RESUMO
Parkinson's disease (PD) is a multifaceted disease characterized by degeneration of nigrostriatal dopaminergic neurons, which results in motor and non-motor dysfunctions. Accumulation of α-synuclein (αSYN) in Lewy bodies is a key pathological feature of PD. Although the exact cause of PD remains unknown, accumulating evidence suggests that brain infiltration of T cells plays a critical role in the pathogenesis of disease, contributing to neuroinflammation and dopaminergic neurodegeneration. Here, we used a mouse model of brain-infused aggregated αSYN, which recapitulates motor and non-motor dysfunctions seen in PD patients. We found that αSYN-induced motor dysfunction in mice is accompanied by an increased number of brain-residing Th17 (IL17+ CD4+) cells, but not CD8+ T cells. To evaluate whether the modulation of T cell response could rescue αSYN-induced damage, we chronically treated animals with abatacept (8 mg/kg, sc, 3x per week), a selective T-cell co-stimulation modulator. We found that abatacept treatment decreased Th1 (IFNÆ+ CD4+) and Th17 (IL17+ CD4+) cells in the brain, rescued motor function and prevented dopaminergic neuronal loss in αSYN-infused mice. These results highlight the significance of effector CD4+ T cells, especially Th17, in the progression of PD and introduce novel possibilities for repurposing immunomodulatory drugs used for arthritis as PD-modifying therapies.
RESUMO
Previously, we reported that Alzheimer's disease (AD) epitope vaccines (EVs) composed of N-terminal ß-amyloid (Aß42) B cell epitope fused with universal foreign T helper (Th) epitope(s) were immunogenic, potent, and safe in different amyloid precursor protein (APP) transgenic mice with early AD-like pathology. However, developing an effective therapeutic vaccine is much more challenging, especially when a self-antigen such as Aß42 is a target. Here, we directly compare the efficacy of anti-Aß42 antibodies in Tg2576 mice with low or high levels of AD-like pathology at the start of immunizations: 6-6.5 months for preventive vaccinations and 16-19 months for therapeutic vaccinations. EV in a preventive setting induced high levels of anti-Aß antibodies, significantly reducing pathologic forms of Aß in the brains of Tg2576 mice. When used therapeutically for immunesenescent Tg2576 mice, EV induced low levels of antibodies not sufficient for clearing of AD-like pathology. Separately, we demonstrated that EV was also not effective in 11-11.5-month-old Tg2576 mice with moderate AD-like pathology. However, we augmented the titers of anti-Aß antibodies in transgenic (Tg) mice of the same age possessing the pre-existing memory Th cells and detected a significant decrease in diffuse and core plaques in cortical regions compared to control animals along with improved novel object recognition performance.
Assuntos
Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/imunologia , Vacinas/imunologia , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/terapia , Animais , Anticorpos/imunologia , Astrócitos/imunologia , Astrócitos/metabolismo , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Epitopos/imunologia , Imunização , Camundongos , Camundongos Transgênicos , Neuroglia/imunologia , Neuroglia/metabolismo , Fragmentos de Peptídeos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Vacinas/administração & dosagemRESUMO
Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during the second/third trimesters of pregnancy in previously normoglycemic women. It is currently estimated that 10% of all pregnancies in the United States show this condition. For many years, the transient nature of GD has led researchers and physicians to assume that long-term consequences were absent. However, GD diagnosis leads to a six-fold increase in the risk of developing type 2 diabetes (T2D) in women and incidence of obesity and T2D is also higher among their infants. Recent and concerning evidences point to detrimental effects of GD on the behavior and cognition of the offspring, which often persist until adolescence or adulthood. Considering that the perinatal period is critical for determination of adult behavior, it is expected that the intra-uterine exposure to hyperglycemia, hyperinsulinemia and pro-inflammatory mediators, hallmark features of GD, might affect brain development. Here, we review early clinical and experimental evidence linking GD to consequences on the behavior of the offspring, focusing on memory and mood disorders. We also discuss initial evidence suggesting that downregulation of insulin signaling cascades are seen in the brains of GD offspring and could contribute to the consequences on their behavior.
Assuntos
Química Encefálica , Diabetes Gestacional , Transtornos da Memória/etiologia , Transtornos Mentais/etiologia , Transtornos do Neurodesenvolvimento/etiologia , Efeitos Tardios da Exposição Pré-Natal , Animais , Modelos Animais de Doenças , Feminino , Insulina , Gravidez , RatosRESUMO
An altered form of the cellular prion protein, the PrPScor PrPRes, is implicated in the occurrence of the still untreatable transmissible spongiform encephalopathies. We have previously synthesized and characterized aromatic compounds that inhibit protease-resistant prion protein (PrPRes) accumulation in scrapie-infected cells. These compounds belong to different chemical classes, including acylhydrazones, chalcones and oxadiazoles. Some of the active compounds were non-toxic to neuroblastoma cells in culture and seem to possess drugable properties, since they are in agreement with the Lipinski´s rule of 5 and present desirable pharmacokinetic profiles as predicted in silico. Before the evaluation of the in vivo efficacy of the aromatic compounds in scrapie-infected mice, safety assessment in healthy mice is needed. Here we used Swiss mice to evaluate the acute toxicity profile of the six most promising anti-prionic compounds, the 2,4,5-trimethoxychalcones (J1, J8, J20 and J35) and the 1,3,4-oxadiazoles (Y13 and Y17). One single oral administration (300 mg/kg) of J1, J8, J20, J35, Y13 and Y17 or repeated intraperitoneal administration (10 mg/kg, 3 times a week, for 4 weeks) of J1, J8 and J35, did not elicit toxicity in mice. We strongly believe that the investigated trimethoxychalcones and oxadiazoles are interesting compounds to be further analyzed in vivo against prion diseases.
Assuntos
Chalconas/toxicidade , Oxidiazóis/toxicidade , Príons/antagonistas & inibidores , Scrapie/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Feminino , Dose Letal Mediana , Masculino , CamundongosRESUMO
The deposition of amyloid-ß peptides (Aß) in the cerebral vasculature, a condition known as cerebral amyloid angiopathy, is increasingly recognized as an important component leading to intracerebral hemorrhage, neuroinflammation, and cognitive impairment in Alzheimer disease (AD) and related disorders. Recent studies demonstrated a role for the bradykinin B1 receptor (B1R) in cognitive deficits induced by Aß in mice; however, its involvement in AD and cerebral amyloid angiopathy is poorly understood. Herein, we investigated the effect of B1R inhibition on AD-like neuroinflammation and amyloidosis using the transgenic mouse model (Tg-SwDI). B1R expression was found to be up-regulated in brains of Tg-SwDI mice, specifically in the vasculature, neurons, and astrocytes. Notably, administration of the B1R antagonist, R715, to 8-month-old Tg-SwDI mice for 8 weeks resulted in higher Aß40 levels and increased thioflavin S-positive fibrillar Aß deposition. Moreover, blockage of B1R inhibited neuroinflammation, as evidenced by the decreased accumulation of activated microglia and reactive astrocytes, diminished NF-κB activation, and reduced cytokine and chemokine levels. Together, our results indicate that B1R activation plays an important role in limiting the accumulation of Aß in AD-like brain, likely through the regulation of activated glial cell accumulation and release of pro-inflammatory mediators. Therefore, the modulation of the receptor may represent a novel therapeutic approach for AD.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Sistema Nervoso/metabolismo , Sistema Nervoso/patologia , Receptor B1 da Bradicinina/metabolismo , Animais , Antagonistas de Receptor B1 da Bradicinina , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Cognição , Humanos , Inflamação/fisiopatologia , Camundongos , Camundongos Transgênicos , Sistema Nervoso/fisiopatologia , Neuroglia/metabolismo , Neuroglia/patologia , Processamento de Proteína Pós-Traducional , Regulação para CimaRESUMO
Microglia play an essential role in innate immunity, homeostasis, and neurotropic support in the central nervous system. In Alzheimer disease (AD), these cells may affect disease progression by modulating the buildup of ß-amyloid (Aß) or releasing proinflammatory cytokines and neurotoxic substances. Discovering agents capable of increasing Aß uptake by phagocytic cells is of potential therapeutic interest for AD. Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory properties directly involved in inflammatory resolution, an active process essential for appropriate host responses, tissue protection, and the return to homeostasis. Herein, we demonstrate that aspirin-triggered LXA4 (15 µg/kg) s.c., twice a day, reduced NF-κB activation and levels of proinflammatory cytokines and chemokines, as well as increased levels of anti-inflammatory IL-10 and transforming growth factor-ß. Such changes in the cerebral milieu resulted in recruitment of microglia in an alternative phenotype, as characterized by the up-regulation of YM1 and arginase-1 and the down-regulation of inducible nitric oxide synthase expression. Microglia in an alternative phenotype-positive cells demonstrated improved phagocytic function, promoting clearance of Aß deposits and ultimately leading to reduction in synaptotoxicity and improvement in cognition. Our data indicate that activating LXA4 signaling may represent a novel therapeutic approach for AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Aspirina/uso terapêutico , Lipoxinas/metabolismo , Microglia/metabolismo , Microglia/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Aspirina/farmacologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Astrócitos/patologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Cognição/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , NF-kappa B/metabolismo , Fármacos Neuroprotetores/farmacologia , Fenótipo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Sinapses/efeitos dos fármacosRESUMO
Oxaliplatin (OXA) is an antineoplastic agent used for the treatment of cisplatin-resistant tumours, presenting lower incidence of nephrotoxicity and myelotoxicity than other platinum-based drugs. However, OXA treatment is highly associated with painful peripheral neuropathy, a well-known and relevant side effect caused by mitochondrial dysfunction. The transfer of functional exogenous mitochondria (mitotherapy) is a promising therapeutic strategy for mitochondrial diseases. We investigated the effect of mitotherapy on oxaliplatin-induced painful peripheral neuropathy (OIPN) in male mice. OIPN was induced by i.p. injections of oxaliplatin (3 mg/kg) over 5 consecutive days. Mechanical (von Frey test) and cold (acetone drop test) allodynia were evaluated between 7 and 17 days after the first OXA treatment. Mitochondria was isolated from donor mouse livers and mitochondrial oxidative phosphorylation was assessed with high resolution respirometry. After confirming that the isolated mitochondria were functional, the organelles were administered at the dose of 0.5 mg/kg of mitochondrial protein on days 1, 3 and 5. Treatment with OXA caused both mechanical and cold allodynia in mice that were significant 7 days after the initial injection of OXA and persisted for up to 17 days. Mitotherapy significantly prevented the development of both sensory alterations, and attenuated body weight loss induced by OXA. Mitotherapy also prevented spinal cord ERK1/2 activation, microgliosis and the increase in TLR4 mRNA levels. Mitotherapy prevented OIPN by inhibiting neuroinflammation and the consequent cellular overactivity in the spinal cord, presenting a potential therapeutic strategy for pain management in oncologic patients undergoing OXA treatment.
Assuntos
Antineoplásicos , Dor , Doenças do Sistema Nervoso Periférico , Humanos , Masculino , Camundongos , Animais , Oxaliplatina/toxicidade , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Hiperalgesia/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Antineoplásicos/toxicidadeRESUMO
Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.
Assuntos
COVID-19 , Disfunção Cognitiva , Humanos , Animais , Camundongos , COVID-19/complicações , Glicoproteína da Espícula de Coronavírus/genética , SARS-CoV-2/metabolismo , Receptor 4 Toll-Like , Síndrome de COVID-19 Pós-AgudaRESUMO
BACKGROUND AND PURPOSE: The aging brain demonstrates frequent MRI and pathological evidence of cerebral microbleeds, which are often associated with cerebral amyloid angiopathy. To develop new therapeutic strategies for this disorder, we studied cerebral microhemorrhage in a well-characterized mouse model of cerebral amyloid angiopathy. METHODS: Tg2576 mice were studied at ages ranging from 2 to 21 months. Spontaneous and induced microscopic bleeding was analyzed with and without a passive anti-amyloid immunization regimen and dietary supplementation of ischemic stroke prevention medication dipyridamole. RESULTS: Areas of microhemorrhage were easily demonstrated and were significantly more prominent in the oldest mice and in animals treated with anti-amyloid immunotherapy. Dipyridamole supplementation in the diet generated plasma levels >790 ng/mL within the range seen clinically. Dipyridamole treatment did not worsen frequency and size of cerebral microscopic bleeding. CONCLUSIONS: The Tg2576 mouse is a useful model to study progression and modification of spontaneous and immunotherapy-induced cerebral microhemorrhage. Absence of microhemorrhage worsening with dipyridamole treatment suggests a potential therapeutic role of this agent when ischemic and microhemorrhagic lesions coexist.
Assuntos
Angiopatia Amiloide Cerebral/terapia , Hemorragia Cerebral/terapia , Dipiridamol/administração & dosagem , Modelos Animais de Doenças , Imunoterapia/métodos , Microcirculação , Animais , Angiopatia Amiloide Cerebral/imunologia , Hemorragia Cerebral/imunologia , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Microcirculação/efeitos dos fármacos , Microcirculação/imunologiaRESUMO
Alzheimer disease (AD) is the most common form of dementia in the elderly, and the neuro-pathological hallmarks of AD include neurofibrillary tangles (NFT), and deposition of beta-amyloid (Abeta) in extracellular plaques. In addition, chronic inflammation due to recruitment of activated glial cells to amyloid plaques are an invariant component in AD, and several studies have reported that the use of non-steroidal anti-inflammatory drugs (NSAIDs) may provide a measure of protection against AD. In this report we have investigated whether phosphoinositide 3-kinase gamma (PI3Kgamma), which is important in inflammatory cell migration, plays a critical role in the neuro-inflammation, synaptic dysfunction, and cognitive deficits induced by intracerebroventricular injection of Abeta(1-40) in mice. We found that the selective inhibitor of PI3Kgamma, AS605240, was able to attenuate the Abeta(1-40)-induced accumulation of activated astrocytes and microglia in the hippocampus, and decrease immuno-staining for p-Akt and cyclooxygenase-2 (COX-2). Interestingly, Abeta(1-40) activated macrophages treated with AS605240 or another PI3Kgamma inhibitor, AS252424, displayed impaired chemotaxis in vitro, but their expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) was unaffected. Finally, AS605240 prevented Abeta(1-40)-induced cognitive deficits and synaptic dysfunction, but failed to modify scopolamine-induced amnesia. Our data suggests that inhibition of PI3Kgamma may represent a novel therapeutic target for treating AD patients.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Cognição/efeitos dos fármacos , Neurite (Inflamação)/enzimologia , Neurite (Inflamação)/psicologia , Fragmentos de Peptídeos/toxicidade , Fosfatidilinositol 3-Quinases/fisiologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Quimiotaxia de Leucócito/efeitos dos fármacos , Classe Ib de Fosfatidilinositol 3-Quinase , Ciclo-Oxigenase 2/metabolismo , Inibidores Enzimáticos/farmacologia , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Isoenzimas/antagonistas & inibidores , Isoenzimas/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Neurite (Inflamação)/induzido quimicamente , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Sinapses/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Taxane-derived drugs are antineoplastic agents used for the treatment of highly common malignancies. Paclitaxel and docetaxel are the most commonly used taxanes; however, other drugs and formulations have been used, such as cabazitaxel and nab-paclitaxel. Taxane treatment is associated with neurotoxicity, a well-known and relevant side effect, very prevalent amongst patients undergoing chemotherapy. Painful peripheral neuropathy is the most dose-limiting side effect of taxanes, affecting up to 97% of paclitaxel-treated patients. Central neurotoxicity is an emerging side effect of taxanes and it is characterized by cognitive impairment and encephalopathy. Besides impairing compliance to chemotherapy treatment, taxane-induced neurotoxicity (TIN) can adversely affect the patient's life quality on a long-term basis. Despite the clinical relevance, not many reviews have comprehensively addressed taxane-induced neurotoxicity when they are used therapeutically. This article provides an up-to-date review on the pathophysiology of TIN and the novel potential therapies to prevent or treat this side effect.
Assuntos
Antineoplásicos , Taxoides , Antineoplásicos/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Docetaxel , Humanos , Paclitaxel , Taxoides/efeitos adversosRESUMO
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.
Assuntos
Plexo Braquial/lesões , Plexo Braquial/fisiologia , Neuralgia/fisiopatologia , Receptor B1 da Bradicinina/fisiologia , Receptor B2 da Bradicinina/fisiologia , Animais , Plexo Braquial/efeitos dos fármacos , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Bradicinina/uso terapêutico , Antagonistas de Receptor B1 da Bradicinina , Antagonistas de Receptor B2 da Bradicinina , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuralgia/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodosRESUMO
Painful diabetic neuropathy (PDN) is a serious symptom that compromises quality of life and remains without effective pharmacological treatment. The transient receptor vanilloid 4 (TRPV4) is a cation-permeable channel implicated in sensory transduction and pain signalling. Therefore, drugs that act on TRPV4 may have therapeutic applications to treat PDN. In the present work, we assessed the effect of the selective TRPV4 channel antagonist HC-067047 on painful neuropathy associated with streptozotocin (STZ)-induced diabetes in mice. STZ-treated animals presented both mechanical and cold allodynia at 6 weeks after diabetes induction. Notably, HC-067047 (1â¯mg/kg, s.c.) given daily between 2 and 6 weeks after diabetes induction significantly prevented the development of mechanical allodynia. Additionally, both single and repeated treatments with HC-067047 (10â¯mg/kg, s.c.) significantly reverted established mechanical allodynia induced by STZ. However, HC-067047 was not capable of affecting either thermal cold allodynia or hyperglycemia. Similarly, HC-067047 treatments showed no effect on body weight, temperature, locomotor activity or motor coordination of control mice. Immunohistochemistry assay showed that TRPV4 expression was not different in sciatic nerve, dorsal root ganglia (DRG) or hind paw plantar skin from diabetic and non-diabetic mice, suggesting that HC-067047 acts on constitutive receptors to inhibit mechanical allodynia. Taken together, the data generated in the present study show the potential relevance of using TRPV4 antagonists to treat painful neuropathy associated with diabetes.
Assuntos
Neuropatias Diabéticas/tratamento farmacológico , Hiperalgesia/tratamento farmacológico , Morfolinas/farmacologia , Pirróis/farmacologia , Canais de Cátion TRPV/antagonistas & inibidores , Animais , Temperatura Corporal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Neuropatias Diabéticas/metabolismo , Neuropatias Diabéticas/fisiopatologia , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Morfolinas/uso terapêutico , Desempenho Psicomotor/efeitos dos fármacos , Pirróis/uso terapêutico , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Canais de Cátion TRPV/metabolismoRESUMO
Gestational diabetes mellitus (GD) is a form of insulin resistance triggered during gestation, which affects approximately 10% of pregnant women. Although previously considered a transient condition with few long-term consequences, growing evidence suggest that GD may be linked to permanent metabolic and neurologic changes in the offspring. Currently available GD models fail to recapitulate the full spectrum of this disease, thus providing limited information about the true burden of this condition. Here, we describe a new mouse model of GD, based on the administration of an insulin receptor antagonist (S961, 30 nmol/kg s.c. daily) during pregnancy. Pregnant mice developed increased fasting glycemia and glucose intolerance in the absence of maternal obesity, with a return to normoglycemia shortly after parturition. Moreover, we showed that the adult offspring of GD dams presented pronounced metabolic and cognitive dysfunction when exposed to short-term high-fat diet (HFD). Our data demonstrate that S961 administration to pregnant mice comprises a valuable approach to study the complex pathophysiology of GD, as well as strategies focused on prevention and treatment of both the mother and the offspring. Our findings suggest that the offspring of GD mothers are more susceptible to metabolic and cognitive impairments when exposed to high-fat diet later in life, thus indicating that approaches to prevent and treat these late effects should be pursued.
Assuntos
Cognição , Diabetes Gestacional/patologia , Animais , Animais Recém-Nascidos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/complicações , Dieta Hiperlipídica , Modelos Animais de Doenças , Suscetibilidade a Doenças , Feminino , Intolerância à Glucose/complicações , Comportamento Materno/efeitos dos fármacos , Camundongos , Peptídeos/farmacologia , Gravidez , Resultado da GravidezRESUMO
Painful peripheral neuropathy is the most dose-limiting side effect of paclitaxel (PTX), a widely used anti-cancer drug to treat solid tumours. The understanding of the mechanisms involved in this side effect is crucial to the development of new therapeutic approaches. CXCL1 chemokine and its receptor CXCR2 have been pointed as promising targets to treat chronic pain. Herein, we sought to evaluate the possible involvement of CXCL1 and CXCR2 in the pathogenesis of PTX-induced neuropathic pain in mice. PTX treatment led to increased levels of CXCL1 in both dorsal root ganglion and spinal cord samples. Systemic treatment with the anti-CXCL1 antibody (10⯵g/kg, i.v.) or the selective CXCR2 antagonist (SB225002, 3â¯mg/kg, i.p.) had minor effect on PTX-induced mechanical hypersensitivity. On the other hand, the intrathecal (i.t.) treatment with anti-CXCL1 (1 ng/site) or SB225002 (10 µg/site) consistently inhibited the nociceptive responses of PTX-treated mice. Similar results were obtained by inhibiting the PI3Kγ enzyme a downstream pathway of CXCL1/CXCR2 signalling with either the selective AS605240 (5 µg/site, i.t.) or the non-selective wortmannin PI3K inhibitor (0.4 µg/site, i.t.). Overall, the data indicates that the up-regulation of CXCL1 is important for the development and maintenance of PTX-induced neuropathic pain in mice. Therefore, the spinal blockage of CXCL1/CXCR2 signalling might be a new innovative therapeutic approach to treat this clinical side effect of PTX.
Assuntos
Antineoplásicos Fitogênicos/efeitos adversos , Quimiocina CXCL1/antagonistas & inibidores , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Receptores de Interleucina-8B/antagonistas & inibidores , Medula Espinal/efeitos dos fármacos , Animais , Quimiocina CXCL1/metabolismo , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Compostos de Fenilureia/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Quinoxalinas/farmacologia , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais/efeitos dos fármacos , Medula Espinal/metabolismo , Tiazolidinedionas/farmacologiaRESUMO
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.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/administração & dosagem , Modelos Animais de Doenças , Óxido Nítrico Sintase Tipo II/biossíntese , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/fisiologia , Animais , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/fisiologia , Injeções Intraventriculares , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/enzimologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genéticaRESUMO
Sepsis survivors frequently develop late cognitive impairment. Because little is known on the mechanisms of post-septic memory deficits, there are no current effective approaches to prevent or treat such symptoms. Here, we subjected mice to severe sepsis induced by cecal ligation and puncture (CLP) and evaluated the sepsis-surviving animals in the open field, novel object recognition (NOR), and step-down inhibitory avoidance (IA) task at different times after surgery. Post-septic mice (30 days post-surgery) failed in the NOR and IA tests but exhibited normal performance when re-evaluated 45 days after surgery. Cognitive impairment in post-septic mice was accompanied by reduced hippocampal levels of proteins involved in synaptic plasticity, including synaptophysin, cAMP response element-binding protein (CREB), CREB phosphorylated at serine residue 133 (CREBpSer133), and GluA1 phosphorylated at serine residue 845 (GluA1pSer845). Expression of tumor necrosis factor α (TNF-α) was increased and brain insulin signaling was disrupted, as indicated by increased hippocampal IRS-1 phosphorylation at serine 636 (IRS-1pSer636) and decreased phosphorylation of IRS-1 at tyrosine 465 (IRS-1pTyr465), in the hippocampus 30 days after CLP. Phosphorylation of Akt at serine 473 (AktpSer473) and of GSK3 at serine 9 (GSK3ßpSer9) were also decreased in hippocampi of post-septic animals, further indicating that brain insulin signaling is disrupted by sepsis. We then treated post-septic mice with liraglutide, a GLP-1 receptor agonist with insulinotropic activity, or TDZD-8, a GSK3ß inhibitor, which rescued NOR memory. In conclusion, these results establish that hippocampal inflammation and disrupted insulin signaling are induced by sepsis and are linked to late memory impairment in sepsis survivors.
Assuntos
Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Insulina/metabolismo , Sepse/metabolismo , Transdução de Sinais/fisiologia , Animais , Encéfalo/patologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Comportamento Exploratório/fisiologia , Masculino , Camundongos , Sepse/complicações , Sepse/patologiaRESUMO
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.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Cordia/química , Sesquiterpenos/farmacologia , Administração Oral , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/isolamento & purificação , Brasil , Ciclo-Oxigenase 2/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Dexametasona/farmacologia , Dinoprostona/biossíntese , Edema/induzido quimicamente , Edema/tratamento farmacológico , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/metabolismo , Masculino , Medicina Tradicional , Camundongos , Sesquiterpenos Monocíclicos , Óxido Nítrico Sintase Tipo II/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/metabolismo , Óleos Voláteis/química , Componentes Aéreos da Planta , Plantas Medicinais , Sesquiterpenos Policíclicos , Ratos , Ratos Wistar , Sesquiterpenos/isolamento & purificação , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
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.
Assuntos
Antialérgicos/farmacologia , Anti-Inflamatórios/farmacologia , Cordia/química , Óleos Voláteis/farmacologia , Extratos Vegetais/farmacologia , Animais , Carragenina , Ciclo-Oxigenase 1/efeitos dos fármacos , Ciclo-Oxigenase 2/efeitos dos fármacos , Dinoprostona , Edema/induzido quimicamente , Edema/tratamento farmacológico , Interleucina-1beta/efeitos dos fármacos , Camundongos , Sesquiterpenos Monocíclicos , Neutrófilos/efeitos dos fármacos , Peroxidase/efeitos dos fármacos , Peroxidase/metabolismo , Fitoterapia , Folhas de Planta , Plantas Medicinais , Sesquiterpenos Policíclicos , Ratos , Ratos Wistar , Sesquiterpenos/farmacologia , Fator de Necrose Tumoral alfa/efeitos dos fármacosRESUMO
Painful peripheral neuropathy is a common side effect of paclitaxel (PTX). The use of analgesics is an important component for management of PTX-induced peripheral neuropathy (PINP). However, currently employed analgesics have several side effects and are poorly effective. ß-caryophyllene (BCP), a dietary selective CB2 agonist, has shown analgesic effect in neuropathic pain models, but its role in chemotherapy-induced neuropathic pain has not yet been investigated. Herein, we used the mouse model of PINP to show the therapeutic effects of BCP in this neuropathy. Male Swiss mice receiving PTX (2 mg kg-1, ip, four alternate days) were treated with BCP (25 mg kg-1, po, twice a day) either during or after PTX administration. Some groups were also pretreated with AM630 (CB2 antagonist, 3 mg kg-1, ip) or AM251 (CB1 antagonist, 1 mg kg-1, ip). Spinal cord samples were collected in different time points to perform immunohistochemical analysis. BCP attenuated the established mechanical allodynia induced by PTX (p < 0.0001) in a CB2-dependent manner. Of note, when given concomitantly with PTX, BCP was able to attenuate the development of PINP (p < 0.0001). Spinal cord immunohistochemistry revealed that preventive treatment with BCP reduced p38 MAPK and NF-κB activation, as well as the increased Iba-1 and IL-1ß immunoreactivity promoted by PTX. Our findings show that BCP effectively attenuated PINP, possibly through CB2-activation in the CNS and posterior inhibition of p38 MAPK/NF-κB activation and cytokine release. Taken together, our results suggest that BCP could be used to attenuate the establishment and/or treat PINP.