared 129. Moreover, mice present increased caspase-1 expression and elevated levels of IL-1β, IL-17 and PGE in the spleen, with increasing corticosterone levels in the frontal cortex but reducing systemic levels. Compared to 129 mice, CUS induced higher levels of systemic, frontal cortex and hippocampal corticosterone, and also reduced sucrose preference, increased levels of splenic IL-1β, IL-17 and PGE and reduced levels of LTB. Interestingly, CUS exposure did not alter the reduced sucrose preference shown by mice but greatly enhanced splenic PGE production. Compared to mice at basal conditions, CUS exposure also increased levels of systemic corticosterone, which remained lower than those of CUS-129 animals. We also observed that treatment with LTB decreased caspase-1 expression and systemic levels of corticosterone in CUS- mice but there was no significant impact on the reduced sucrose preference. Our results demonstrate that LTB controls the hypothalamic-pituitary-adrenal (HPA) axis by regulating levels of systemic corticosterone associated with the repression of caspase-1 expression and production of inflammatory mediators. One limitation of our study is that 129 and mice were not littermates, not sharing, therefore, the same intra-uterine and preweaning environment. Even so, taken together our results indicate that 5-LO activity is critical for the regulation of stress-induced symptoms, suggesting that the mouse could be a natural model of corticosterone-independent reduced reward sensitivity.
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http://dx.doi.org/10.3389/fnbeh.2019.00073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477085PMC
April 2019

Suppressing nNOS Enzyme by Small-Interfering RNAs Protects SH-SY5Y Cells and Nigral Dopaminergic Neurons from 6-OHDA Injury.

Neurotox Res 2019 Jul 30;36(1):117-131. Epub 2019 Apr 30.

Department of Basic and Oral Biology, Dental School, University of São Paulo (USP), Ribeirão Preto, SP, 14040-904, Brazil.

Nitric oxide (NO) has chemical properties that make it uniquely suitable as an intracellular and intercellular messenger. NO is produced by the activity of the enzyme nitric oxide synthases (NOS). There is substantial and mounting evidence that slight abnormalities of NO may underlie a wide range of neurodegenerative disorders. NO participates of the oxidative stress and inflammatory processes that contribute to the progressive dopaminergic loss in Parkinson's disease (PD). The present study aimed to evaluate in vitro and in vivo the effects of neuronal NOS-targeted siRNAs on the injury caused in dopaminergic neurons by the toxin 6-hidroxydopamine (6-OHDA). First, we confirmed (immunohistochemistry and Western blotting) that SH-SY5Y cell lineage expresses the dopaminergic marker tyrosine hydroxylase (TH) and the protein under analysis, neuronal NOS (nNOS). We designed four siRNAs by using the BIOPREDsi algorithm choosing the one providing the highest knockdown of nNOS mRNA in SH-SY5Y cells, as determined by qPCR. siRNA 4400 carried by liposomes was internalized into cells, caused a concentration-dependent knockdown on nNOS, and reduced the toxicity induced by 6-OHDA (p < 0.05). Regarding in vivo action in the dopamine-depleted animals, intra-striatal injection of siRNA 4400 at 4 days prior 6-OHDA produced a decrease in the rotational behavior induced by apomorphine. Finally, siRNA 4400 mitigated the loss of TH(+) cells in substantia nigra dorsal and ventral part. In conclusion, the suppression of nNOS enzyme by targeted siRNAs modified the progressive death of dopaminergic cells induced by 6-OHDA and merits further pre-clinical investigations as a neuroprotective approach for PD.
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http://dx.doi.org/10.1007/s12640-019-00043-9DOI Listing
July 2019

The Neuroprotective Effect of Doxycycline on Neurodegenerative Diseases.

Neurotox Res 2019 May 23;35(4):981-986. Epub 2019 Feb 23.

Institut du Cerveau et de la Moelle épinière (ICM), Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, F-75013, Paris, France.

Neurodegenerative diseases (NDs) are a group of chronic, progressive disorders characterized by the gradual loss of neurons that affect specific regions of the brain, which leads to deficits in specific functions (e.g., memory, movement, cognition). The mechanism that drives chronic progression of NDs remains elusive. Among the proposed underlying pathophysiological mechanisms, aggregation and accumulation of misfolded proteins and neuroinflammation have been credited to contribute to extensive neural loss. Therapeutic agents that confer neuroprotection by downregulating these shared characteristics could therefore have beneficial effects on a wide range of NDs. In this regard, a commonly used antibiotic, doxycycline (Doxy), has been shown to reduce the progression and severity of disease in different experimental models of neurodegeneration by counteracting these common features. This review will focus on the effects reported for Doxy regarding its neuroprotective properties, the "off-target" effects, thereby supporting its evaluation as a new therapeutic approach for diseases associated with a neurodegeneration.
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http://dx.doi.org/10.1007/s12640-019-00015-zDOI Listing
May 2019

The nitrergic neurotransmission contributes to the anxiolytic-like effect of Citrus sinensis essential oil in animal models.

Phytother Res 2019 Apr 3;33(4):901-909. Epub 2019 Feb 3.

Laboratory of Physiology and Pharmacology of the Central Nervous System, Department of Pharmacology, Federal University of Paraná, Curitiba, Brazil.

Citrus fragrances have been used in aromatherapy for the treatment of anxiety, and the essential oil of Citrus sinensis (sweet orange) has shown promising results, although its mechanism of action was not known. The objective of this study was to evaluate the involvement of nitric oxide (NO) neurotransmission in the anxiolytic-like effect of C. sinensis essential oil. Swiss male mice were submitted to 15 min of C. sinensis essential oil inhalation (1%, 2.5%, 5%, and 10%) and tested in the marble-burying test, neophobia-induced hypophagia, and light/dark test. Locomotor activity was evaluated in an automated locomotor activity box. The coadministration of C. sinensis essential oil with L-arginine (200 mg/kg, i.p.), an NO precursor, was used for the behavioral evaluation of nitrergic system mediation. Additionally, the NO synthase activity was measured by nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) analysis in the cerebral cortex. C. sinensis essential oil exerted anxiolytic-like effect at dose that did not change locomotor activity. Moreover, L-arginine pretreatment prevented this anxiolytic-like effect on marble-burying test. Finally, C. sinensis essential oil reduced the NADPH-d positive cells. Thus, the nitrergic neurotransmission plays a relevant role in the anxiolytic-like effect C. sinensis essential oil.
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http://dx.doi.org/10.1002/ptr.6281DOI Listing
April 2019

Microglial glutamate release evoked by α-synuclein aggregates is prevented by dopamine.

Glia 2018 11 5;66(11):2353-2365. Epub 2018 Nov 5.

Institut du Cerveau et de la Moelle épinière (ICM), Inserm U 1127, CNRS UMR 7225, Sorbonne Université, Paris, F-75013, France.

When activated, microglial cells have the potential not only to secrete typical proinflammatory mediators but also to release the neurotransmitter glutamate in amounts that may promote excitotoxicity. Here, we wished to determine the potential of the Parkinson's disease (PD) protein α-Synuclein (αS) to stimulate glutamate release using cultures of purified microglial cells. We established that glutamate release was robustly increased when microglial cultures were treated with fibrillary aggregates of αS but not with the native monomeric protein. Promotion of microglial glutamate release by αS aggregates (αSa) required concomitant engagement of TLR2 and P2X7 receptors. Downstream to cell surface receptors, the release process was mediated by activation of a signaling cascade sequentially involving phosphoinositide 3-kinase (PI3K) and NADPH oxidase, a superoxide-producing enzyme. Inhibition of the Xc- antiporter, a plasma membrane exchange system that imports extracellular l-cystine and exports intracellular glutamate, prevented the release of glutamate induced by αSa, indicating that system Xc- was the final effector element in the release process downstream to NADPH oxidase activation. Of interest, the stimulation of glutamate release by αSa was abrogated by dopamine through an antioxidant effect requiring D dopamine receptor activation and PI3K inhibition. Altogether, present data suggest that the activation of microglial cells by αSa may possibly result in a toxic build-up of extracellular glutamate contributing to excitotoxic stress in PD. The deficit in dopamine that characterizes this disorder may further aggravate this process in a vicious circle mechanism.
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http://dx.doi.org/10.1002/glia.23472DOI Listing
November 2018

Cannabidiol prevents haloperidol-induced vacuos chewing movements and inflammatory changes in mice via PPARγ receptors.

Brain Behav Immun 2018 11 11;74:241-251. Epub 2018 Sep 11.

Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo, Brazil.

The chronic use of drugs that reduce the dopaminergic neurotransmission can cause a hyperkinetic movement disorder called tardive dyskinesia (TD). The pathophysiology of this disorder is not entirely understood but could involve oxidative and neuroinflammatory mechanisms. Cannabidiol (CBD), the major non-psychotomimetic compound present in Cannabis sativa plant, could be a possible therapeutic alternative for TD. This phytocannabinoid shows antioxidant, anti-inflammatory and antipsychotic properties and decreases the acute motor effects of classical antipsychotics. The present study investigated if CBD would attenuate orofacial dyskinesia, oxidative stress and inflammatory changes induced by chronic administration of haloperidol in mice. Furthermore, we verified in vivo and in vitro (in primary microglial culture) whether these effects would be mediated by PPARγ receptors. The results showed that the male Swiss mice treated daily for 21 days with haloperidol develop orofacial dyskinesia. Daily CBD administration before each haloperidol injection prevented this effect. Mice treated with haloperidol showed an increase in microglial activation and inflammatory mediators in the striatum. These changes were also reduced by CBD. On the other hand, the levels of the anti-inflammatory cytokine IL-10 increased in the striatum of animals that received CBD and haloperidol. Regarding oxidative stress, haloperidol induced lipid peroxidation and reduced catalase activity. This latter effect was attenuated by CBD. The combination of CBD and haloperidol also increased PGC-1α mRNA expression, a co-activator of PPARγ receptors. Pretreatment with the PPARγ antagonist, GW9662, blocked the behavioural effect of CBD in our TD model. CBD also prevented LPS-stimulated microglial activation, an effect that was also antagonized by GW9662. In conclusion, our results suggest that CBD could prevent haloperidol-induced orofacial dyskinesia by activating PPARγ receptors and attenuating neuroinflammatory changes in the striatum.
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http://dx.doi.org/10.1016/j.bbi.2018.09.014DOI Listing
November 2018

Tetracycline repurposing in neurodegeneration: focus on Parkinson's disease.

J Neural Transm (Vienna) 2018 10 14;125(10):1403-1415. Epub 2018 Aug 14.

Department of Morphology, Physiology and Basic Pathology, Faculty of Odontology of Ribeirão Preto, University of São Paulo (USP), Av do Café s/n, São Paulo, Brazil.

The prevalence of Parkinson's disease, which affects millions of people worldwide, is increasing due to the aging population. In addition to the classic motor symptoms caused by the death of dopaminergic neurons, Parkinson's disease encompasses a wide range of nonmotor symptoms. Although novel disease-modifying medications that slow or stop Parkinson's disease progression are being developed, drug repurposing, which is the use of existing drugs that have passed numerous toxicity and clinical safety tests for new indications, can be used to identify treatment compounds. This strategy has revealed that tetracyclines are promising candidates for the treatment of Parkinson's disease. Tetracyclines, which are neuroprotective, inhibit proinflammatory molecule production, matrix metalloproteinase activity, mitochondrial dysfunction, protein misfolding/aggregation, and microglial activation. Two commonly used semisynthetic second-generation tetracycline derivatives, minocycline and doxycycline, exhibit effective neuroprotective activity in experimental models of neurodegenerative/ neuropsychiatric diseases and no substantial toxicity. Moreover, novel synthetic tetracyclines with different biological properties due to chemical tuning are now available. In this review, we discuss the multiple effects and clinical properties of tetracyclines and their potential use in Parkinson's disease treatment. In addition, we examine the hypothesis that the anti-inflammatory activities of tetracyclines regulate inflammasome signaling. Based on their excellent safety profiles in humans from their use for over 50 years as antibiotics, we propose the repurposing of tetracyclines, a multitarget antibiotic, to treat Parkinson's disease.
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http://dx.doi.org/10.1007/s00702-018-1913-1DOI Listing
October 2018

Opposing roles of CB and CB cannabinoid receptors in the stimulant and rewarding effects of cocaine.

Br J Pharmacol 2019 05 14;176(10):1541-1551. Epub 2018 Sep 14.

Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.

Background And Purpose: The endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) bind to CB and CB cannabinoid receptors in the brain and modulate the mesolimbic dopaminergic pathway. This neurocircuitry is engaged by psychostimulant drugs, including cocaine. Although CB receptor antagonism and CB receptor activation are known to inhibit certain effects of cocaine, they have been investigated separately. Here, we tested the hypothesis that there is a reciprocal interaction between CB receptor blockade and CB receptor activation in modulating behavioural responses to cocaine.

Experimental Approach: Male Swiss mice received i.p. injections of cannabinoid-related drugs followed by cocaine, and were then tested for cocaine-induced hyperlocomotion, c-Fos expression in the nucleus accumbens and conditioned place preference. Levels of endocannabinoids after cocaine injections were also analysed.

Key Results: The CB receptor antagonist, rimonabant, and the CB receptor agonist, JWH133, prevented cocaine-induced hyperlocomotion. The same results were obtained by combining sub-effective doses of both compounds. The CB receptor antagonist, AM630, reversed the inhibitory effects of rimonabant in cocaine-induced hyperlocomotion and c-Fos expression in the nucleus accumbens. Selective inhibitors of anandamide and 2-AG hydrolysis (URB597 and JZL184, respectively) failed to modify this response. However, JZL184 prevented cocaine-induced hyperlocomotion when given after a sub-effective dose of rimonabant. Cocaine did not change brain endocannabinoid levels. Finally, CB receptor blockade reversed the inhibitory effect of rimonabant in the acquisition of cocaine-induced conditioned place preference.

Conclusion And Implications: The present data support the hypothesis that CB and CB receptors work in concert with opposing functions to modulate certain addiction-related effects of cocaine.

Linked Articles: This article is part of a themed section on 8 European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.
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http://dx.doi.org/10.1111/bph.14473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487550PMC
May 2019

Repurposing an established drug: an emerging role for methylene blue in L-DOPA-induced dyskinesia.

Eur J Neurosci 2019 03 25;49(6):869-882. Epub 2018 Sep 25.

Department of Morphology, Physiology and Pathology, Dentistry School, University of São Paulo, Ribeirão Preto, SP, Brazil.

The nitric oxide (NO) system has been proven to be a valuable modulator of L-DOPA-induced dyskinesia in Parkinsonian rodents. NO activates the enzyme soluble guanylyl cyclase and elicits the synthesis of the second-messenger cGMP. Although we have previously described the anti-dyskinetic potential of NO synthase inhibitors on L-DOPA-induced dyskinesia, the effect of soluble guanylyl cyclase inhibitors remains to be evaluated. The aim of this study was to analyze whether the clinically available non-selective inhibitor methylene blue, or the selective soluble guanylyl cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), could mitigate L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats. Here, we demonstrated that methylene blue was able to reduce L-DOPA-induced dyskinesia incidence when chronically co-administered with L-DOPA during 3 weeks. Methylene blue chronic (but not acute) administration (2 weeks) was effective in attenuating L-DOPA-induced dyskinesia in rats rendered dyskinetic by a previous course of L-DOPA chronic treatment. Furthermore, discontinuous methylene blue treatment (e.g., co-administration of methylene blue and L-DOPA for 2 consecutive days followed by vehicle and L-DOPA co-administration for 5 days) was effective in attenuating dyskinesia. Finally, we demonstrated that microinjection of methylene blue or ODQ into the lateral ventricle effectively attenuated L-DOPA-induced dyskinesia. Taken together, these results demonstrate an important role of NO-soluble guanylyl cyclase-cGMP signaling on L-DOPA-induced dyskinesia. The clinical implications of this discovery are expected to advance the treatment options for patients with Parkinson's disease.
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http://dx.doi.org/10.1111/ejn.14079DOI Listing
March 2019

Extrasynaptic Neurotransmission Mediated by Exocytosis and Diffusive Release of Transmitter Substances.

Front Synaptic Neurosci 2018 8;10:13. Epub 2018 Jun 8.

Instituto de Fisiología Celular-Neurociencias, Centro de Ciencias de la Complejidad, Universidad Nacional Autónoma de México, Mexico City, Mexico.

This review article deals with the mechanisms of extrasynaptic release of transmitter substances, namely the release from the soma, axon and dendrites in the absence of postsynaptic counterparts. Extrasynaptic release occurs by exocytosis or diffusion. Spillover from the synaptic cleft also contributes to extrasynaptic neurotransmission. Here, we first describe two well-known examples of exocytosis from the neuronal soma, which may release copious amounts of transmitter for up to hundreds of seconds after electrical stimulation. The mechanisms for somatic exocytosis of the low molecular weight transmitter serotonin, and the peptides oxytocin and vasopressin have been studied in detail. Serotonin release from leech neurons and oxytocin and vasopressin from rodent neurons have a common multi-step mechanism, which is completely different from that for exocytosis from presynaptic endings. Most transmitters and peptides released extrasynaptically seem to follow this same mechanism. Extrasynaptic exocytosis may occur onto glial cells, which act as intermediaries for long-term and long-distance transmission. The second part of this review article focuses on the release upon synthesis of the representative diffusible molecules nitric oxide (NO) and endocannabinoids. Diffusible molecules are synthesized "on demand" from postsynaptic terminals in response to electrical activity and intracellular calcium elevations. Their effects include the retrograde modulation of presynaptic electrical activity and transmitter release. Extrasynaptic neurotransmission is well exemplified in the retina. Light-evoked extrasynaptic communication sets the gain for visual responses and integrates the activity of neurons, glia and blood vessels. Understanding how extrasynaptic communication changes the function of hard-wired circuits has become fundamental to understand the function of the nervous system.
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http://dx.doi.org/10.3389/fnsyn.2018.00013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003215PMC
June 2018

Differential behavioral and glial responses induced by dopaminergic mechanisms in the iNOS knockout mice.

Behav Brain Res 2018 09 8;350:44-53. Epub 2018 May 8.

University of São Paulo (USP), Dental School of Ribeirão Preto, Department of Morphology, Physiology and Basic Pathology, Ribeirão Preto, SP, Brazil; USP, Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), Brazil. Electronic address:

The interaction between distinctive nitric oxide synthase (NOS) isoforms and the dopamine system provides new avenues to the development of pharmacological tools for the pathophysiological conditions of the dopaminergic system. Our aim was to investigate the influences of dopamine-induced effects in inducible NOS knockout (iNOS KO) mice. In order to characterize iNOS KO mice phenotype, the animals were submitted to the basal analyses of motor, sensorimotor and sensorial abilities. Pharmacological challenging of the dopaminergic system included the investigation of amphetamine-induced prepulse inhibition (PPI) disruption, haloperidol-induced catalepsy, reserpine-induced oral involuntary movements and hyperlocomotion induced by amphetamine in reserpine treated mice. The iNOS KO mice showed significant reduction of spontaneous motor activity, but there was no significant difference in sensorimotor or sensorial responses of iNOS KO mice compared to wild type (WT). Regarding the dopaminergic system, iNOS KO mice showed a significant increase of haloperidol-induced catalepsy. This effect was confirmed through an iNOS pharmacological inhibitor (1400 W) in WT mice. In addition, iNOS KO reserpine treated mice showed reduced oral involuntary movements and amphetamine-induced hyperlocomotion. Knowing that iNOS is mainly expressed in glial cells we analyzed the immunoreactivity (ir) for GFAP (astrocyte marker) and IBA-1 (microglial marker) in the striatum, an area enrolled in motor planning among other functions. iNOS KO presented reduced GFAP-ir and IBA-1-ir compared with WT. Reserpine treatment increased GFAP-ir in both WT and iNOS KO. However, these effects were slighter in iNOS KO. Activated state of microglia was increased by reserpine only in WT mice. Our results further demonstrated that the absence of iNOS interfered with dopamine-mediated behavioral and molecular responses. These results increase the understanding of the dopamine and NO system interaction, which is useful for the management of the dopamine-related pathologies.
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http://dx.doi.org/10.1016/j.bbr.2018.05.002DOI Listing
September 2018

Effects of the monoamine stabilizer (-)-OSU6162 on locomotor and sensorimotor responses predictive of antipsychotic activity.

Naunyn Schmiedebergs Arch Pharmacol 2018 07 24;391(7):761-768. Epub 2018 Apr 24.

Department of Pharmacology, Institute of Biological Sciences, Universidade Federal de Minas Gerais (UFMG), Av. Pres. Antônio Carlos 6627, Belo Horizonte, MG, 31270-901, Brazil.

The monoamine stabilizer (3S)-3-[3-(methenesulfonyl)phenyl]-1-propylpiperidine hidrochloride [(-)-OSU6162] is a promising compound for the treatment of neurological and psychiatric disorders, such as schizophrenia. Here, we tested the hypothesis that (-)-OSU6162 prevents hyperlocomotion and sensorimotor deficits in prepulse inhibition of the startle response (PPI) induced by psychomimetic drugs. Male Swiss mice received injections of (-)-OSU6162 (1, 3, 10, or 30 mg/kg), and their motor responses were investigated in the open field and in the catalepsy tests, which predicts liability to induce sedation and extrapyramidal side effects, respectively. Next, in independent experiments, this compound was evaluated for its efficacy to prevent hyperlocomotion induced by cocaine (10 mg/kg; dopamine transporter inhibitor) or ketamine (60 mg/kg; glutamate NMDA channel blocker) in the open field. Finally, we tested if (-)-OSU6162 prevents PPI disruption induced by MK-801 (0.5 mg/kg; glutamate NMDA channel blocker). (-)-OSU6162 induced neither locomotion impairment nor catalepsy. This compound prevented cocaine-induced hyperlocomotion at the doses of 10 and 30 mg/kg and ketamine-induced hyperlocomotion at the doses of 1 and 3 mg/kg. In the sensorimotor test, (-)-OSU6162 failed to reverse MK-801-induced PPI deficits. The dopamine stabilizer (-)-OSU6162 prevents the hyperactivity induced by dopaminergic and anti-glutamatergic drugs at doses that preserve motor functions, although it failed in the PPI test. Its therapeutic potential for specific symptoms of schizophrenia warrants further investigation in both preclinical and clinical studies.
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http://dx.doi.org/10.1007/s00210-018-1500-xDOI Listing
July 2018