Stroke epidemiology in southern Brazil: Investigating the relationship between stroke severity, hospitalization costs, and health-related quality of life.

We aimed with the present study to fill the gap on the performance and safety of stroke management and the costs related to hospitalizations, the relevant comorbidities associated with stroke patients, and the stroke patient outcomes health-related quality of life (HRQOL) progress. Our study investigated the clinical, neurological, and social impact of stroke in 220 patients in a tertiary hospital located in the countryside of the state of Santa Catarina, Brazil. Description of clinical and neurological characteristics of stroke patients between 2015 to 2020 was analyzed using electronic medical records. The most affected age group was 61-80 years, being female the most affected sex. Almost 89.5% of the patients had some risk factor, with a higher prevalence of ischemic stroke. This type of stroke was the expensive, in terms of hospitalization, with an average cost of $74.10. Considering the stroke-specific quality of life scale (SSQOL) score, 88.3% of patients who demonstrated some comorbidity and 47.6% of women had lower quality of life levels post-stroke. Our data could be useful to substantiate a data-base with epidemiology statistics characterization of stroke hospitalizations, indicating the severity of stroke for the patient.

Bradykinin Receptors Play a Critical Role in the Chronic Post-ischaemia Pain Model.

Complex regional pain syndrome type-I (CRPS-I) is a chronic painful condition resulting from trauma. Bradykinin (BK) is an important inflammatory mediator required in acute and chronic pain response. The objective of this study was to evaluate the association between BK receptors (B1 and B2) and chronic post-ischaemia pain (CPIP) development in mice, a widely accepted CRPS-I model. We assessed mechanical and cold allodynia, and paw oedema in male and female Swiss mice exposed to the CPIP model. Upon induction, the animals were treated with BKR antagonists (HOE-140 and DALBK); BKR agonists (Tyr-BK and DABK); antisense oligonucleotides targeting B1 and B2 and captopril by different routes in the model (7, 14 and 21 days post-induction). Here, we demonstrated that treatment with BKR antagonists, by intraperitoneal (i.p.), intraplantar (i.pl.), and intrathecal (i.t.) routes, mitigated CPIP-induced mechanical allodynia and oedematogenic response, but not cold allodynia. On the other hand, i.pl. administration of BKR agonists exacerbated pain response. Moreover, a single treatment with captopril significantly reversed the anti-allodynic effect of BKR antagonists. In turn, the inhibition of BKRs gene expression in the spinal cord inhibited the nociceptive behaviour in the 14th post-induction. The results of the present study suggest the participation of BKRs in the development and maintenance of chronic pain associated with the CPIP model, possibly linking them to CRPS-I pathogenesis.

Citral Inhibits the Inflammatory Response and Hyperalgesia in Mice: The Role of TLR4, TLR2/Dectin-1, and CB2 Cannabinoid Receptor/ATP-Sensitive K+ Channel Pathways.

Citral ((2E)-3,7-dimethylocta-2,6-dienal), a bioactive component of lemongrass, inhibits oxidant activity, nuclear factor kappa B (NF-κB) activation, and cyclooxygenase-2 (COX-2) expression, even as it activates peroxisome proliferator-activated receptor (PPAR)-α and γ. Additionally, citral produces long-lasting inhibition of transient receptor potential (TRP) channels that are found in sensory neurons, such as TRPV1-3 and TRPM8, while it transiently blocks TRPV4 and TRPA1. Here, the effect of citral in experimental models of acute inflammation and hyperalgesia in mice, and the underlying citral mechanisms of action were investigated. ADMET properties and molecular targets were predicted using the online server. The immunomodulatory and antihyperalgesic effects of citral were evaluated, using mechanical and thermal stimuli, at different time-points on carrageenan, lipopolysaccharides (LPS), and zymosan-induced paw edema and hyperalgesia in mice. ADMET analysis ensures that the citral has not violated Lipinski's rule of five, indicating its safety consumption, and molecular target prediction software identified that citral is a potential fatty acid amide hydrolase (FAAH) inhibitor. Oral treatment with citral (50-300 mg/kg) significantly inhibited carrageenan-induced paw edema and thermal allodynia. Furthermore, citral modulated the inflammation induced by LPS and zymosan, toll-like receptor (TLR) 4, and TLR2/dectin-1 ligands, respectively. Moreover, pretreatment with cannabinoid receptor type 2 (CB2R) antagonists and ATP-sensitive K+ channel inhibitor, but not with a cannabinoid receptor type 1 (CB1R) antagonist, significantly reversed the anti-inflammatory effect of citral. Intriguingly, citral did not cause any relevant action in the central nervous system, and it was safe when assessed in a 14 day toxicity assay in male mice. Therefore, citral constitutes a promising, innovative, and safe molecule for the management of immunoinflammatory conditions and pain states.

Terpenoids, Cannabimimetic Ligands, beyond the Cannabis Plant.

Medicinal use of Cannabis sativa L. has an extensive history and it was essential in the discovery of phytocannabinoids, including the Cannabis major psychoactive compound-Δ9-tetrahydrocannabinol (Δ9-THC)-as well as the G-protein-coupled cannabinoid receptors (CBR), named cannabinoid receptor type-1 (CB1R) and cannabinoid receptor type-2 (CB2R), both part of the now known endocannabinoid system (ECS). Cannabinoids is a vast term that defines several compounds that have been characterized in three categories: (i) endogenous, (ii) synthetic, and (iii) phytocannabinoids, and are able to modulate the CBR and ECS. Particularly, phytocannabinoids are natural terpenoids or phenolic compounds derived from Cannabis sativa. However, these terpenoids and phenolic compounds can also be derived from other plants (non-cannabinoids) and still induce cannabinoid-like properties. Cannabimimetic ligands, beyond the Cannabis plant, can act as CBR agonists or antagonists, or ECS enzyme inhibitors, besides being able of playing a role in immune-mediated inflammatory and infectious diseases, neuroinflammatory, neurological, and neurodegenerative diseases, as well as in cancer, and autoimmunity by itself. In this review, we summarize and critically highlight past, present, and future progress on the understanding of the role of cannabinoid-like molecules, mainly terpenes, as prospective therapeutics for different pathological conditions.

Medicinal plants in Brazil: Pharmacological studies, drug discovery, challenges and perspectives.

This review article focuses on pre-clinical and clinical studies with some selected Brazilian medicinal plants in different areas of interest, conducted by research groups in Brazil and abroad. It also highlights the Brazilian market of herbal products and the efforts of Brazilian scientists to develop new phytomedicines. This review is divided into three sections. The section I describes the Brazilian large biodiversity and some attempts of Brazilian scientists to assess the pharmacological profile of most plant extracts or isolated active principles. Of note, Brazilian scientists have made a great effort to study the Brazilian biodiversity, especially among the higher plants. In fact, more than 10,000 papers were published on plants in international scientific journals between 2011 and 2013. This first part also discussed the main efforts to develop new medicines from plants, highlighting the Brazilian phytomedicines market. Despite the large Brazilian biodiversity, notably with the higher plants, which comprise over 45,000 species (20-22% of the total worldwide), and the substantial number of scientific publications on medicinal plants, only one phytomedicine is found in the top 20 market products. Indeed, this market is still only worth about 261 million American dollars. This represents less than 5% of the global Brazilian medicine market. The section II of this review focus on the use of Brazilian plant extract and/or active principles for some selected diseases, namely: central nervous systems disorders, pain, immune response and inflammation, respiratory diseases, gastrointestinal tract and metabolic diseases. Finally, section III discusses in more details some selected Brazilian medicinal plants including: Cordia verbenacea, Euphorbia tirucalli, Mandevilla velutina, Phyllanthus spp., Euterpe oleracea, Vitis labrusca, Hypericum caprifoliatum and Hypericum polyanthemum, Maytenus ilicifolia, Protium kleinii and Protium heptaphylium and Trichilia catigua. Most of these publications are preliminary and only report the effects of crude extracts, both in vitro and in vivo studies. Only very few studies have been dedicated to investigate the mechanisms of action of isolated compounds. Likewise, studies on safety (toxicology), pharmacokinetic, and especially on well-conducted clinical trials are rare. In conclusion, in spite of the abundant Brazilian biodiversity and the thousands of academic publications on plants in international peer-reviewed scientific journals, few patents and medicines have been derived from such studies. Undoubtedly, great efforts must be made to improve the development of plant-derived medicine market in Brazil, especially by involving the partnership between academia and pharmaceutical companies.

Maresin 1, a proresolving lipid mediator derived from omega-3 polyunsaturated fatty acids, exerts protective actions in murine models of colitis.

It has been previously reported that dietary fish oils, which are rich in the polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid, can exert beneficial effects in inflammatory bowel disease. In this study, we investigated the effects of docosahexaenoic acid-derived lipid mediator maresin 1 (MaR1) in dextran sulfate sodium (DSS)- and 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice. Systemic treatment with MaR1 significantly attenuated both DSS- and 2,4,6-trinitrobenzene sulfonic acid-induced colonic inflammation by improving the disease activity index and reducing body weight loss and colonic tissue damage. MaR1 treatment also induced a significant decrease in levels of inflammatory mediators, such as IL-1ß, TNF-α, IL-6, and IFN-γ, in the acute protocol, as well as IL-1ß and IL-6, but not TNF-α and INF-γ, in the chronic DSS colitis protocol. Additionally, MaR1 decreased ICAM-1 mRNA expression in both the acute and chronic protocols of DSS-induced colitis. Furthermore, the beneficial effects of MaR1 seem to be associated with inhibition of the NF-κB pathway. Moreover, incubation of LPS-stimulated bone marrow-derived macrophage cultures with MaR1 reduced neutrophil migration and reactive oxygen species production, besides decreasing IL-1ß, TNF-α, IL-6, and INF-γ production. Interestingly, macrophages incubated only with MaR1 showed a significant upregulation of mannose receptor C, type 1 mRNA expression, an M2 macrophage phenotype marker. These results indicate that MaR1 consistently protects mice against different models of experimental colitis, possibly by inhibiting the NF-κB pathway and consequently multiple inflammatory mediators, as well as by enhancing the macrophage M2 phenotype.

The role of kinin B1 and B2 receptors in the persistent pain induced by experimental autoimmune encephalomyelitis (EAE) in mice: evidence for the involvement of astrocytes.

Multiple sclerosis (MS) is a progressive, demyelinating inflammatory disease of the human central nervous system (CNS). While the primary symptoms of MS affect motor function, it is now recognized that chronic pain is a relevant symptom that affects both animals and MS patients. There is evidence that glial cells, such as astrocytes, play an important role in the development and maintenance of chronic pain. Kinins, notably bradykinin (BK) acting through B1 (B1R) and B2 (B2R) receptors, play a central role in pain and inflammatory processes. However, it remains unclear whether kinin receptors are involved in neuropathic pain in MS. Here we investigated by genetic and pharmacological approaches the role of kinin receptors in neuropathic pain behaviors induced in the experimental autoimmune encephalomyelitis (EAE) mouse model. Our results showed that gene deletion or antagonism of kinin receptors, especially B1R, significantly inhibited both tactile and thermal hypersensitivity in EAE animals. By contrast, animals with EAE and treated with a B1R selective agonist displayed a significant increase in tactile hypersensitivity. We also observed a marked increase in B1R mRNA and protein level in the mouse spinal cord 14days after EAE immunization. Blockade of B1R significantly suppressed the levels of mRNAs for IL-17, IFN-γ, IL-6, CXCL-1/KC, COX-2 and NOS2, as well as glial activation in the spinal cord. Of note, the selective B1 antagonist DALBK consistently prevented IFN-induced up-regulation of TNF-α and IL-6 release in astrocyte culture. Finally, both B1R and B2R antagonists significantly inhibited COX-2 and NOS2 expression in primary astrocyte culture. The B1R was co-localized with immunomarker of astrocytes in the spinal cord of EAE-treated animals. The above data constitute convincing experimental evidence indicating that both kinin receptors, especially the B1 subtype, exert a critical role in the establishment of persistent hypersensitivity observed in the EAE model, an action that seems to involve a central inflammatory process, possibly acting on astrocytes. Thus, B1 selective antagonists or drugs that reduce kinin release may have the potential to treat neuropathic pain in patients suffering from MS.

Spatial reference memory deficits precede motor dysfunction in an experimental autoimmune encephalomyelitis model: the role of kallikrein-kinin system.

Multiple sclerosis (MS) is a progressive T cell-mediated autoimmune demyelinating inflammatory disease of the central nervous system (CNS). Although it is recognized that cognitive deficits represent a manifestation of the disease, the underlying pathogenic mechanisms remain unknown. Here we provide evidence of spatial reference memory impairments during the pre-motor phase of experimental autoimmune encephalomyelitis (EAE) in mice. Specifically, these cognitive deficits were accompanied by down-regulation of choline acetyltransferase (ChAT) mRNA expression on day 5 and 11 post-immunization, and up-regulation of inflammatory cytokines in the hippocampus and prefrontal cortex. Moreover, a marked increase in B1R mRNA expression occurred selectively in the hippocampus, whereas protein level was up-regulated in both brain areas. Genetic deletion of kinin B1R attenuated cognitive deficits and cholinergic dysfunction, and blocked mRNA expression of both IL-17 and IFN-γ in the prefrontal cortex, lymph node and spleen of mice subjected to EAE. The discovery of kinin receptors, mainly B1R, as a target for controlling neuroinflammatory response, as well as the cognitive deficits induced by EAE may foster the therapeutic exploitation of the kallikrein-kinin system (KKS), in particular for the treatment of autoimmune disorders, such as MS, mainly during pre-symptomatic phase.

Therapeutic ultrasound ameliorates hyperalgesia and edema on CFA-induced persistent inflammatory response in mice.

BACKGROUND: The present study investigated the effects of pulsed and continuous ultrasound (USP and USC) in edema and hyperalgesia after chronic inflammatory process induced by Complete Freund's Adjuvant-CFA and analyzing the relationship of the application frequency of ultrasound, in pro- and anti-inflammatory cytokine production. METHODS: Forty-five animals were divided into 9 groups; all animals from groups 2 to 9 were subjected to a persistent inflammation model induced by CFA in mice. We report the effects and the underlying action mechanisms of USP and USC in the animals which were irradiated two, three or five times a week on the left hind paw. The analyses performed in this study were: evaluation of hind paw edema through the plethysmometer, evaluation of thermal hyperalgesia through withdrawal test using a water container at 44.5°C (± 0.5°C), and the plantar region of the left paw which was removed for analysis of cytokines. RESULTS: Our results showed that USP and USC consistently reduced paw edema, and pulsed ultrasound showed a higher significant effect than the continuous mode. Moreover, groups with irradiation frequency of five times a week presented an inhibition of the edema, and groups with frequency of three or two times a week reduced mainly hyperalgesia, in comparison with the control group. The beneficial effects of the US then seem to be associated with upregulation of anti- and pro-inflammatory mediators, such as IL-10 and IL-6, respectively. CONCLUSION: This study provided evidence that ultrasound constitutes an important non-pharmacological intervention for the management of inflammatory and pain states.

Hippocampal PKA/CREB pathway is involved in the improvement of memory induced by spermidine in rats.

Spermidine (SPD) is an endogenous polyamine that modulates N-methyl-D-aspartate (NMDA) receptor function, and has been reported to facilitate memory formation. In the current study we determined whether or not the PKA/CREB signaling pathway is involved in SPD-induced facilitation of memory of inhibitory avoidance task in adult rats. The post-training administration of the cAMP-dependent protein kinase (PKA) inhibitor, N-[2-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide [H-89, 0.5 ρmol intrahippocampal (ih)] or the antagonist of the NMDA receptor polyamine-binding site (arcaine, 0.02 nmol ih) with SPD (0.2 nmol ih) prevented memory improvement induced by SPD. Intrahippocampal administration of SPD (0.2 nmol) facilitated PKA and cAMP response element-binding protein (CREB) phosphorylation in the hippocampus 180 min, but not 30 min, after administration, and increased translocation of the catalytic subunit of PKA into the nucleus. Arcaine (0.02 nmol) and H-89 (0.5 ρmol) prevented the stimulatory effect of SPD on PKA and CREB phosphorylation. These results suggest that memory enhancement induced by the ih administration of SPD involves the PKA/CREB pathways in rats.

Chia oil prevents chemical and immune-mediated inflammatory responses in mice: Evidence for the underlying mechanisms.

Chia (Salvia hispanica L.) is an herbaceous plant used as omega-3 polyunsaturated fatty acid (ω-3 PUFA) source that presents a range of beneficial effects on human health. Herein, it was used a chia oil containing over than 62% of α-linolenic acid (ALA), a compound widely related to anti-inflammatory actions. Chia oil effect was tested using paw edema and mechanical hyperalgesia induced by carrageenan, and ear edema induced by croton oil, histamine, and capsaicin. Croton oil was used in both preventive and therapeutic treatment schedules of chia oil while histamine and capsaicin were used only in preventive treatment schedule. Chia oil mechanism of action was investigated using nociception and paw edema response induced by intraplantar injection of acidified saline (ASIC activator), PGE2 (prostaglandin pathway), cinnamaldehyde (TRPA1 activator), bradykinin (BK pathway), menthol (TRPM8 activator), and capsaicin (TRPV1 activator). Further, RT-PCR for inflammatory mediators (TRPA1, NF-κB, PPAR-γ, COX-2, IL-6, TNF, FPR2, FAAH, MAGL, and IL-12A) induced by carrageenan, NLRP3 inflammasome activation, and the cell viability were then accessed. Later, chia oil actions were evaluated in the experimental autoimmune encephalomyelitis (EAE), a multiple sclerosis (MS) model. Chia oil showed anti-edematogenic and anti-hyperalgesic effects when administered 1 h before pro-inflammatory stimulus - particularly carrageenan and croton oil. Moreover, chia oil upregulated the mRNA levels of COX-2 and formyl peptide receptor 2 (FPR2) while reduced IL-6 expression in the spinal cord of mice submitted to i.pl. injection of carrageenan. Interestingly, chia oil mediates antinociceptive effects in mice decreasing the nociceptive response induced by acidified saline, PGE2, and cinnamaldehyde, but not by bradykinin, menthol, and capsaicin. On the EAE model, chia oil preventively administered attenuated EAE-induced motor deficits and mechanical hyperalgesia in mice, suggesting a valuable effect of chia oil supplementation in regulating inflammatory responses and some immune functions during immune-mediated inflammatory disorders (IMID). Nonetheless, additional reports will need to assess the effect of chia oil in well-controlled clinical trials performed in MS patients.

Involvement of Opioid System and TRPM8/TRPA1 Channels in the Antinociceptive Effect of Spirulina platensis.

Spirulina platensis is a "super-food" and has attracted researchers' attention due to its anti-inflammatory, antioxidant, and analgesic properties. Herein, we investigated the antinociceptive effects of Spirulina in different rodent behavior models of inflammatory pain. Male Swiss mice were treated with Spirulina (3-300 mg/kg, p.o.), indomethacin (10 mg/kg, p.o.), or vehicle (0.9% NaCl 10 mL/kg). Behavioral tests were performed with administration of acetic acid (0.6%, i.p.), formalin 2.7% (formaldehyde 1%, i.pl.), menthol (1.2 µmol/paw, i.pl.), cinnamaldehyde (10 nmol/paw, i.pl.), capsaicin (1.6 µg/paw, i.pl.), glutamate (20 µmol/paw, i.pl.), or naloxone (1 mg/kg, i.p.). The animals were also exposed to the rotarod and open field test to determine possible effects of Spirulina on locomotion and motor coordination. The quantitative phytochemical assays exhibited that Spirulina contains significant concentrations of total phenols and flavonoid contents, as well as it showed a powerful antioxidant effect with the highest scavenging activity. Oral administration of Spirulina completely inhibited the abdominal contortions induced by acetic acid (ED50 = 20.51 mg/kg). Spirulina treatment showed significant inhibition of formalin-induced nociceptive behavior during the inflammatory phase, and the opioid-selective antagonist markedly blocked this effect. Furthermore, our data indicate that the mechanisms underlying Spirulina analgesia appear to be related to its ability to modulate TRMP8 and TRPA1, but not by TRPV1 or glutamatergic system. Spirulina represents an orally active and safe natural analgesic that exhibits great therapeutic potential for managing inflammatory pain disorders.

Antidepressant-Like Effect of Terpineol in an Inflammatory Model of Depression: Involvement of the Cannabinoid System and D2 Dopamine Receptor.

Depression has a multifactorial etiology that arises from environmental, psychological, genetic, and biological factors. Environmental stress and genetic factors acting through immunological and endocrine responses generate structural and functional changes in the brain, inducing neurogenesis and neurotransmission dysfunction. Terpineol, monoterpenoid alcohol, has shown immunomodulatory and neuroprotective effects, but there is no report about its antidepressant potential. Herein, we used a single lipopolysaccharide (LPS) injection to induce a depressive-like effect in the tail suspension test (TST) and the splash test (ST) for a preventive and therapeutic experimental schedule. Furthermore, we investigated the antidepressant-like mechanism of action of terpineol while using molecular and pharmacological approaches. Terpineol showed a coherent predicted binding mode mainly against CB1 and CB2 receptors and also against the D2 receptor during docking modeling analyses. The acute administration of terpineol produced the antidepressant-like effect, since it significantly reduced the immobility time in TST (100-200 mg/kg, p.o.) as compared to the control group. Moreover, terpineol showed an antidepressant-like effect in the preventive treatment that was blocked by a nonselective dopaminergic receptor antagonist (haloperidol), a selective dopamine D2 receptor antagonist (sulpiride), a selective CB1 cannabinoid receptor antagonist/inverse agonist (AM281), and a potent and selective CB2 cannabinoid receptor inverse agonist (AM630), but it was not blocked by a nonselective adenosine receptor antagonist (caffeine) or a ß-adrenoceptor antagonist (propranolol). In summary, molecular docking suggests that CB1 and CB2 receptors are the most promising targets of terpineol action. Our data showed terpineol antidepressant-like modulation by CB1 and CB2 cannabinoid receptors and D2-dopaminergic receptors to further corroborate our molecular evidence.

Antiulcerogenic and anti-inflammatory activities of the essential oil from Pterodon emarginatus seeds.

OBJECTIVES: The objective of this work was to investigate the antiulcerogenic and anti-inflammatory activities of the essential oil from Pterodon emarginatus seeds. METHODS: The following tests were used: ulcers induced by ethanol, indometacin and HCl/ethanol, and pleurisy induced by carrageenan in Swiss albino rats. The rats were treated by the oral route with essential oil of P. emarginatus seeds. KEY FINDINGS: The essential oil at 100, 300 and 500 mg/kg exhibited significant protection against ulcers induced by ethanol, indometacin and HCl/ethanol (P < 0.001). The essential oil caused a marked reduction in the exudate volume and inhibited leucocyte and neutrophil influx (P < 0.05) in carrageenan-induced pleurisy. Moreover, the essential oil significantly decreased nitric oxide (NO) and interleukin-1 (IL-1) levels, without affecting tumour necrosis factor-alpha production. CONCLUSIONS: The results demonstrated the marked antiulcerogenic and anti-inflammatory effects of the essential oil from P. emarginatus, which are, at least in part, a consequence of NO and IL-1 modulation. P. emarginatus or its constituents might represent new therapeutic options to treat gastric ulcers and inflammatory diseases.

Antioxidant and cytotoxic activities of Centella asiatica (L) Urb.

In the present study, the phenolic (Folin-Dennis) and flavonoid (colorimetric assay) constituents, antioxidant [2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH) assay] and cytotoxic activities of an aqueous extract (AE) of Centella asiatica leaves were investigated. The aqueous extract (50 g/L) was obtained by infusion followed by cold maceration for 24 h. The levels of phenolic and flavonoid compounds were 2.86 g/100 g and 0.361 g/100 g, respectively. The AE showed elevated DPPH scavenging activity, with an IC(50) value of 31.25 microg/mL. The AE had a promising activity against mouse melanoma (B(16)F(1)), human breast cancer (MDA MB-231) and rat glioma (C(6)) cell lines, with IC(50) values of 698.0, 648.0 and 1000.0 microg/mL, respectively. A positive correlation was established between the level of flavonoids, antioxidant and antitumor activities.

Cannabinoid receptors as therapeutic targets for autoimmune diseases: where do we stand?

Described during the late 1980s and 1990s, cannabinoid receptors (CB1R and CB2R) are G-protein-coupled receptors (GPCRs) activated by endogenous ligands and cannabinoid drug compounds, such as Δ9-THC. Whereas CB1R has a role in the regulation of neurotransmission in different brain regions and mainly mediates the psychoactive effects of cannabinoids, CB2R is found predominantly in the cells and tissues of the immune system and mediates anti-inflammatory and immunomodulatory processes. Studies have demonstrated that CB1R and CB2R can affect the activation of T cells, B cells, monocytes, and microglial cells, inhibiting proinflammatory cytokine expression and upregulating proresolution mediators. Thus, in this review, we summarize the mechanisms by which CBRs interact with the autoimmune environment and the potential to suppress the development and activation of autoreactive cells. Finally, we highlight how the modulation of CB1R and CB2R is advantageous in the treatment of autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes mellitus (T1DM) and rheumatoid arthritis (RA).

Quantification of phenolic constituents and antioxidant activity of Pterodon emarginatus vogel seeds.

In the present study the phenolic (Folin-Dennis) and flavonoid (colorimetric assay) constituents and the antioxidant activity of Pterodon emarginatus seeds were investigated in several samples prepared with different extraction procedures: essential oil (EO) using a Clevenger-type apparatus; hexanic (HF), ethyl acetate (EAF), buthanolic (BF) and methanolic (MF) fractions using Soxhlet extraction, and extracts (1 g/extract) obtained from different methods: reflux 80 degrees C/30 min, ultrasound/30 min, static maceration/48 h and heating plate 100 degrees C/45 min. These extracts were prepared using water or ethanol/water at 30:70 v/v, 50:50 v/v or 70:30 v/v. Antioxidant activity [2,2-diphenyl-2-picrylhydrazyl hydrate (DPPH)] was tested only in the fractions obtained from Soxhlet extraction. The extract obtained from reflux using ethanol/water (70:30, v/v) showed the highest phenolic constituents level. The EAF, BF and MF showed DPPH scavenging activities with IC(50)=163.22, 18.89 and 10.15 microg/ml, respectively.

Therapeutic ultrasound ameliorates hyperalgesia and edema on CFA-induced persistent inflammatory response in mice

Abstract Background: The present study investigated the effects of pulsed and continuous ultrasound (USP and USC) in edema and hyperalgesia after chronic inflammatory process induced by Complete Freund's Adjuvant-CFA and analyzing the relationship of the application frequency of ultrasound, in pro- and anti-inflammatory cytokine production. Methods: Forty-five animals were divided into 9 groups; all animals from groups 2 to 9 were subjected to a persistent inflammation model induced by CFA in mice. We report the effects and the underlying action mechanisms of USP and USC in the animals which were irradiated two, three or five times a week on the left hind paw. The analyses performed in this study were: evaluation of hind paw edema through the plethysmometer, evaluation of thermal hyperalgesia through withdrawal test using a water container at 44.5°C (± 0.5°C), and the plantar region of the left paw which was removed for analysis of cytokines. Results: Our results showed that USP and USC consistently reduced paw edema, and pulsed ultrasound showed a higher significant effect than the continuous mode. Moreover, groups with irradiation frequency of five times a week presented an inhibition of the edema, and groups with frequency of three or two times a week reduced mainly hyperalgesia, in comparison with the control group. The beneficial effects of the US then seem to be associated with upregulation of anti- and pro-inflammatory mediators, such as IL-10 and IL-6, respectively. Conclusion: This study provided evidence that ultrasound constitutes an important non-pharmacological intervention for the management of inflammatory and pain states.

Photobiomodulation Therapy Improves Acute Inflammatory Response in Mice: the Role of Cannabinoid Receptors/ATP-Sensitive K+ Channel/p38-MAPK Signalling Pathway.

Although photobiomodulation therapy (PBM) has been applied clinically for the treatment of pain and inflammation, wound healing, sports and soft tissue injuries, as well as to repair injured spinal cords and peripheral nerves, it remains unclear which molecular substrates (receptor) are implicated in the cellular mechanisms of PBM. Here, we reported that PBM (660 nm, 30 mW, 0.06 cm2, 50 J/cm2, plantar irradiation) significantly inhibited carrageenan-induced paw oedema, but not noxious thermal response, through positive modulation to both CB1 and CB2 cannabinoid receptors. The use of CB1 antagonist AM281 or CB2 antagonist AM630 significantly reversed the anti-inflammatory effect of PBM. Analysis of signalling pathway downstream of cannabinoid receptors activation reveals that anti-inflammatory effects of PBM depend, in great extent, on its ability to activate ATP-dependent K+ channels and p38 mitogen-activated protein kinase. Moreover, PBM therapy significantly reduced the levels of pro-inflammatory cytokine IL-6 in both paw and spinal cord, and restored the reduction of the level of anti-inflammatory cytokine IL-10 in spinal cord after carrageenan injection. Unlike the potent cannabinoid receptor agonist (WIN 55212-2), PBM did not exert any CNS-mediated effects in the tetrad assay. Finally, PBM does not reduce inflammation and noxious thermal response induced by LPS and zymosan, a TLR4 and TLR2/dectin-1 ligand, respectively. Thus, cannabinoid receptors and, possibly, the endocannabinoid system, represent an important site of action of PBM that opens the possibility of complementary and nonpsychotropic therapeutic interventions in clinical practice. Graphical Abstract ᅟ.

Effects of Simvastatin Beyond Dyslipidemia: Exploring Its Antinociceptive Action in an Animal Model of Complex Regional Pain Syndrome-Type I.

Simvastatin is a lipid-lowering agent that blocks the production of cholesterol through inhibition of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. In addition, recent evidence has suggested its anti-inflammatory and antinociceptive actions during inflammatory and pain disorders. Herein, we investigated the effects of simvastatin in an animal model of complex regional pain syndrome-type I, and its underlying mechanisms. Chronic post-ischemia pain (CPIP) was induced by ischemia and reperfusion (IR) injury of the left hind paw. Our findings showed that simvastatin inhibited mechanical hyperalgesia induced by CPIP model in single and repeated treatment schedules, respectively; however simvastatin did not alter inflammatory signs during CPIP model. The mechanisms underlying those actions are related to modulation of transient receptor potential (TRP) channels, especially TRMP8. Moreover, simvastatin oral treatment was able to reduce the nociception induced by acidified saline [an acid-sensing ion channels (ASICs) activator] and bradykinin (BK) stimulus, but not by TRPA1, TRPV1 or prostaglandin-E2 (PGE2). Relevantly, the antinociceptive effects of simvastatin did not seem to be associated with modulation of the descending pain circuits, especially noradrenergic, serotoninergic and dopaminergic systems. These results indicate that simvastatin consistently inhibits mechanical hyperalgesia during neuropathic and inflammatory disorders, possibly by modulating the ascending pain signaling (TRPM8/ASIC/BK pathways expressed in the primary sensory neuron). Thus, simvastatin open-up new standpoint in the development of innovative analgesic drugs for treatment of persistent pain, including CRPS-I.