-
[show abstract]
[hide abstract]
ABSTRACT: There is a current need for new therapeutic options for acetaminophen (APAP)-induced hepatotoxicity. Herein, we assessed the effects of prophylactic and therapeutic treatment with the angiotensin-converting enzyme (ACE) inhibitor, enalapril, on APAP-caused hepatotoxicity. Male and female C57BL/6 J mice were used, and hepatotoxicity was induced by a single application of APAP (400 mg/kg, i.p.). Macroscopic and histological liver alterations, serum alanine transaminase (ALT) and aspartate transaminase (AST) activity, liver catalase activity (CAT), reduced glutathione concentrations (GSH), hepatic measurement of neutrophil migration (myeloperoxidase, MPO activity), and caspase-3 liver expression were evaluated. The prophylactic and the therapeutic treatments with enalapril were able to markedly reduce the macroscopic and histological liver alterations as well as the caspase-3 immunopositivity. Both schedules of treatment were also effective in reducing GSH concentrations as well as neutrophil migration. Conversely, only the pre-treatment (but not the post-administration) with enalapril significantly reversed APAP-induced CAT decrease. Furthermore, the pre- or the post-treatment with enalapril largely reduced ALT and AST serum activity in APAP-intoxicated mice. The hepatoprotective effects of enalapril were comparable to those obtained with the clinically used compound N-acetylcysteine (NAC) when given in a therapeutic regimen. Data obtained with the prophylactic protocol of treatment might indicate that individuals under treatment with ACE inhibitors are less susceptible to the toxic effects of APAP. Additionally, the therapeutic approach allows us to suggest that enalapril might represent an innovative tool for treating APAP intoxication.
Archiv für Experimentelle Pathologie und Pharmakologie 07/2012; 385(9):933-43. · 2.65 Impact Factor
-
Valnês S Rodrigues-Junior,
André Dos Santos Junior,
Anderson Jader Dos Santos,
Cristopher Zandoná Schneider,
João B Calixto,
Eduardo Henrique Silva Sousa,
Luiz Gonzaga de França Lopes,
André Arigony Souto,
Luiz Augusto Basso,
Diógenes Santiago Santos, Maria M Campos
[show abstract]
[hide abstract]
ABSTRACT: We have previously demonstrated a potent in vitro inhibitory activity for two pentacyano(isoniazid)ferrate(II) compounds, namely IQG-607 and IQG-639, against the Mycobacterium tuberculosis enoyl-acyl carrier protein reductase enzyme. In this study, the activity of these compounds was evaluated using an in vivo murine model of tuberculosis. Swiss mice were infected with M. tuberculosis H37Rv strain and then IQG-607 or IQG-639 (250 mg/kg) was administered for 28 days or 56 days. In addition, a dose-response study was performed with IQG-607 at 5, 10, 25, 50, 100, 200 and 250 mg/kg. The activity of test compounds was compared with that of the positive control drug isoniazid (INH) (25 mg/kg). After 28 days or 56 days of treatment, both IQG-607 and INH significantly reduced M. tuberculosis-induced splenomegaly as well as significantly diminishing the colony-forming units in the spleen and lungs. IQG-607 and INH ameliorated the lung macroscopic aspect, reducing lung lesions to a similar extent. However, IQG-639 did not significantly modify any evaluated parameter. Experiments using early and late controls of infection revealed a bactericidal activity for IQG-607. IQG-607 might well represent a good candidate for clinical development as a new antimycobacterial agent.
International journal of antimicrobial agents 06/2012; 40(2):182-5. · 3.03 Impact Factor
-
Tânia R Mielcke,
Alessandra Mascarello,
Eduardo Filippi-Chiela,
Rafael F Zanin,
Guido Lenz,
Paulo César Leal,
Louise Domeneghini Chiaradia,
Louise D Chirardia,
Rosendo A Yunes,
Ricardo J Nunes,
Ana M O Battastini,
Fernanda B Morrone, Maria M Campos
[show abstract]
[hide abstract]
ABSTRACT: Gliomas are the most common and devastating tumors of the central nervous system (CNS). Many pieces of evidence point out the relevance of natural compounds for cancer therapy and prevention, including chalcones. In the present study, eight synthetic quinoxaline-derived chalcones, structurally based on the selective PI3Kγ inhibitor AS605240, were evaluated for anti-proliferative activity and viability inhibition using glioma cell lines from human and rat origin (U-138 MG and C6, respectively), at different time-periods of incubation and concentrations. The results revealed that four chalcones (compounds 1, 6, 7 and 8), which present methoxy groups at A-ring, displayed higher efficacies and potencies, being able to inhibit either cell proliferation or viability, in a time- and concentration-dependent manner, with an efficacy that was greater than that seen for the positive control compound AS605240. Flow cytometry analysis demonstrated that incubation of C6 cells with compound 6 led to G1 phase arrest, likely indicating an interference with apoptosis. Furthermore, compound 6 was able to visibly inhibit AKT activation, allied to the stimulation of ERK MAP-kinase. The chalcones tested herein, especially those displaying a methoxy substituent, might well represent promising molecules for the adjuvant treatment of glioma progression.
European journal of medicinal chemistry 12/2011; 48:255-64. · 3.27 Impact Factor
-
Elizandra Braganhol,
Rafael F Zanin,
Andressa Bernardi,
Leticia S Bergamin,
Angelica R Cappellari,
Luis F Campesato,
Fernanda B Morrone, Maria M Campos,
João B Calixto,
Maria Isabel A Edelweiss,
Márcia R Wink,
Jean Sévigny,
Simon C Robson,
Ana Maria O Battastini
[show abstract]
[hide abstract]
ABSTRACT: Gliomas are the most common and devastating type of primary brain tumor. Many non-neoplastic cells, including immune cells, comprise the tumor microenvironment where they create a milieu that appears to dictate cancer development. ATP and the phosphohydrolytic products ADP and adenosine by activating P2 and P1 receptors may participate in these interactions among malignant and immune cells. Purinergic receptor-mediated cell communication is closely regulated by ectonucleotidases, such as by members of the ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) family, which hydrolyze extracellular nucleotides. We have shown that gliomas, unlike astrocytes, exhibit low NTPDase activity. Furthermore, ATP induces glioma cell proliferation and the co-administration of apyrase decreases progression of injected cells in vivo. We have previously shown that NTPDase2 reconstitution dramatically increases tumor growth in vivo. Here we evaluated whether NTPDase2 reconstitution to gliomas modulates systemic inflammatory responses. We observed that NTPDase2 overexpression modulated pro-inflammatory cytokine production and platelet reactivity. Additionally, pathological alterations in the lungs were observed in rats bearing these tumors. Our results suggest that disruption of purinergic signaling via ADP accumulation creates an inflammatory state that may promote tumor spread and dictate clinical progression.
Purinergic Signalling 10/2011; 8(2):235-43. · 3.16 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The effects of Phyllanthus niruri hydroalcoholic extract and the isolated compounds quercetin, rutin, and gallic acid were examined in the mouse model of cyclophosphamide (CYP)-induced hemorrhagic cystitis (HC). HC was induced by a single CYP injection (300 mg/kg, IP), and the animals were evaluated 4 and 6 h after. Some animals were orally treated with the reference compound 2-mercaptoethane sodium sulfonate (Mesna) 80 mg/kg (30 min before CYP) and 160 mg/kg (2 h after CYP). Other groups were treated with P. niruri extract (30 and 50 mg/kg), or quercetin, rutin, and gallic acid (10 and 20 mg/kg), given orally, at the same intervals described for Mesna. P. niruri extract and its active components produced a significant attenuation of the nociception, edema, and hemorrhage evoked by CYP, which was similar to that seen for Mesna. Gallic acid and rutin displayed greater anti-inflammatory effects, whereas quercetin presented superior antinociceptive activities. Noteworthy is that P. niruri extract and compounds significantly reduced CYP-induced liver lipid peroxidation. Our results shed new light on the beneficial effects of P. niruri extract and its active compounds in attenuating the collateral effects elicited by the chemotherapeutic agent CYP.
Archiv für Experimentelle Pathologie und Pharmakologie 09/2011; 384(3):265-75. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This study evaluated the relevance of CXCR2 chemokine receptors in oral squamous cell carcinoma, by means of in vitro and in vivo approaches. The in vitro incubation of the selective and non-peptide CXCR2 receptor antagonist N-(2-hydroxy-4-nitrophenyl)-N9-(2-bromophenyl) Urea (SB225002; 25 to 800 nM) produced a time- and concentration-dependent inhibition of SCC158 (rat) and HN30 (human) cell lines viability. Conversely, this antagonist did not significantly affect the viability of the immortalized keratinocyte lineage, HaCaT. Additionally, the incubation of human IL-8 and rat CINC-1 CXCR2 agonists produced a concentration-related increase on HN30 and SCC158 proliferation. The submucosal injection of SCC158 cells (5 × 10(6) cells) into the tongue of Fischer 344 rats induced tumor development, which displayed typical clinical features. Immunohistochemical analysis of rat tongue biopsies revealed a marked increase of CXCR2 receptor immunoreactivity, which was accompanied by augumented expression of VEGF and caspase-3. Our data suggests an important role for CXCR2 receptors in oral squamous cell carcinoma.
Investigational New Drugs 06/2011; 30(4):1371-8. · 3.36 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Oral squamous cell carcinoma (OSCC) is the most frequent malignant neoplasia of the oral cavity, which largely compromises the patient's life quality. Therefore, the identification of biomarkers for this kind of cancer is essential to provide a better diagnosis and prognosis for patients. Endothelin-1 is a peptide produced mainly by endothelial cells, and might be found in several body fluids, such as saliva, milk, urine, cerebrospinal fluid and plasma. It has been demonstrated that expression of this peptide is increased in a great number of neoplasias, including oral carcinoma. The identification of salivary biomarkers would be a useful tool for scanning and monitoring patients with risk of developing OSCC, as well to early detect recurrence, or the formation of a new primary tumor. In the present study, we have analyzed the levels of endothelin-1 in saliva obtained from patients with OSCC or oral leukoplakia, in comparison to healthy control patients. This study also evaluated the salivary ET-1 levels in patients with complete remission of OSCC. The results revealed no statistical difference in salivary endothelin-1 levels, neither in OSCC nor in oral leukoplakia, even when conditions such as elderly, sex and hypertension were taken into consideration. Although, ET-1 might display an important role in OSCC, its levels in saliva do not seem to be a good marker of neoplasias grade or malignant transformation.
Regulatory Peptides 01/2011; 166(1-3):55-8. · 2.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Many studies have shown the antinociceptive effects of cannabinoid (CB) agonists in different models of pain. Herein, we have investigated their relevance in neuropathic pain induced by brachial plexus avulsion (BPA) in mice.
Mice underwent BPA or sham surgery. The mRNA levels and protein expression of CB(1) and CB(2) receptors were assessed by RT-PCR and immunohistochemistry, respectively. The activation of glial cells, MAP kinases and transcription factors were evaluated by immunohistochemistry. The antinociceptive properties induced by cannabinoid agonists were assessed on the 5(th) and 30(th) days after surgery. We observed a marked increase in CB(1) and CB(2) receptor mRNA and protein expression in the spinal cord and dorsal root ganglion, either at the 5(th) or 30(th) day after surgery. BPA also induced a marked activation of p38 and JNK MAP kinases (on the 30(th) day), glial cells, such as microglia and astrocytes, and the transcription factors CREB and NF-κB (at the 5(th) and 30(th) days) in the spinal cord. Systemic treatment with cannabinoid agonists reduced mechanical allodynia on both the 5(th) and 30(th) days after surgery, but the greatest results were observed by using central routes of administration, especially at the 30(th) day. Treatment with WIN 55,212-2 prevented the activation of both glial cells and MAP kinases, associated with an enhancement of CREB and NF-κB activation.
Our results indicate a relevant role for cannabinoid agonists in BPA, reinforcing their potential therapeutic relevance for the management of chronic pain states.
PLoS ONE 01/2011; 6(9):e24034. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Hemorrhagic cystitis (HC) is a common side effect observed in patients under chemotherapy with cyclophosphamide (CYP). The urotoxic side effects of CYP are attributed to the metabolic compound acrolein, and can be partially prevented by the uroprotector agent 2-mercaptoethene sulfate (Mesna). The present study analyzed the anti-inflammatory and the antinociceptive effects of compounds MV8608 and MV8612 obtained from Mandevilla velutina in the rat model of CYP-induced HC. Male Wistar rats were used (six to eight per group, 220-250 g). HC was induced by a single administration of CYP (100 mg/kg, ip). Three behavioral parameters--breathing rate, closing of the eyes, and specific posture--were used as nociception indexes, and scored at different time intervals (15-180 min) after cystitis induction. As inflammatory parameters, hemorrhage presence, edema formation, and bladder weight were determined at 24 h after CYP administration. The neutrophil migration was assessed by means of myeloperoxidase (MPO activity), 4 h after cystitis induction. As expected, Mesna treatment was able to reduce in a significant manner all the inflammatory and the nociceptive parameters induced by CYP. Of note, the administration of MV8608 significantly inhibited the hemorrhage formation and the neutrophil recruitment, while the MV8612 treatment markedly reduced the bladder weight, without interfering with neutrophil influx. Interestingly, the treatment with either MV8608 or MV8612 markedly reduced the nociceptive responses. The present results clearly indicate that MV8608 and MV8612 might represent important alternatives to prevent side effects, especially the nociception, following chemotherapy with CYP.
Archiv für Experimentelle Pathologie und Pharmakologie 12/2010; 382(5-6):399-407. · 2.65 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Oral squamous cell carcinoma (OSCC) is one of the most common malignancies recognized nowadays, and represents a public health problem. Its early detection is the better alternative to provide a good quality of life for the patients. During the last years, several studies have identified potential biomarkers of OSCC progression and prognosis. Endothelins and their receptors are involved in several pathophysiological conditions and in various cancer types. The present review article discusses whether the endothelin system would represent a biomarker for OSCC.
Oral Oncology 09/2010; 46(9):644-7. · 2.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Kinin B1 receptors are inducible molecules up-regulated after inflammatory stimuli. This study evaluated the relevance of kinin B1 receptors in a mouse depression behavior model.
Mice were exposed to a 5-min swimming session, and 30 min later they were injected with E. coli lipopolysaccharide (LPS). Depression-like behavior was assessed by determining immobility time in a tail suspension test. Different brain structures were collected for molecular and immunohistochemical studies. Anhedonia was assessed by means of a sucrose intake test.
Our protocol elicited an increase in depression-like behavior in CF1 mice, as assessed by the tail-suspension test, at 24 h. This behavior was significantly reduced by treatment with the selective B1 receptor antagonists R-715 and SSR240612. Administration of SSR240612 also prevented an increase in number of activated microglial cells in mouse hippocampus, but did not affect a reduction in expression of mRNA for brain-derived neurotrophic factor. The increased immobility time following LPS treatment was preceded by an enhancement of hippocampal and cortical B1 receptor mRNA expression (which were maximal at 1 h), and a marked production of TNFα in serum, brain and cerebrospinal fluid (between 1 and 6 h). The depression-like behavior was virtually abolished in TNFα p55 receptor-knockout mice, and increased B1 receptor mRNA expression was completely absent in this mouse strain. Furthermore, treatment with SSR240612 was also effective in preventing anhedonia in LPS-treated mice, as assessed using a sucrose preference test.
Our data show, for the first time, involvement of kinin B1 receptors in depressive behavioral responses, in a process likely associated with microglial activation and TNFα production. Thus, selective and orally active B1 receptor antagonists might well represent promising pharmacological tools for depression therapy.
Journal of Neuroinflammation 01/2010; 7:98. · 3.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Trichilia catigua is a native plant of Brazil; its barks are used by some local pharmaceutical companies to prepare tonic drinks, such as Catuama. The present study was addressed to evaluate the effects of T. catigua hydroalcoholic extract in mouse nociception behavioral models, and to evaluate the possible mechanisms involved in its actions. Male Swiss mice were submitted to hot-plate, writhing and von Frey tests, after oral treatment with T. catigua extract (200 mg kg(-1), p.o.). The extract displayed antinociceptive effect in all three models. For characterization of the mechanisms involved in the antinociceptive action of the extract, the following pharmacological treatments were done: naloxone (2.5 mg kg(-1), s.c.), SR141716A (10 mg kg(-1), i.p.), SCH23390 (15 μg kg(-1), i.p.), sulpiride (50 mg kg(-1), i.p.), prazosin (1 mg kg(-1), i.p.), bicuculline (1 mg kg(-1), i.p.) or dl-p-chlorophenylalanine methyl ester (PCPA, 100 mg kg(-1), i.p.). In these experiments, the action of T. catigua extract was evaluated in the hot-plate test. The treatment with SCH23390 completely prevented the antinociceptive effect, while naloxone partially prevented it. The possible involvement of the dopaminergic system in the actions of T. catigua extract was substantiated by data showing the potentiation of apomorphine-induced hypothermia and by the prevention of haloperidol-induced catalepsy. In conclusion, the antinociceptive effects of T. catigua extract seem to be mainly associated with the activation of dopaminergic system and, to a lesser extent, through interaction with opioid pathway.
Evidence-based Complementary and Alternative Medicine 10/2009; 2011:120820. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: It has been demonstrated that kinin B(1) receptors are highly up-regulated under several stressful stimuli, such as infection. However, there is no evidence indicating whether Porphyromonas gingivalis lipopolysaccharide (Pg-LPS) might lead to B(1) receptor up-regulation. In this study, we demonstrate that Pg-LPS injection into the rat paw resulted in a marked functional up-regulation of B(1) receptors (as measured by an increase of B(1) receptor-induced edema), which was preceded by a rapid rise in B(1) receptor mRNA expression. The local administration of Pg-LPS also resulted in a prominent production of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha), followed by an increase of neutrophil influx; both events were observed at periods before B(1) receptor induction. The functional and molecular Pg-LPS-elicited B(1) receptor up-regulation was significantly reduced by the glucocorticoid dexamethasone (0.5 mg/kg s.c.), and to a lesser extent by the chimeric anti-TNF-alpha antibody infliximab (1 mg/kg s.c.). Of high relevance, we show for the first time that a single administration of the proresolution lipid mediator (5S,12R,18R)-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid (resolvin E1; 300 ng/rat i.p.) was able to markedly down-regulate Pg-LPS-driven B(1) receptor expression, probably by inhibiting TNF-alpha production and neutrophil migration. Collectively, the present findings clearly suggest that Pg-LPS is able to induce the up-regulation of B(1) receptors through mechanisms involving TNF-alpha release and neutrophil influx, which are largely sensitive to resolvin E1. It is tempting to suggest that kinin B(1) receptors might well represent a pivotal pathway for the inflammatory responses evoked by P. gingivalis and its virulence factors.
Journal of Pharmacology and Experimental Therapeutics 07/2009; 330(3):756-63. · 3.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Platelet-activating factor (PAF) is an inflammatory mediator widely known to exert relevant pathophysiological functions. However, the relevance of PAF in nociception has received much less attention. Herein, we have investigated the mechanisms underlying PAF-induced spontaneous nociception and mechanical hypersensitivity in the rat paw. PAF injection (1- 30 nmol/paw) resulted in a dose-related overt nociception, whilst only the dose of 10 nmol/ paw produced a significant and time-related mechanical hypersensitivity. Local coinjection of PAF antagonist WEB2086 significantly inhibited both spontaneous nociception and mechanical hypersensitivity. Moreover, the coinjection of the natural IL-1beta receptor antagonist (IRA) notably prevented both PAF-induced nociceptive responses, whilst these responses were not altered by anti-TNFalpha coinjection. Interestingly, pretreatment with the ultrapotent vaniloid agonist resiniferotoxin, coinjection of the TRPV1 receptor antagonist SB366791, or mast cell depletion with compound 48/80 markedly prevented PAF-induced spontaneous nociception. Conversely, PAF-elicited mechanical hypersensitivity was strikingly susceptible to distinct antineutrophil-related strategies, namely the antineutrophil antibody, the selectin blocker fucoidin, the chemokine CXCR2 receptor antagonist SB225002, and the C5a receptor antibody anti-CD88. Notably, the same antineutrophil migration strategies significantly prevented the increase of myeloperoxidase activity induced by PAF. The mechanical hypersensitivity caused by PAF was also prevented by the cyclooxygenase inhibitors indomethacin or celecoxib, and by the selective beta(1) adrenergic receptor antagonist atenolol. Collectively, the present results provide consistent evidence indicating that distinct mechanisms are involved in the spontaneous nociception and mechanical hypersensitivity caused by PAF. They also support the concept that selective PAF receptor antagonists might constitute interesting targets for the development of new analgesic drugs.
Biochemical pharmacology 05/2009; 77(7):1223-35. · 4.25 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The relevance of kinin B(1) (B(1)R) and B(2) (B(2)R) receptors in the brachial plexus avulsion (BPA) model was evaluated in mice, by means of genetic and pharmacological tools. BPA-induced hypernociception was absent in B(1)R, but not in B(2)R, knock-out mice. Local or intraperitoneal administration of the B(2)R antagonist Hoe 140 failed to affect BPA-induced mechanical hypernociception. Interestingly, local or intraperitoneal treatment with B(1)R antagonists, R-715 or SSR240612, dosed at the time of surgery, significantly reduced BPA-evoked mechanical hypernociception. Intrathecal or intracerebroventricular administration of these antagonists, at the surgery moment, did not prevent the hypernociception. Both antagonists, dosed by intraperitoneal or intrathecal routes (but not intracerebroventricularly) 4 d after the surgery, significantly inhibited the mechanical hypernociception. At 30 d after the BPA, only the intracerebroventricular treatment effectively reduced the hypernociception. A marked increase in B(1)R mRNA was observed in the hypothalamus, hippocampus, thalamus, and cortex at 4 d after BPA and only in the hypothalamus and cortex at 30 d. In the spinal cord, a slight increase in B(1)R mRNA expression was observed as early as at 2 d. Finally, an enhancement of B(1)R protein expression was found in all the analyzed brain structures at 4 and 30 d after the BPA, whereas in the spinal cord, this parameter was augmented only at 4 d. The data provide new evidence on the role of peripheral and central kinin B(1)R in the BPA model of neuropathic pain. Selective B(1)R antagonists might well represent valuable tools for the management of neuropathic pain.
Journal of Neuroscience 04/2008; 28(11):2856-63. · 7.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This study evaluated the anti-inflammatory properties of two sesquiterpenes isolated from Cordia verbenacea's essential oil, alpha-humulene and (-)-trans-caryophyllene. Our results revealed that oral treatment with both compounds displayed marked inhibitory effects in different inflammatory experimental models in mice and rats. alpha-humulene and (-)-trans-caryophyllene were effective in reducing platelet activating factor-, bradykinin- and ovoalbumin-induced mouse paw oedema, while only alpha-humulene was able to diminish the oedema formation caused by histamine injection. Also, both compounds had important inhibitory effects on the mouse and rat carrageenan-induced paw oedema. Systemic treatment with alpha-humulene largely prevented both tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta) generation in carrageenan-injected rats, whereas (-)-trans-caryophyllene diminished only TNFalpha release. Furthermore, both compounds reduced the production of prostaglandin E(2) (PGE(2)), as well as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) expression, induced by the intraplantar injection of carrageenan in rats. The anti-inflammatory effects of alpha-humulene and (-)-trans-caryophyllene were comparable to those observed in dexamethasone-treated animals, used as positive control drug. All these findings indicate that alpha-humulene and (-)-trans-caryophyllene, derived from the essential oil of C. verbenacea, might represent important tools for the management and/or treatment of inflammatory diseases.
European Journal of Pharmacology 09/2007; 569(3):228-36. · 2.52 Impact Factor
-
Rodrigo Medeiros,
Rui D S Prediger,
Giselle F Passos,
Pablo Pandolfo,
Filipe S Duarte,
Jeferson L Franco,
Alcir L Dafre,
Gabriella Di Giunta,
Cláudia P Figueiredo,
Reinaldo N Takahashi, Maria M Campos,
João B Calixto
[show abstract]
[hide abstract]
ABSTRACT: Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signals of Alzheimer's disease (AD) that have been highly associated with inflammatory alterations. The present work was designed to determine the correlation between tumor necrosis factor-alpha (TNF-alpha)-related signaling pathways and inducible nitric oxide synthase (iNOS) expression in a mouse model of AD, by means of both in vivo and in vitro approaches. The intracerebroventricular injection of Abeta(1-40) in mice resulted in marked deficits of learning and memory, according to assessment in the water maze paradigm. This cognition impairment seems to be related to synapse dysfunction and glial cell activation. The pharmacological blockage of either TNF-alpha or iNOS reduced the cognitive deficit evoked by Abeta(1-40) in mice. Similar results were obtained in TNF-alpha receptor 1 and iNOS knock-out mice. Abeta(1-40) administration induced an increase in TNF-alpha expression and oxidative alterations in prefrontal cortex and hippocampus. Likewise, Abeta(1-40) led to activation of both JNK (c-Jun-NH2-terminal kinase)/c-Jun and nuclear factor-kappaB, resulting in iNOS upregulation in both brain structures. The anti-TNF-alpha antibody reduced all of the molecular and biochemical alterations promoted by Abeta(1-40). These results provide new insights in mouse models of AD, revealing TNF-alpha and iNOS as central mediators of Abeta action. These pathways might be targeted for AD drug development.
Journal of Neuroscience 06/2007; 27(20):5394-404. · 7.11 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The anti-inflammatory and anti-allergic effects of the essential oil of Cordia verbenacea (Boraginaceae) and some of its active compounds were evaluated. Systemic treatment with the essential oil of Cordia verbenacea (300-600mg/kg, p.o.) reduced carrageenan-induced rat paw oedema, myeloperoxidase activity and the mouse oedema elicited by carrageenan, bradykinin, substance P, histamine and platelet-activating factor. It also prevented carrageenan-evoked exudation and the neutrophil influx to the rat pleura and the neutrophil migration into carrageenan-stimulated mouse air pouches. Moreover, Cordia verbenacea oil inhibited the oedema caused by Apis mellifera venom or ovalbumin in sensitized rats and ovalbumin-evoked allergic pleurisy. The essential oil significantly decreased TNFalpha, without affecting IL-1beta production, in carrageenan-injected rat paws. Neither the PGE(2) formation after intrapleural injection of carrageenan nor the COX-1 or COX-2 activities in vitro were affected by the essential oil. Of high interest, the paw edema induced by carrageenan in mice was markedly inhibited by both sesquiterpenic compounds obtained from the essential oil: alpha-humulene and trans-caryophyllene (50mg/kg, p.o.). Collectively, the present results showed marked anti-inflammatory effects for the essential oil of Cordia verbenacea and some active compounds, probably by interfering with TNFalpha production. Cordia verbenacea essential oil or its constituents might represent new therapeutic options for the treatment of inflammatory diseases.
Journal of Ethnopharmacology 04/2007; 110(2):323-33. · 3.01 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Kinin B1 and B2 receptors are central to the aetiology of pain and inflammation. Constitutive B2 receptors are commonly associated with the acute phase of inflammation and nociception, whereas the inducible B1 receptors are mostly linked to the chronic or persistent phase (or both). Therefore, selective, orally active kinin B1 receptor antagonists could be potentially therapeutic. B1 receptor antagonists have long been exclusively peptides, but recently a few non-peptide representatives have been identified. The clinical potential of these non-peptide molecules has not yet been evaluated, but they might have a role in treating persistent inflammation and pain, especially when no satisfactory therapy is available. This review summarizes recent advances in the identification and the potential therapeutic properties of these molecules.
Trends in Pharmacological Sciences 01/2007; 27(12):646-51. · 10.93 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Two novel selective non-peptide kinin B(1) receptor antagonists, the benzodiazepine antagonist and SSR240612, were evaluated in carrageenan-induced mouse pleurisy. The peptide R-715 (0.5 mg/kg, i.p.) and the non-peptide benzodiazepine (3 mg/kg, i.p.) antagonists significantly decreased cellular migration (predominantly neutrophils), without altering plasma exudation. SSR240612 (1 mg/kg, i.p.) diminished total cells and neutrophils, besides exudation. Oral administration of SSR240612 (10 mg/kg) also reduced total cell and neutrophil counts. Only the benzodiazepine antagonist inhibited the lung myeloperoxidase activity. No tested antagonist significantly altered the lung and pleural TNFalpha and IL-1beta production. We provide interesting evidence on the anti-inflammatory in vivo effects of non-peptide B(1) receptor antagonists.
Peptides 12/2006; 27(11):2967-75. · 2.43 Impact Factor
