Publications by authors named "Francisco S Guimarães"

120 Publications

Effect of two oral formulations of cannabidiol on responses to emotional stimuli in healthy human volunteers: pharmaceutical vehicle matters.

Braz J Psychiatry 2021 May 28. Epub 2021 May 28.

Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.

Objective: To compare plasma concentrations of cannabidiol (CBD) following oral administration of two formulations of the drug (powder and dissolved in oil), and to evaluate the effects of these distinct formulations on responses to emotional stimuli in healthy human volunteers.

Methods: In a randomized, double-blind, placebo-controlled, parallel-group design, 45 healthy male volunteers were randomly assigned to three groups of 15 subjects that received either 150 mg of CBD powder; 150 mg of CBD dissolved in corn oil; or placebo. Blood samples were collected at different times after administration, and a facial emotion recognition task was completed after 150 min.

Results: There were no significant differences across groups in the subjective and physiological measures, nor in the facial emotion recognition task. However, groups that received the drug showed statistically significant differences in baseline measures of plasma CBD, with a significantly greater difference in favor of the oil formulation.

Conclusion: When administered as a single 150-mg dose, neither formulation of oral CBD altered responses to emotional stimuli in healthy subjects. The oil-based CBD formulation resulted in more rapid achievement of peak plasma level, with an approximate fourfold increase in oral bioavailability.
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http://dx.doi.org/10.1590/1516-4446-2020-1684DOI Listing
May 2021

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

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

Glial Cells and Their Contribution to the Mechanisms of Action of Cannabidiol in Neuropsychiatric Disorders.

Front Pharmacol 2020 4;11:618065. Epub 2021 Feb 4.

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

Cannabidiol (CBD) is a phytocannabinoid with a broad-range of therapeutic potential in several conditions, including neurological (epilepsy, neurodegenerative diseases, traumatic and ischemic brain injuries) and psychiatric disorders (schizophrenia, addiction, major depressive disorder, and anxiety). The pharmacological mechanisms responsible for these effects are still unclear, and more than 60 potential molecular targets have been described. Regarding neuropsychiatric disorders, most studies investigating these mechanisms have focused on neuronal cells. However, glial cells (astrocytes, oligodendrocytes, microglia) also play a crucial role in keeping the homeostasis of the central nervous system. Changes in glial functions have been associated with neuropathological conditions, including those for which CBD is proposed to be useful. Mostly studies have indicated that CBD modulate the activation of proinflammatory pathways, energy metabolism, calcium homeostasis, and the proliferative rate of glial cells. Likewise, some of the molecular targets proposed for CBD actions are f expressed in glial cells, including pharmacological receptors such as CB1, CB2, PPAR-γ, and 5-HT1A. In the present review, we discuss the currently available evidence suggesting that part of the CBD effects are mediated by interference with glial cell function. We also propose additional studies that need to be performed to unveil the contribution of glial cells to CBD effects in neuropsychiatric disorders.
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http://dx.doi.org/10.3389/fphar.2020.618065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890128PMC
February 2021

Role of 5-HT and 5-HT receptors of the dorsal periaqueductal gray in the anxiety- and panic-modulating effects of antidepressants in rats.

Behav Brain Res 2021 Apr 8;404:113159. Epub 2021 Feb 8.

Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP, Brazil. Electronic address:

Antidepressant drugs are first-line treatment for panic disorder. Facilitation of 5-HT receptor-mediated neurotransmission in the dorsal periaqueductal gray (dPAG), a key panic-associated area, has been implicated in the panicolytic effect of the selective serotonin reuptake inhibitor fluoxetine. However, it is still unknown whether this mechanism accounts for the antipanic effect of other classes of antidepressants drugs (ADs) and whether the 5-HT interaction with 5-HT receptors in this midbrain area (which increases anxiety) is implicated in the anxiogenic effect caused by short-term treatment with ADs. The results showed that previous injection of the 5-HT receptor antagonist WAY-100635 in the dPAG blocked the panicolytic-like effect caused by chronic systemic administration of the tricyclic AD imipramine in male Wistar rats tested in the elevated T-maze. Neither chronic treatment with imipramine nor fluoxetine changed the expression of 5-HT receptors in the dPAG. Treatment with these ADs also failed to significantly change ERK1/2 (extracellular-signal regulated kinase) phosphorylation level in this midbrain area. Blockade of 5-HT receptors in the dPAG with the 5-HT receptor antagonist SB-242084 did not change the anxiogenic effect caused by a single acute injection of fluoxetine or imipramine in the Vogel conflict test. These results reinforce the view that the facilitation of 5-HT receptor-mediated neurotransmission in the dPAG is a common mechanism involved in the panicolytic effect caused by chronic administration of ADs. On the other hand, the anxiogenic effect observed after short-term treatment with these drugs does not depend on 5-HT receptors located in the dPAG.
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http://dx.doi.org/10.1016/j.bbr.2021.113159DOI Listing
April 2021

Increased body sway in phobic patients exposed to images of spiders.

Braz J Psychiatry 2020 Dec 14. Epub 2020 Dec 14.

Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Institutos Nacionais de Ciência e Tecnologia, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.

Objective: The aim of the present study was to analyze the body sway response in specific phobia (SP) patients and healthy controls while viewing neutral, phobic, and disgusting images.

Methods: The participants' heart rate (HR) and skin conductance were also recorded during the procedure. Nineteen patients with arachnophobia and 19 healthy volunteers matched by age, gender, and years of education underwent a postural control test on a stabilometric platform.

Results: The platform recorded increased body sway in the SP group when exposed to spider images (SPI). The SP group presented increases in most parameters (SD, velocity, frequency, area, p ≤ 0.05) when viewing pictures of the SPI category. Psychometric measures of subjective anxiety (State-Trait Anxiety Inventory, STAI) and physiological states (HR; skin conductance responses; spontaneous fluctuations in skin conductance) showed increased anxiety (p ≤ 0.05) in the SP group compared to healthy volunteers. High anxiety levels were observed throughout the assessment, including the task of exposure to SPI (p ≤ 0.05). No significant effect or correlation was found between skin conductance and body sway measures (p > 0.05).

Conclusions: The results of the postural control test suggest the occurrence of a defensive escape response in SP, in agreement with previous evidence.
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http://dx.doi.org/10.1590/1516-4446-2020-1466DOI Listing
December 2020

Are CB2 Receptors a New Target for Schizophrenia Treatment?

Front Psychiatry 2020 30;11:587154. Epub 2020 Oct 30.

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

Schizophrenia is a complex disorder that involves several neurotransmitters such as dopamine, glutamate, and GABA. More recently, the endocannabinoid system has also been associated with this disorder. Although initially described as present mostly in the periphery, cannabinoid type-2 (CB2) receptors are now proposed to play a role in several brain processes related to schizophrenia, such as modulation of dopaminergic neurotransmission, microglial activation, and neuroplastic changes induced by stress. Here, we reviewed studies describing the involvement of the CB2 receptor in these processes and their association with the pathophysiology of schizophrenia. Taken together, these pieces of evidence indicate that CB2 receptor may emerge as a new target for the development of antipsychotic drugs.
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http://dx.doi.org/10.3389/fpsyt.2020.587154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673393PMC
October 2020

Hemopressin as a breakthrough for the cannabinoid field.

Neuropharmacology 2021 02 16;183:108406. Epub 2020 Nov 16.

Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, 7610001, Israel; Department of Pharmacology, Biomedical Science Institute, University of São Paulo, 05508-000, São Paulo, SP, Brazil. Electronic address:

Hemopressin (PVNFKFLSH in rats, and PVNFKLLSH in humans and mice), a fragment derived from the α-chain of hemoglobin, was the first peptide described to have type 1 cannabinoid receptor activity. While hemopressin was shown to have inverse agonist/antagonistic activity, extended forms of hemopressin (i.e. RVD-hemopressin, also called pepcan-12) exhibit type 1 and type 2 cannabinoid receptor agonistic/allosteric activity, and recent studies suggest that they can activate intracellular mitochondrial cannabinoid receptors. Therefore, hemopressin and hemopressin-related peptides could have location-specific and biased pharmacological action, which would increase the possibilities for fine-tunning and broadening cannabinoid receptor signal transduction. Consistent with this, hemopressins were shown to play a role in a number of physiological processes including antinociceptive and anti-inflammatory activity, regulation of food intake, learning and memory. The shortest active hemopressin fragment, NFKF, delays the first seizure induced by pilocarpine, and prevents neurodegeneration in an experimental model of autoimmune encephalomyelitis. These functions of hemopressins could be due to engagement of both cannabinoid and non-cannabinoid receptor systems. Self-assembled nanofibrils of hemopressin have pH-sensitive switchable surface-active properties, and show potential as inflammation and cancer targeted drug-delivery systems. Upon disruption of the self-assembled hemopressin nanofibril emulsion, the intrinsic analgesic and anti-inflammatory properties of hemopressin could help bolster the therapeutic effect of anti-inflammatory or anti-cancer formulations. In this article, we briefly review the molecular and behavioral pharmacological properties of hemopressins, and summarize studies on the intricate and unique mode of generation and binding of these peptides to cannabinoid receptors. Thus, the review provides a window into the current status of hemopressins in expanding the repertoire of signaling and activity by the endocannabinoid system, in addition to their new potential for pharmaceutic formulations.
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http://dx.doi.org/10.1016/j.neuropharm.2020.108406DOI Listing
February 2021

CBD modulates DNA methylation in the prefrontal cortex and hippocampus of mice exposed to forced swim.

Behav Brain Res 2020 06 26;388:112627. Epub 2020 Apr 26.

Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Department of Biomolecular Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; Aarhus Institute of Advanced Studies (AIAS), Aarhus University, Aarhus, Denmark. Electronic address:

Cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa plant, shows therapeutic potential in psychiatric disorders, including depression. The molecular mechanisms underlying the antidepressant-like effects of CBD are not yet understood. Previous studies in differentiated skin cells demonstrated that CBD regulates DNA methylation, an overall repressive epigenetic mechanism. Both stress exposure and antidepressant treatment can modulate DNA methylation in the brain, and lead to gene expression changes associated with depression neurobiology. We investigated herein if the antidepressant effect of CBD could be associated with changes in DNA methylation in the prefrontal cortex (PFC) and hippocampus (HPC) of mice submitted to the forced swimming test (FST). Therefore, we assessed: i) the behavioral effects induced by CBD and DNA methylation inhibitors (DNMTi: 5-AzaD and RG108), alone or in association; ii) the effects induced by CBD and DNMTi in global DNA methylation and DNMT activity, in PFC and HPC. Results showed that treatment with CBD (10 mg/kg), 5-AzaD and RG108 (0.2 mg/kg) induced an antidepressant-like effect in the FST. Similar effects were observed after the combination of sub-effective doses of CBD (7 mg/kg) and 5-AzaD or CBD (7 mg/kg) and RG108 (0.1 mg/kg). Also, stress reduced DNA methylation and DNMT activity in the HPC and increased it in the PFC. CBD and DNMTi treatment prevented these changes in both brain structures. Altogether, our results indicate that CBD regulates DNA methylation in brain regions relevant for depression neurobiology, suggesting that this mechanism could be related to CBD-induced antidepressant effects.
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http://dx.doi.org/10.1016/j.bbr.2020.112627DOI Listing
June 2020

Oral Cannabidiol Does Not Convert to Δ-THC or Δ-THC in Humans: A Pharmacokinetic Study in Healthy Subjects.

Cannabis Cannabinoid Res 2020 Mar 27;5(1):89-98. Epub 2020 Feb 27.

Prati Donaduzzi & Cia Ltda, Toledo, Brazil.

Recent studies have suggested that cannabidiol (CBD) could interconvert into Delta-8- and Delta-9- tetrahydrocannabinol. Thus, we tested the plasma samples of 120 healthy human subjects (60 male and 60 female), 60 in fasting and the other 60 under normal feeding conditions after acute administration of an oral solution containing CBD 300 mg. To do this, we developed a bioanalytical method to determine CBD and the presence of THC in plasma samples by Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry. The results showed that THC was not detected in plasma after the administration of CBD, and those study participants did not present psychotomimetic effects. The findings presented here are consistent with previous evidence suggesting that the oral administration of CBD in a corn oil formulation is a safe route for the administration of the active substance without bioconversion to THC in humans.
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http://dx.doi.org/10.1089/can.2019.0024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173681PMC
March 2020

Serious adverse effects of cannabidiol (CBD): a review of randomized controlled trials.

Expert Opin Drug Metab Toxicol 2020 Jun 27;16(6):517-526. Epub 2020 Apr 27.

Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo , Ribeirão Preto, Brazil.

Introduction: Recent trials using cannabidiol (CBD) have shown that most acute and prolonged adverse effects of CBD are mild to moderate, with rare serious adverse effects (SAEs). This review focused on analyzing SAEs of CBD and their possible relation to drug-drug interactions.

Areas Covered: We systematically analyzed the SAEs reported in randomized controlled trials (RCTs) involving the administration of oral CBD for at least 1 week in both healthy volunteers and clinical samples.

Expert Opinion: SAEs related to CBD in RCT are rare and include mainly elevated transaminases, convulsion, sedation, lethargy, and upper respiratory tract infections. Elevated transaminases are related to concomitant valproate use, while sedation, lethargy, and upper respiratory tract infections are related to concomitant clobazam use. Epileptic patients should be monitored when using CBD concomitantly with these and other antiepileptic drugs for other possible drug-drug interactions.
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http://dx.doi.org/10.1080/17425255.2020.1754793DOI Listing
June 2020

A time-dependent contribution of hippocampal CB , CB and PPARγ receptors to cannabidiol-induced disruption of fear memory consolidation.

Br J Pharmacol 2020 02 21;177(4):945-957. Epub 2020 Jan 21.

Department of Pharmacology, Federal University of Parana, Curitiba, Brazil.

Background And Purpose: In preclinical studies, cannabidiol (CBD) mitigates fear memories by facilitating their extinction or interfering with their generalization and reconsolidation. The brain regions and mechanisms underlying these effects, and their temporal window, are still poorly understood. Here, we have investigated related questions in the dorsal hippocampus (DH) during contextual fear consolidation.

Experimental Approach: Adult male Wistar rats received CBD (10-30 pmol) intra-DH immediately, 1 or 3 hr after fear conditioning. Effects of CBD on consolidation were inferred behaviourally and by analysing expression of the activity-regulated, cytoskeleton-associated (Arc) protein. The contribution of anandamide, CB , CB , 5-HT , A , and PPARγ receptors was also assessed.

Key Results: CBD impaired memory consolidation when given immediately or 1 hr after fear conditioning, but not after 3 hr. Expression of Arc protein in DH was reduced by systemic CBD treatment in both cases. Immediately after fear conditioning, CBD effects were abolished by CB or CB receptor blockade, partly reduced by 5-HT or A antagonism, and remained unchanged after antagonism of PPARγ receptors. One hour after fear conditioning, CBD effects were prevented only by PPARγ receptor antagonism. Also, inhibition of fatty acid amide hydrolase by URB597, impaired memory consolidation when infused immediately, but not 1 hr after fear conditioning.

Conclusions And Implications: CBD disrupts memory consolidation up to 1 hr after fear conditioning, allowing an extended window of opportunity to mitigate aversive memories after their acquisition. Our results suggest time-dependent participation of anandamide, CB , CB and PPARγ receptors in the DH, during this process.
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http://dx.doi.org/10.1111/bph.14895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024734PMC
February 2020

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

Dual mechanism of TRKB activation by anandamide through CB1 and TRPV1 receptors.

PeerJ 2019 21;7:e6493. Epub 2019 Feb 21.

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

Background: Administration of anandamide (AEA) or 2-arachidonoylglycerol (2AG) induces CB1 coupling and activation of TRKB receptors, regulating the neuronal migration and maturation in the developing cortex. However, at higher concentrations AEA also engages vanilloid receptor TRPV1, usually with opposed consequences on behavior.

Methods And Results: Using primary cell cultures from the cortex of rat embryos (E18) we determined the effects of AEA on phosphorylated TRKB (pTRK). We observed that AEA (at 100 and 200 nM) induced a significant increase in pTRK levels. Such effect of AEA at 100 nM was blocked by pretreatment with the CB1 antagonist AM251 (200 nM) and, at the higher concentration of 200 nM by the TRPV1 antagonist capsazepine (200 nM), but mildly attenuated by AM251. Interestingly, the effect of AEA or capsaicin (a TRPV1 agonist, also at 200 nM) on pTRK was blocked by TRKB.Fc (a soluble form of TRKB able to bind BDNF) or capsazepine, suggesting a mechanism dependent on BDNF release. Using the marble-burying test (MBT) in mice, we observed that the local administration of ACEA (a CB1 agonist) into the prelimbic region of prefrontal cortex (PL-PFC) was sufficient to reduce the burying behavior, while capsaicin or BDNF exerted the opposite effect, increasing the number of buried marbles. In addition, both ACEA and capsaicin effects were blocked by previous administration of k252a (an antagonist of TRK receptors) into PL-PFC. The effect of systemically injected CB1 agonist WIN55,212-2 was blocked by previous administration of k252a. We also observed a partial colocalization of CB1/TRPV1/TRKB in the PL-PFC, and the localization of TRPV1 in CaMK2+ cells.

Conclusion: Taken together, our data indicate that anandamide engages a coordinated activation of TRKB, via CB1 and TRPV1. Thus, acting upon CB1 and TRPV1, AEA could regulate the TRKB-dependent plasticity in both pre- and postsynaptic compartments.
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http://dx.doi.org/10.7717/peerj.6493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387754PMC
February 2019

DMH-CBD, a cannabidiol analog with reduced cytotoxicity, inhibits TNF production by targeting NF-kB activity dependent on A receptor.

Toxicol Appl Pharmacol 2019 04 20;368:63-71. Epub 2019 Feb 20.

Department of Pharmacology, Ribeirao Preto Medical School, University of São Paulo, Ribeirao Preto, Brazil. Electronic address:

Cannabidiol (CBD) is a natural compound with psychoactive therapeutic properties well described. Conversely, the immunological effects of CBD are still poorly explored. In this study, the potential anti-inflammatory effects and underlying mechanisms of CBD and its analog Dimethyl-Heptyl-Cannabidiol (DMH-CBD) were investigated using RAW 264.7 macrophages. CBD and DMH-CBD suppressed LPS-induced TNF production and NF-kB activity in a concentration-dependent manner. Both compounds reduced the NF-kB activity in a μM concentration range: CBD (IC = 15 μM) and DMH-CBD (IC = 38 μM). However, the concentrations of CBD that mediated NF-kB inhibition were similar to those that cause cytotoxicity (LC = 58 μM). Differently, DMH-CBD inhibited the NF-kB activation without cytotoxic effects at the same concentrations, although it provokes cytotoxicity at long-term exposure. The inhibitory action of the DMH-CBD on NF-kB activity was not related to the reduction in IkBα degradation or either p65 (NF-kB) translocation to the nucleus, although it decreased p38 MAP kinase phosphorylation. Additionally, 8-(3-Chlorostyryl) caffeine (CSC), an A antagonist, reversed the effect of DMH-CBD on NF-kB activity in a concentration-dependent manner. Collectively, our results demonstrated that CBD reduces NF-kB activity at concentrations intimately associated with those that cause cell death, whereas DMH-CBD decreases NF-kB activity at non-toxic concentrations in an A receptor dependent-manner.
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http://dx.doi.org/10.1016/j.taap.2019.02.011DOI Listing
April 2019

Role of the endocannabinoid system in the dorsal hippocampus in the cardiovascular changes and delayed anxiety-like effect induced by acute restraint stress in rats.

J Psychopharmacol 2019 05 21;33(5):606-614. Epub 2019 Feb 21.

1 Department of Pharmacology, Medical School of Ribeirão Preto, University of São Paulo (FMRP-USP), Ribeirão Preto, São Paulo, Brazil.

Background: The dorsal hippocampus has a central role in modulating cardiovascular responses and behavioral adaptation to stress. The dorsal hippocampus also plays a key role in stress-associated mental disorders. The endocannabinoid system is widely expressed in the dorsal hippocampus and modulates defensive behaviors under stressful conditions. The endocannabinoid anandamide activates cannabinoid type 1 receptors and is metabolized by the fatty acid amide hydrolase enzyme.

Aims: We sought to verify whether cannabinoid type 1 receptors modulate stress-induced cardiovascular changes, and if pharmacological fatty acid amide hydrolase inhibition in the dorsal hippocampus would prevent the cardiovascular responses and the delayed anxiogenic-like behavior evoked by restraint stress in rats via cannabinoid type 1 receptors.

Methods: Independent groups received intra-dorsal-hippocampal injections of N-(piperidin-1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-hpyrazole-3-carboxamide (AM251; cannabinoid type 1 receptor antagonist/inverse agonist, 10-300 pmol) and/or cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB597; fatty acid amide hydrolase inhibitor, 10 pmol) before the restraint stress session. Cardiovascular response during restraint stress or later behavioral parameters were evaluated.

Results: Acute restraint stress altered the cardiovascular response, characterized by increased heart rate and mean arterial pressure, as well as decreased tail cutaneous temperature. It also induced a delayed anxiogenic-like effect, evidenced by reduced open arm exploration in the elevated plus maze 24 h after stress. AM251 exacerbated the stress-induced cardiovascular responses after injection into the dorsal hippocampus. In contrast, local injection of URB597 prevented the cardiovascular response and the delayed (24 h) behavioral consequences of restraint stress, effects attenuated by pretreatment with AM251.

Conclusion: Our data corroborate previous results indicating that the hippocampal endocannabinoid system modulates the outcome of stress exposure and suggest that this could involve modulation of the cardiovascular response during stress exposure.
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http://dx.doi.org/10.1177/0269881119827799DOI Listing
May 2019

Is cannabidiol the ideal drug to treat non-motor Parkinson's disease symptoms?

Eur Arch Psychiatry Clin Neurosci 2019 Feb 31;269(1):121-133. Epub 2019 Jan 31.

Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by motor symptoms such as bradykinesia, rest tremor, postural disturbances, and rigidity. PD is also characterized by non-motor symptoms such as sleep disturbances, cognitive deficits, and psychiatric disorders such as psychosis, depression, and anxiety. The pharmacological treatment for these symptoms is limited in efficacy and induce significant adverse reactions, highlighting the need for better treatment options. Cannabidiol (CBD) is a phytocannabinoid devoid of the euphoriant and cognitive effects of tetrahydrocannabinol, and preclinical and preliminary clinical studies suggest that this compound has therapeutic effect in non-motor symptoms of PD. In the present text, we review the clinical studies of cannabinoids in PD and the preclinical and clinical studies specifically on CBD. We found four randomized controlled trials (RCTs) involving the administration of agonists/antagonists of the cannabinoid 1 receptor, showing that these compounds were well tolerated, but only one study found positive results (reductions on levodopa-induced dyskinesia). We found seven preclinical models of PD using CBD, with six studies showing a neuroprotective effect of CBD. We found three trials involving CBD and PD: an open-label study, a case series, and an RCT. CBD was well tolerated, and all three studies reported significant therapeutic effects in non-motor symptoms (psychosis, rapid eye movement sleep behaviour disorder, daily activities, and stigma). However, sample sizes were small and CBD treatment was short (up to 6 weeks). Large-scale RCTs are needed to try to replicate these results and to assess the long-term safety of CBD.
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http://dx.doi.org/10.1007/s00406-019-00982-6DOI Listing
February 2019

Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test.

Braz J Psychiatry 2019 Jan-Feb;41(1):9-14. Epub 2018 Oct 11.

Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.

Objective: Cannabidiol (CBD), one of the non-psychotomimetic compounds of Cannabis sativa, causes anxiolytic-like effects in animals, with typical bell-shaped dose-response curves. No study, however, has investigated whether increasing doses of this drug would also cause similar curves in humans. The objective of this study was to compare the acute effects of different doses of CBD and placebo in healthy volunteers performing a simulated public speaking test (SPST), a well-tested anxiety-inducing method.

Method: A total of 57 healthy male subjects were allocated to receive oral CBD at doses of 150 mg (n=15), 300 mg (n=15), 600 mg (n=12) or placebo (n=15) in a double-blind procedure. During the SPST, subjective ratings on the Visual Analogue Mood Scale (VAMS) and physiological measures (systolic and diastolic blood pressure, heart rate) were obtained at six different time points.

Results: Compared to placebo, pretreatment with 300 mg of CBD significantly reduced anxiety during the speech. No significant differences in VAMS scores were observed between groups receiving CBD 150 mg, 600 mg and placebo.

Conclusion: Our findings confirm the anxiolytic-like properties of CBD and are consonant with results of animal studies describing bell-shaped dose-response curves. Optimal therapeutic doses of CBD should be rigorously determined so that research findings can be adequately translated into clinical practice.
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http://dx.doi.org/10.1590/1516-4446-2017-0015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781714PMC
February 2019

Translational Investigation of the Therapeutic Potential of Cannabidiol (CBD): Toward a New Age.

Front Immunol 2018 21;9:2009. Epub 2018 Sep 21.

Department of Neurosciences and Behavior, Faculty of Medicine of Ribeirão Preto, University of São Paulo, São Paulo, Brazil.

Among the many cannabinoids in the cannabis plant, cannabidiol (CBD) is a compound that does not produce the typical subjective effects of marijuana. The aim of the present review is to describe the main advances in the development of the experimental and clinical use of cannabidiol CBD in neuropsychiatry. A non-systematic search was performed for studies dealing with therapeutic applications of CBD, especially performed by Brazilian researchers. CBD was shown to have anxiolytic, antipsychotic and neuroprotective properties. In addition, basic and clinical investigations on the effects of CBD have been carried out in the context of many other health conditions, including its potential use in epilepsy, substance abuse and dependence, schizophrenia, social phobia, post-traumatic stress, depression, bipolar disorder, sleep disorders, and Parkinson. CBD is an useful and promising molecule that may help patients with a number of clinical conditions. Controlled clinical trials with different neuropsychiatric populations that are currently under investigation should bring important answers in the near future and support the translation of research findings to clinical settings.
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http://dx.doi.org/10.3389/fimmu.2018.02009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161644PMC
September 2019

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

Hippocampal mammalian target of rapamycin is implicated in stress-coping behavior induced by cannabidiol in the forced swim test.

J Psychopharmacol 2018 08 3;32(8):922-931. Epub 2018 Jul 3.

1 Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil.

Background: Cannabidiol is a non-psychotomimetic compound with antidepressant-like effects. However, the mechanisms and brain regions involved in cannabidiol effects are not yet completely understood. Brain-derived neurotrophic factor/tropomyosin-receptor kinase B/mammalian target of rapamycin (BDNF-TrkB-mTOR) signaling, especially in limbic structures, seems to play a central role in mediating the effects of antidepressant drugs.

Aim: Since it is not yet known if BDNF-TrkB-mTOR signaling in the hippocampus is critical to the antidepressant-like effects of cannabidiol, we investigated the effects produced by cannabidiol (10/30/60 nmol/0.2 µL) micro-injection into the hippocampus of mice submitted to the forced swim test and to the open field test.

Methods: Independent groups received intra-hippocampal injections of rapamycin (mTOR inhibitor, 0.2 nmol/0.2 µL) or K252 (Trk antagonist, 0.01 nmol/0.2 µL), before the systemic (10 mg/kg) or hippocampal (10 nmol/0.2µL) injection of cannabidiol, and were submitted to the same tests. BDNF levels were analyzed in the hippocampus of animals treated with cannabidiol (10 mg/kg).

Results: Systemic cannabidiol administration induced antidepressant-like effects and increased BDNF levels in the dorsal hippocampus. Rapamycin, but not K252a, injection into the dorsal hippocampus prevented the antidepressant-like effect induced by systemic cannabidiol treatment (10 mg/kg). Differently, hippocampal administration of cannabidiol (10 nmol/0.2 µL) reduced immobility time, an effect that was blocked by both rapamycin and K252a local microinjection.

Conclusion: Altogether, our data suggest that the hippocampal BDNF-TrkB-mTOR pathway is vital for cannabidiol-induced antidepressant-like effect when the drug is locally administered. However, other brain regions may also be involved in cannabidiol-induced antidepressant effect upon systemic administration.
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http://dx.doi.org/10.1177/0269881118784877DOI Listing
August 2018

Chronic cannabidiol exposure promotes functional impairment in sexual behavior and fertility of male mice.

Reprod Toxicol 2018 10 21;81:34-40. Epub 2018 Jun 21.

Department of Pharmacology, Laboratory of Physiology and Pharmacology of Reproduction, Universidade Federal de Goiás, Goiânia, GO, Brazil. Electronic address:

Cannabidiol (CBD) is a potent substance extracted from Cannabis sativa. As it has been suggested that marijuana can affect the reproductive system, we decided to assess the effects of chronic CBD exposure on the male reproductive system in an animal model. 21-day old male Swiss mice received CBD for 34 consecutive days at doses (p.o.) of either 15 or 30 mg/kg, and a control group received sunflower oil. Body weight gain and circulating progesterone concentration did not significantly change in CBD-treated animals. In the sexual behavior analysis, the CBD 15 group presented a delay in performing the first mount and intromission, and a reduced number of mounts and ejaculations. The CBD 30 group showed a 30% reduction in fertility rate and a 23% reduction in the number of litters. Our results indicate that chronic CBD exposure promotes functional impairment of the reproductive system of male Swiss mice.
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http://dx.doi.org/10.1016/j.reprotox.2018.06.013DOI Listing
October 2018

Antidepressant-like effect induced by Cannabidiol is dependent on brain serotonin levels.

Prog Neuropsychopharmacol Biol Psychiatry 2018 08 6;86:255-261. Epub 2018 Jun 6.

Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, Brazil; Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Denmark. Electronic address:

Cannabidiol (CBD) is a compound of Cannabis sativa with relevant therapeutic potential in several neuropsychiatric disorders including depression. CBD treatment has shown significant antidepressant-like effects in different rodent preclinical models. However, the mechanisms involved in CBD-induced antidepressant effects are still poorly understood. Therefore, this work aimed at investigating the participation of serotonin (5-HT) and/or noradrenaline (NA) in CBD-induced antidepressant-like effects in the forced swimming test (FST) by: 1) testing if CBD co-administration with serotonergic (fluoxetine, FLX) or noradrenergic (desipramine, DES) antidepressants would have synergistic effects; and 2) investigating if 5-HT or NA depletion would impair CBD-induced behavioral effects. Results showed that CBD (10 mg/kg), FLX (10 mg/kg) and DES (5 mg/kg) induced antidepressant-like effects in mice submitted to FST. Ineffective doses of CBD (7 mg/kg), when co-administered with ineffective doses of FLX (5 mg/kg) or DES (2.5 mg/kg) resulted in significant antidepressant-like effects, thus implicating synergistic and/or additive mechanisms. Pretreatment with PCPA (an inhibitor of serotonin synthesis: 150 mg/kg, i.p., once per day for 4 days), but not DSP-4 (a noradrenergic neurotoxin: 1 μg/μl, i.c.v., 24 h before the test), reduced monoamine levels in the brain. However, only PCPA treatment abolished CBD-induced behavioral effects in FST, indicating the participation of serotonergic mechanisms. None of the treatments induced locomotor effects. Our results suggest that the antidepressant-like effect induced by CBD in the FST is dependent on serotonin levels in the central nervous system (CNS).
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http://dx.doi.org/10.1016/j.pnpbp.2018.06.002DOI Listing
August 2018

Cannabidiol Induces Rapid and Sustained Antidepressant-Like Effects Through Increased BDNF Signaling and Synaptogenesis in the Prefrontal Cortex.

Mol Neurobiol 2019 Feb 4;56(2):1070-1081. Epub 2018 Jun 4.

Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.

Currently available antidepressants have a substantial time lag to induce therapeutic response and a relatively low efficacy. The development of drugs that addresses these limitations is critical to improving public health. Cannabidiol (CBD), a non-psychotomimetic component of Cannabis sativa, is a promising compound since it shows large-spectrum therapeutic potential in preclinical models and humans. However, its antidepressant properties have not been completely investigated. Therefore, the aims of this study were to investigate in male rodents (i) whether CBD could induce rapid and sustained antidepressant-like effects after a single administration and (ii) whether such effects could be related to changes in synaptic proteins/function. Results showed that a single dose of CBD dose-dependently induced antidepressant-like effect (7-30 mg/kg) in Swiss mice submitted to the forced swim test (FST), 30 min (acute) or 7 days (sustained) following treatment. Similar effects were observed in the Flinders Sensitive and Flinders Resistant Line (FSL/FRL) rats and the learned helplessness (LH) paradigm using Wistar rats. The acute antidepressant effects (30 min) were associated with increased expression of synaptophysin and PSD95 in the medial prefrontal cortex (mPFC) and elevated BDNF levels in both mPFC and hippocampus (HPC). CBD also increased spine density in the mPFC after 30 min, but not 7 days later. Intracerebroventricular injection of the TrkB antagonist, K252a (0.05 nmol/μL), or the mTOR inhibitor, rapamycin (1 nmol/μL), abolished the behavioral effects of CBD. These results indicate that CBD induces fast and sustained antidepressant-like effect in distinct animal models relevant for depression. These effects may be related to rapid changes in synaptic plasticity in the mPFC through activation of the BDNF-TrkB signaling pathway. The data support a promising therapeutic profile for CBD as a new fast-acting antidepressant drug.
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http://dx.doi.org/10.1007/s12035-018-1143-4DOI Listing
February 2019

Chronic exposure to cannabidiol induces reproductive toxicity in male Swiss mice.

J Appl Toxicol 2018 09 16;38(9):1215-1223. Epub 2018 May 16.

Department of Pharmacology, Laboratory of Physiology and Pharmacology of Reproduction, Universidade Federal de Goiás, Goiânia, GO, Brazil.

Children and adults with frequent and severe episodes of epilepsy that do not respond to standard treatments (such as carbamazepine, phenytoin and valproate) have long been prescribed cannabidiol (CBD) as an anticonvulsant drug. However, the safety of its chronic use in relation to reproduction has not been fully examined. This study aimed to assess the effects of chronic CBD exposure on the male reproductive system. CBD was orally administered to 21-day-old male Swiss mice at doses of 15 and 30 mg kg daily (CBD 15 and 30 groups, respectively), with a control group receiving sunflower oil, for 34 consecutive days. After a 35 day recovery period, the following parameters were evaluated: weight of reproductive organs, testosterone concentration, spermatogenesis, histomorphometry, daily sperm production and its morphology. The CBD 30 group had a 76% decrease in total circulating testosterone, but it remained within the physiological normal range (240-1100 ng dl ). CBD treatment induced a significant increase in the frequency of stages I-IV and V-VI of spermatogenesis, and a decrease in the frequency of stages VII-VIII and XII. A significant decrease in the number of Sertoli cells was observed only in the CBD 30 group. In both CBD groups the number of spermatozoa in the epididymis tail was reduced by 38%, sperm had head abnormalities, and cytoplasmic droplets were observed in the medial region of flagellum. These results indicated that chronic CBD exposure was associated with changes in the male reproductive system, suggesting its reproductive toxicity.
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http://dx.doi.org/10.1002/jat.3631DOI Listing
September 2018

Cannabinoid signalling in embryonic and adult neurogenesis: possible implications for psychiatric and neurological disorders.

Acta Neuropsychiatr 2019 Feb 16;31(1):1-16. Epub 2018 May 16.

3Department of Pharmacology,School of Medicine of Ribeirão Preto,University of São Paulo,Ribeirão Preto,Brazil.

Cannabinoid signalling modulates several aspects of brain function, including the generation and survival of neurons during embryonic and adult periods. The present review intended to summarise evidence supporting a role for the endocannabinoid system on the control of neurogenesis and neurogenesis-dependent functions. Studies reporting participation of cannabinoids on the regulation of any step of neurogenesis and the effects of cannabinoid compounds on animal models possessing neurogenesis-dependent features were selected from Medline. Qualitative evaluation of the selected studies indicated that activation of cannabinoid receptors may change neurogenesis in embryonic or adult nervous systems alongside rescue of phenotypes in animal models of different psychiatric and neurological disorders. The text offers an overview on the effects of cannabinoids on central nervous system development and the possible links with psychiatric and neurological disorders such as anxiety, depression, schizophrenia, brain ischaemia/stroke and Alzheimer's disease. An understanding of the mechanisms by which cannabinoid signalling influences developmental and adult neurogenesis will help foster the development of new therapeutic strategies for neurodevelopmental, psychiatric and neurological disorders.
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http://dx.doi.org/10.1017/neu.2018.11DOI Listing
February 2019

CD36 Shunts Eicosanoid Metabolism to Repress CD14 Licensed Interleukin-1β Release and Inflammation.

Front Immunol 2018 27;9:890. Epub 2018 Apr 27.

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

Interleukin (IL)-1β is a potential target for treatment of several inflammatory diseases, including envenomation by the scorpion . In this context, bioactive lipids such as prostaglandin (PG)E and leukotriene (LT)B modulate the production of IL-1β by innate immune cells. Pattern recognition receptors (PRRs) that perceive venom (TsV), and orchestrate LTB, PGE, and cyclic adenosine monophosphate (cAMP) production to regulate IL-1β release are unknown. Furthermore, molecular mechanisms driving human cell responses to TsV remain uncharacterized. Here, we identified that both CD14 and CD36 control the synthesis of bioactive lipids, inflammatory cytokines, and mortality mediated by TsV. CD14 induces PGE/cAMP/IL-1β release and inflammation. By contrast, CD36 shunts eicosanoid metabolism toward production of LTB, which represses the PGE/cAMP/IL-1β axis and mortality. Of importance, the molecular mechanisms observed in mice strongly correlate with those of human cell responses to TsV. Overall, this study provides major insights into molecular mechanisms connecting CD14 and CD36 with differential eicosanoid metabolism and inflammation mediated by IL-1β.
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http://dx.doi.org/10.3389/fimmu.2018.00890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5934479PMC
July 2019