RESUMO
The use of standardized internal hospital phone numbers for cardiac arrest is advocated in Europe. We evaluated the current status of variations in medical emergency call numbers for in-hospital patients in Japan and whether anesthesiologists would approve a standardized number. From June 2018 to August 2018, a questionnaire survey was mailed to anesthesiologists in 1373 Japanese Society of Anesthesiologists (JSA)-accredited hospitals. The basis for opinions on using a standardized cardiac arrest call number in all Japanese hospitals was evaluated. Of 1373 facilities (response rate, 58%, n = 800), 741/776 (96%) reported a response system for in-hospital cardiac arrest; 638/710 (90%) responded to cardiac arrest through loudspeaker broadcast, audible to both patients and staff; 346/777 (48%) used a number between one and five digits long, four-digit numbers being the most common. Across Japan, 370 different numbers were reported. Only 385/688 (56%) of respondents had the emergency number memorized. Finally, 423/776 (55%) respondents approved standardizing a hospital telephone number for summoning help. Multivariate analysis showed that facilities where the anesthesiologists already memorized the call number were the only reason identified for opposition to the standardization. Although 96% of JSA-accredited hospitals had a response system for in-hospital cardiac arrests, discussions for standardization of a unified number need to be encouraged for improved emergency response.
Assuntos
Reanimação Cardiopulmonar , Serviços Médicos de Emergência , Parada Cardíaca , Parada Cardíaca/epidemiologia , Parada Cardíaca/terapia , Hospitais , Humanos , Japão/epidemiologia , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Hyperuricemia has been reported to be associated with the development of postoperative acute kidney injury (pAKI). However, it remains underdetermined whether hyperuricemia treatment could decrease the potential risk of pAKI. Here, we investigated this hypothesis among hyperuricemia patients with previously normal renal function by performing a retrospective database analysis. RESULTS: The study screened 18,169 patients, and were examined preoperative serum creatinine, uric acid, and postoperative serum creatinine. Eight hundred thirty-six patients were finally analyzed for the study, of whom 232 were in the treatment group and 604 were in the non-treatment control group. After adjustment for multi-covariates including baseline (pre-treatment) serum uric acid (SUA) levels, the incidence of pAKI in the treatment group (9.05%; 95% CI 6.04-12.1%) was significantly lower than that in the control group (14.2%; 95% CI 11.2-17.2%). On the other hand, further adjusting for preoperative SUA levels, there was no significant difference in the expected incidence of pAKI between the groups.
Assuntos
Injúria Renal Aguda/etiologia , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Complicações Pós-Operatórias , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/prevenção & controle , Idoso , Alopurinol/uso terapêutico , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Hiperuricemia/sangue , Incidência , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Estudos Retrospectivos , Fatores de Risco , Ácido Úrico/sangueRESUMO
PURPOSE: Neuroinflammation may contribute to the pathogenesis of the cognitive symptoms of postoperative delirium (POD) and its subsequent long-term cognitive impairment. Haloperidol (HAL), a dopamine receptor antagonist, is widely used to treat POD, whereas the effects of HAL on postoperative neuroinflammation and related cognitive deficits have been underdetermined. METHODS: Aged rats underwent sham or abdominal surgery and were subcutaneously treated with either vehicle, low-dose (0.5 mg/kg bolus, then 0.5 mg/kg/day infusion), or high-dose (2.0 mg/kg bolus, then 2.0 mg/kg/day infusion) HAL. All treatments were initiated immediately after surgery and continued for 48 h. On either postoperative day 2 (early) or 7 (late), all rats were tested for trace and context fear memory retention after acquisition of trace fear conditioning. Following the cognitive testing, the levels of pro-inflammatory cytokines, as well as dopamine and its metabolite, in hippocampus and medial prefrontal cortex (mPFC) were measured. RESULTS: In the early postoperative period, surgery induced acute neuroinflammation along with related trace and context memory dysfunction. Dopamine turnover was increased in both hippocampus and mPFC, whereas no relationship with memory functions was observed. However, HAL even at high-dose failed to restore the surgery-induced neuroinflammation and related cognitive deficits. In the late postoperative period, chronic neuroinflammation was detected only in hippocampus, which was associated with context, but not trace memory dysfunction. Neither low- nor high-dose HAL could prevent the development of these late-phase neurocognitive deficits. CONCLUSION: Our findings indicate that perioperative administration with HAL may have no effects on postoperative neuroinflammation and related cognitive impairment.
Assuntos
Cognição/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Haloperidol/farmacologia , Animais , Citocinas/metabolismo , Delírio/prevenção & controle , Medo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Memória/fisiologia , Período Pós-Operatório , Ratos , Ratos Wistar , Fatores de TempoRESUMO
The acute neuroinflammatory response to surgery may play a key pathogenic role in postoperative delirium (POD). Here, we investigated the contribution of acute postoperative pain to neuroinflammation and related delirium-like behaviors after surgery in adult and aged rats. Animals were assigned into four groups: control, abdominal surgery, surgery with analgesia using local ropivacaine, and surgery with analgesia using systemic morphine. Pain was assessed by the Rat Grimace Scale (RGS). Trace and context memory retention was evaluated following trace fear conditioning during the first 2 days after surgery. Pro-inflammatory cytokines in medial prefrontal cortex and hippocampus were measured by enzyme-linked immunosorbent assay. In both age groups, the RGS increased significantly from baseline until 6 h after surgery. The postoperative analgesia with either local or systemic regimens comparably alleviated the RGS increase in adult and aged animals. The two analgesic regimens attenuated the surgery-induced trace and context memory deficits, as well as cytokines overproduction in both medial prefrontal cortex and hippocampus. No age-related differences were found in the neuro-cognitive effectiveness of postoperative analgesia. Our experimental findings provide proof-of-concept for adequate postoperative pain management as one of the main preventive strategies of POD.
Assuntos
Dor Aguda/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Delírio/fisiopatologia , Dor Pós-Operatória/fisiopatologia , Animais , Citocinas/metabolismo , Medo/fisiologia , Hipocampo/metabolismo , Masculino , Memória/fisiologia , Transtornos da Memória/fisiopatologia , Morfina/farmacologia , Ratos , Ratos WistarRESUMO
The beneficial effects of physical activity for pain are denominated exercise-induced hypoalgesia (EIH). Here, we examined the age-related change and potential role of the neurosteroid allopregnanolone (ALLO) on EIH in rats. Adult and aged rats were randomly divided into one of three groups; non-exercise control, Low-exercise, and High-exercise. The animals in the Low- and High-exercise groups were subjected to a 10-minute treadmill workout at 40% and 80% maximum oxygen intake intensity, respectively. In the Low-exercise groups, a significant EIH response was observed in aged but not in adult rats. The pre-treatment with ALLO synthesis inhibitor finasteride, but not opioid-receptor antagonist naloxone, inhibited the Low-exercise induced EIH response in aged rats. Furthermore, the Low-exercise increased brain ALLO levels in aged animals compared with controls, which was correlated with the mechanical pain sensitivity. On the other hand, High-exercise could induce EIH response in both adult and aged animals, but it was more effective in adult rats. The pre-treatment with naloxone, but not finasteride, reduced the EIH observed after High-exercise in both adult and aged rats. Our findings demonstrated that effective EIH can be achieved even by mild-intensity exercise in aged animals via an increase of the brain ALLO levels.
Assuntos
Envelhecimento/fisiologia , Dor/fisiopatologia , Condicionamento Físico Animal/fisiologia , Pregnanolona/fisiologia , Animais , Comportamento Animal , Encéfalo/metabolismo , Masculino , Limiar da Dor , Progesterona/metabolismo , Ratos Wistar , Reflexo , Medula Espinal/metabolismoRESUMO
The maladaptive response of aged microglia to surgery and consequent neuroinflammation plays a key pathogenic role in postoperative cognitive dysfunction (POCD). Here, we assessed the preventive effect of resveratrol (RESV) for POCD in aged rats. The emulsified form of RESV (e-RESV) was selected to improve its oral and brain bioavailability. Animals were assigned to one of four groups: e-RESV (80 mg/kg) versus vehicle treatment by abdominal surgery versus isoflurane anesthesia alone (n = 8 in each group). The dose-dependent effects of e-RESV were also assessed in dose range of 0-60 mg/kg. Either vehicle or e-RESV was administered intragastrically 24 h before surgery. Seven days after procedure, cognitive function was evaluated using a novel object recognition test, followed by measurement of hippocampal pro-inflammatory cytokine levels. Our results showed that pre-treatment with e-RESV attenuated the surgery-induced cognitive impairment and related hippocampal neuroinflammation at 40 mg/kg or higher doses. Additionally, the ex-vivo experiments revealed that the preemptive e-RESV regimen reduced the hippocampal microglial immune reactivity to lipopolysaccharide. Furthermore, e-RESV induced neuroprotective benefits were inhibited by the concomitant administration of sirtinol, a specific SIRT1 inhibitor. Our findings imply the preventive potential of e-RESV for POCD via the SIRT1 signaling pathway.
Assuntos
Envelhecimento/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Estilbenos/administração & dosagem , Administração Oral , Animais , Disponibilidade Biológica , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Emulsões , Hipocampo/metabolismo , Inflamação/prevenção & controle , Mediadores da Inflamação/metabolismo , Masculino , Microglia/imunologia , Microglia/fisiologia , Ratos Wistar , Resveratrol , Transdução de Sinais , Sirtuína 1/fisiologia , Estilbenos/farmacocinética , Estilbenos/farmacologiaRESUMO
PURPOSE: The purpose of this study was to investigate the age-, time-, and brain region-dependent postoperative neuroinflammatory trajectory, and its association with neurocognitive outcomes in rats. METHODS: Adult and aged rats were randomly assigned to one of three groups: control, isoflurane anesthesia alone, and isoflurane anesthesia with abdominal surgery. On either postoperative day 2 (early phase) or 7 (late phase), all rats were tested for trace and context fear memory retention after acquisition of trace fear conditioning. Freezing behavior was used as an index of fear memory. Following the cognitive testing, the levels of pro-inflammatory cytokines in several brain regions were measured using enzyme-linked immunosorbent assay (n = 8 in each group). RESULTS: In the early postoperative period, surgery under isoflurane anesthesia induced acute neuroinflammation along with related trace and context memory dysfunction. Such acute neuroinflammatory responses were comparably observed in both adult and aged animals, whereas the aged rats were more likely to exhibit behavioral changes. On the other hand, in the late postoperative period, neither neuroinflammation in all tested brain regions nor concomitant memory decline were found in adult animals. Significant neuroinflammation was detected only in the hippocampus of aged rats, which was associated with context, but not trace memory dysfunction. CONCLUSION: Our findings indicate that surgery-induced acute, transient, brain-wide neuroinflammation may be involved in the pathogenesis of the postoperative delirium-like cognitive deficits in rats. Furthermore, neuroinflammation may convert from acute to chronic in an age- and hippocampal-specific manner, likely resulting in the development of sustained cognitive dysfunction.
Assuntos
Disfunção Cognitiva/etiologia , Delírio/etiologia , Hipocampo/patologia , Isoflurano/administração & dosagem , Animais , Encéfalo/metabolismo , Cognição , Transtornos Cognitivos/etiologia , Citocinas/metabolismo , Medo/psicologia , Hipocampo/metabolismo , Masculino , Memória , Ratos , Ratos WistarRESUMO
AIMS: This study was aimed to explore the contribution of central brain-derived neurotrophic factor (BDNF) in the neuropathic pain pathogenesis using an aged rodent model. MAIN METHODS: Adult and aged rats were randomly assigned to either a sciatic nerve ligation (SNL) group or a control skin sham surgery group. Sensory behavioral testing were performed on the day before surgery and on the 3rd, 7th, 14th, and 21st days after surgery, followed by measurement of BDNF protein levels in different brain regions. In another experiment, the hippocampal BDNF gene expression after SNL surgery was assessed at different time-points. Furthermore, the analgesic effects of intranasal BDNF administration were tested in SNL animals. KEY FINDINGS: Our behavioral results demonstrated that the hyperalgesia-like behavior after painful nerve injury has a higher incidence in aged rats compared with in adult animals. In particular, the hippocampal BDNF levels were inversely correlated with the probability of hyperalgesia-type behavior, in both brain-region specific and age-dependent manner. Time-course analysis showed that the hippocampal levels of BDNF mRNA in aged and adult rats started to decrease 7 and 14â¯days after surgery, respectively. However, the decrease was more pronounced in aged animals. Moreover, the repeated intranasal BDNF treatment could restore the central BDNF signaling, counteracting the age-related exacerbation of hyperalgesic behavior. SIGNIFICANCE: Our findings imply that hippocampal BDNF may be related with the pathogenesis of elderly neuropathic pain. Pharmacological data further suggest that brain BDNF may be modifiable in aged neuropathic animals, and therefore, represent a promising target for intervention.
Assuntos
Envelhecimento/metabolismo , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Regulação da Expressão Gênica , Hipocampo/metabolismo , Neuralgia/metabolismo , Envelhecimento/patologia , Animais , Hipocampo/patologia , Masculino , Neuralgia/patologia , RNA Mensageiro/biossíntese , Ratos , Ratos WistarRESUMO
PURPOSE: In this study, we examined the effects of epigallocatechin-3-gallate (EGCG), a green tea polyphenol, on sepsis-induced neurocognitive abnormity in aged rats. METHODS: Aged rats received an intraperitoneal (i.p.) injection of 5.0 mg/kg lipopolysaccharide (LPS) or saline. Animals were further divided into three groups: control, low-dose EGCG (4.0 mg/kg), and high-dose EGCG (20 mg/kg). EGCG was i.p. injected at the same time, 24 and 48 h after LPS administration. Survival rate was recorded for 1 week. All surviving animals were assessed for cognitive function using the novel object recognition test, followed by measurement of hippocampal cytokine levels. In an additional set of experiments, the liver function test was performed. Furthermore, the effects of EGCG on cytokine release from microglia isolated from young and aged rats were assessed. RESULTS: The survival rate in LPS-treated control rats was 77.8%, which was decreased to 72.2 and 33.3% in the low and high EGCG groups, respectively. In the surviving animals, the LPS-treated control rats exhibited impaired cognitive performance and increased pro-inflammatory cytokine levels compared with untreated animals. None of these neurocognitive alterations were affected by low or high EGCG treatment. Blood chemical analysis showed co-administration of EGCG with LPS resulted in a marked increase in both aspartate aminotransferase and alanine aminotransferase levels. In addition, EGCG inhibited LPS-induced cytokine release, whereas the suppressive ability of EGCG was lower in aged microglia compared with in young microglia. CONCLUSIONS: Our findings demonstrated that EGCG cannot prevent hippocampal neuroinflammation and related memory deficits in aged rats surviving sepsis.
Assuntos
Catequina/análogos & derivados , Disfunção Cognitiva/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Aspartato Aminotransferases/metabolismo , Catequina/farmacologia , Citocinas/metabolismo , Hipocampo/metabolismo , Lipopolissacarídeos/administração & dosagem , Masculino , Transtornos da Memória/prevenção & controle , Microglia/metabolismo , Ratos , Ratos Sprague-Dawley , Sepse/tratamento farmacológicoRESUMO
PURPOSE: Low-grade endotoxin (lipopolysaccharide; LPS) exposure may contribute to the development of exaggerated acute postoperative pain. In the present study, we investigated the possible impact of intraoperative administration of dexmedetomidine (DEX) on LPS-induced postoperative hyperalgesia in a rat incisional pain model. METHODS: The surgical and sham-surgical animals were randomly divided into saline-treated control, 5.0 mg/kg LPS-treated, 10 µg/kg DEX-treated, and 5.0 mg/kg LPS + 10 µg/kg DEX-treated groups. In the surgical animals, a 1-cm-long plantar incision was made through the skin and fascia under isoflurane anesthesia. The sham-surgical rats were only anesthetized. All treatments were administered by a single intraperitoneal (i.p.) injection 60 min before surgery. Acute postoperative pain was assessed using the Rat Grimace Scale (RGS) one day before surgery (baseline) and at 2 h post incision. In another experiment, the involvement of the α2-adrenergic receptor was tested using atipamezole, an α2-adrenergic receptor antagonist. RESULTS: In the sham-surgical animals, the RGS did not increase at 2 h after sham surgery compared with the corresponding baseline values in all groups. In the surgical rats, however, the postoperative RGS value of the LPS group was significantly higher than the control group, indicating LPS-induced postoperative hyperalgesia. Administration of intraoperative DEX could prevent the development of such LPS-induced exacerbated post-incisional pain. In addition, the preventive effects of intraoperative DEX were inhibited by pretreatment with atipamezole. CONCLUSION: Our findings indicate that intraoperative DEX treatment can prevent LPS-induced exacerbated post-incisional pain via the α2-adrenergic receptor signaling pathway.
Assuntos
Dexmedetomidina/administração & dosagem , Hiperalgesia/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Animais , Endotoxinas/toxicidade , Imidazóis/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: In the present study, we examined whether and by what mechanisms dexmedetomidine (DMED) prevents the development of systemic inflammation (SI)-induced cognitive dysfunction in aged rats. METHODS: Animals received a single intraperitoneal (i.p.) injection of either 5.0 mg/kg lipopolysaccharide (LPS) or vehicle. LPS-treated rats were further divided into three groups: early DMED, late DMED, or midazolam (MDZ) treatment (n = 12 each). Seven days after LPS injection, cognitive function was evaluated using a novel object recognition task, followed by measurement of hippocampal levels of proinflammatory cytokines and Toll-like receptor 4 (TLR-4) expression. For ex vivo experiments, microglia were isolated from the hippocampus for assessment of cytokine response to LPS. RESULTS: LPS-treated rats showed memory deficits, hippocampal neuroinflammation, and TLR-4 upregulation as compared to saline-treated animals. However, early DMED treatment was able to attenuate these SI-induced neurocognitive changes, whereas no benefits were observed in the MDZ and late DMED treatment groups. In ex vivo experiments, early DMED treatment prevented the development of SI-induced excessive microglial hyperactivation, which was blocked by the nonspecific α2-adrenergic receptor (AR) antagonist atipamezole or the specific α2A-AR antagonist BRL-44408, but not by the specific α2B/C-AR antagonist ARC-239. On the other hand, neither DMED nor MDZ had a direct effect on LPS-induced release of pro-inflammatory cytokines from hippocampal microglia at clinically relevant concentrations. CONCLUSION: Our findings highlight that treatment with DMED during, but not after, peripheral SI can prevent subsequent hippocampal neuroinflammation, overexpression of TLR-4 in microglia, and cognitive dysfunction, as mediated by the α2A-AR signaling pathway.
Assuntos
Disfunção Cognitiva/prevenção & controle , Dexmedetomidina/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Envelhecimento , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/etiologia , Hipocampo/fisiopatologia , Imidazóis/farmacologia , Inflamação/complicações , Isoindóis/farmacologia , Isoquinolinas/farmacologia , Lipopolissacarídeos , Masculino , Transtornos da Memória , Piperazinas/farmacologia , Ratos , Transdução de SinaisRESUMO
BACKGROUND: Anti-N-methyl-d-aspartate receptor (NMDA-R) encephalitis is a recently identified but increasingly recognized autoimmune paraneoplastic disease. Because these patients present complex neuropsychiatric symptoms due to NMDA-R dysfunction, the optimal methods of sedation/anesthesia remain controversial. Here, we present animal experiment data, along with a related case report, implying the safe and effective use of dexmedetomidine in patients with anti-NMDA-R encephalitis. FINDINGS: (1) Animal experiment: in order to investigate whether dexmedetomidine may interfere with NMDA-R activity, an NMDA antagonist (MK-801) model in rats was used to simulate anti-NMDA-R encephalitis. Administration of MK-801 produced well-characterized schizophrenia-like behaviors, i.e. hyperlocomotion and stereotyped sniffing. Ketamine, an NMDA receptor-dependent anesthetic, exaggerated both behaviors, even at sub-anesthetic doses. On the other hand, dexmedetomidine did not show any exacerbation, suggesting that dexmedetomidine has no clinically relevant interaction with the NMDA-R in vivo. (2) CASE REPORT: our patient, a 27-year-old female, was diagnosed with anti-NMDA-R encephalitis secondary to ovarian teratoma. She underwent laparoscopic ovariectomy under general anesthesia using thiopental, sevoflurane, and remifentanil, which were well tolerated. After transfer to the intensive care unit, she became increasingly agitated despite repeated boluses of intravenous fentanyl. Infusion of dexmedetomidine (0.5-1.0 µg/kg/h) was started, and an adequate level of sedation was achieved uneventfully. After discontinuation of dexmedetomidine, recovery from sedation was smooth and quick without any deterioration of neurological or psychological symptoms. CONCLUSIONS: Our experimental findings and the presented case suggest that dexmedetomidine may be safely used in patients with anti-NMDA-R encephalitis. Further clinical evaluation is warranted to validate this finding.
RESUMO
AIMS: This study aimed to investigate the role of central insulin signaling, including glycogen synthase kinase 3ß (GSK-3ß), and its therapeutic potential for the prevention of postoperative neurocognitive deficits. MAIN METHODS: In non-insulin experiment, aged rats were divided into a sham group and abdominal surgery group. In insulin experiment, sham and surgically treated rats were distributed into two groups: an intranasal denatured insulin-treated group and intranasal insulin-treated group. Insulin administration started the day of surgery and continued for 3days. Fourteen-days after surgery, cognitive function was assessed using a novel object recognition test, followed by measurement of hippocampal levels of pro-inflammatory cytokines, GSK-3ß, and phosphorylated GSK-3ß (pGSK-3ß(ser9)). Under identical conditions, lipopolysaccharide (LPS)-induced cytokine release from isolated hippocampal microglia was also tested. KEY FINDINGS: In non-insulin experiment, compared with non-surgical animals, the rats that underwent abdominal surgery showed memory deficits and increased hippocampal cytokine levels. The hippocampal ratio of pGSK-3ß(ser9)/GSK-3ß decreased after surgery, a ratio that was positively correlated with novel object recognition performance in the testing phase. Insulin experiment revealed that perioperative intranasal insulin administration could restore the surgery-induced hippocampal neuroinflammation and hyperactivation of GSK-3ß, and prevent impairment in novel object recognition. Furthermore, ex vivo experiments indicated that intranasal insulin administration, as well as pretreatment with SB216763, a GSK-3ß inhibitor, resulted in reduction of the surgery-related microglial hyper-reactivity to LPS. SIGNIFICANCE: Our findings in aged rats suggest that surgical procedures could impair central insulin signaling including GSK-3ß, which makes the individual more susceptible to hippocampal neuroinflammation and related cognitive disorders.
Assuntos
Transtornos Cognitivos/metabolismo , Hipocampo/metabolismo , Insulina/metabolismo , Transdução de Sinais , Animais , Quinase 3 da Glicogênio Sintase/metabolismo , Hipocampo/enzimologia , Masculino , Período Pós-Operatório , Ratos , Ratos WistarRESUMO
Bacteria belonging to the Streptomyces genus are characterized by a complex life cycle and the production of many bioactive secondary metabolites. Trace metals play an important role in streptomycete metabolism and development, however, their mechanism of action is not fully understood. In this review, we summarize the present knowledge on metallosensing regulators and trace metal action, as well as discuss the possible application in natural product discovery.
Assuntos
Metais/farmacologia , Streptomyces/efeitos dos fármacos , Oligoelementos/farmacologia , Streptomyces/crescimento & desenvolvimentoRESUMO
Intranasal (i.n.) administration of midazolam has been shown to be effective and safe for its sedative, anxiolytic, and anticonvulsant effects. However, there has been no investigation on the influence of i.n. administration on midazolam-induced anterograde amnesia. In addition, although the potential of direct drug delivery from the nose to the central nervous system (CNS) has recently become a topic of great interest, it remains unclear whether this pathway is also involved after i.n. midazolam. In this study, we examined the efficacy and the underlying mechanism of i.n. administration compared with intramuscular (i.m.) administration on midazolam-induced amnesia in rats. Equivalent doses of 0.6 mg/kg midazolam were administered via either the i.m or the i.n. route. Anterograde amnesia was assessed by a contextual/cued fear conditioning test. Each animal was conditioned 20 min after drug administration and then tested for a freezing response 24 h later. Midazolam administration by either route produced a similar level of light sedation (minimum spontaneous activity). However, i.n. administration of midazolam induced significantly less freezing behavior compared with i.m. midazolam. Furthermore, in rats with disrupted electrical input from the olfactory epithelium after an olfactotoxicant 3-methylindole administration, the i.n.-mediated enhanced amnesic effect of midazolam was not observed. Our findings indicate that i.n midazolam could probably generate olfactory signals to the brain via benzodiazepine receptors and, compared with i.m. administration, can produce a more significant amnesic effect without alteration in sedative levels. Further clinical studies are warranted.
Assuntos
Amnésia/induzido quimicamente , Hipnóticos e Sedativos/administração & dosagem , Midazolam/administração & dosagem , Administração Intranasal , Anestesia/métodos , Animais , Ansiolíticos/administração & dosagem , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/efeitos adversos , Humanos , Hipnóticos e Sedativos/efeitos adversos , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
AIMS: The aim of the present study was to investigate the effects and underlying mechanisms of endotoxin (lipopolysaccharide, LPS) on postoperative pain using a rat model of incisional pain. MAIN METHODS: Animals were assigned to one of four groups using a 2×2 experimental design: a single intraperitoneal injection of 5mg/kg LPS versus vehicle, by plantar incision versus anesthesia alone. Spontaneous pain and mechanical paw withdrawal threshold (PWT) were evaluated using Rat Grimace Scale (RGS) and von Frey fibers, respectively. Analgesic effects of ketoprofen, morphine, and wound infiltration with ropivacaine, as well as the contribution of the Toll-like receptor (TLR) 4 pathway, were also evaluated. In vivo single fiber recordings were performed to assess the nociceptive afferent signals from the surgical site. KEY FINDINGS: Systemic administration of LPS significantly increased the pain intensity at 2h after hind paw incision, but did not affect the PWT. The duration of post-incisional pain assessed by both scales did not significantly differ in the presence or absence of LPS. The analgesic efficiency of ketoprofen and morphine was reduced by LPS, while that of wound infiltration with ropivacaine was preserved. On the other hand, in vivo single fiber recording failed to demonstrate any significant effects of LPS on the activity of primary afferents due to mechanical stimuli. Pre-treatment with intrathecal LPS from Rhodobacter sphaeroides, a TLR-4 antagonist, almost completely inhibited LPS-induced exacerbated post-incisional pain, and decreased analgesic responsiveness. SIGNIFICANCE: The present results suggested that LPS exacerbates post-incisional pain via the central TLR-4 pathway.
Assuntos
Endotoxemia/complicações , Endotoxemia/metabolismo , Medição da Dor/métodos , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/metabolismo , Animais , Relação Dose-Resposta a Droga , Endotoxemia/induzido quimicamente , Injeções Espinhais , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/toxicidade , Masculino , Medição da Dor/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/metabolismoRESUMO
AIMS: The present study aimed to explore the preventive or therapeutic effect of peri-operative pregabalin treatment on the memory deficits and related hippocampal inflammation following surgery in aged rats. MAIN METHODS: Aged rats underwent abdominal or sham surgery, and were then divided into 2 groups, either early or late pregabalin treatment. Fourteen days after surgery, the cognitive function was assessed using novel object recognition test, followed by measurement of hippocampal cytokines and voltage-dependent calcium channel α2δ subunit (CACNA2D1). The parabiotic experiments determined whether the humoral or neuronal pathway was involved in the neuroinflammation development following the abdominal surgery. The effects of pregabalin on LPS-induced cytokine release from hippocampal microglia were also evaluated. KEY FINDINGS: Early pregabalin treatment, which was administered pre-operatively and continued for 3 or 7days after surgery, prevented memory deficits and decreased hippocampal pro-inflammatory cytokine levels. In contrast, no beneficial effects were observed when pregabalin was administered late in the post-operative period. The hippocampal levels of CACNA2D1 did not change under any experimental condition. The data from the cross-circulation (parabiosis) experiments indicated that abdominal surgery may induce neuroinflammation via a neural transmission pathway from the periphery to the brain. The ex vivo experiments further demonstrated that pregabalin had no effect on LPS-induced cytokines release from hippocampal microglia. SIGNIFICANCE: Our findings highlight reveal that peri-operative pregabalin treatment during the early post-operative period can prevent neuroinflammation and memory deficits after surgery. It is likely this occurs through a peripheral and central neuro-immune interaction rather than through direct anti-inflammatory effects.
Assuntos
Músculos Abdominais/cirurgia , Envelhecimento/efeitos dos fármacos , Transtornos Cognitivos/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Pregabalina/uso terapêutico , Envelhecimento/psicologia , Animais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/psicologia , Masculino , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/psicologia , Pregabalina/farmacologia , Cuidados Pré-Operatórios/métodos , Ratos , Ratos Wistar , Resultado do TratamentoRESUMO
Leishmaniasis is a parasitic disease caused by hemoflagellates of the genus Leishmania and is transmitted to humans by the bite of infected phlebotomine sandflies. Depending on the Leishmania species, the disease has different clinical forms including cutaneous, mucocutaneous, and visceral manifestations. Previous studies performed in endemic zones of northwestern-Argentina, during epidemic outbreaks, have been important for detecting patients suffering from the acute phase of the disease, but have not given a complete representation of the clinical and epidemiological features in the region. Furthermore, due to the resurgence of leishmaniasis worldwide and in particular the large increase of international tourism to the region, it seems pertinent to update the current epidemiological and clinical profile of leishmaniasis in northwestern-Argentina. Here we present a retrospective analysis of 95 Leishmania positive cases, presenting between 2000 and 2014. Patients were derived from hospitals and diagnosed in our lab at the University of Salta, located in a non-endemic area in Salta, Argentina. We detected numerous extensive mucocutaneous cases (34/95, 35.8%) distinct from mucosal affected patients, some instances originating in locations with no previously reported human cases. Additionally patients suffering from concomitant diseases, besides leishmaniasis, were assessed. These included Chagas disease, syphilis, deep mycoses, tuberculosis, toxoplasmosis and intestinal parasitosis. This study updates the clinical and epidemiological features of leishmaniasis in northwestern-Argentina, and discusses the implications and management strategy for patients who acquire the disease in this region.
Assuntos
Leishmaniose Mucocutânea/epidemiologia , Leishmaniose Visceral/epidemiologia , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/imunologia , Argentina/epidemiologia , Doença de Chagas/epidemiologia , Criança , Pré-Escolar , Comorbidade , Surtos de Doenças , Feminino , Humanos , Lactente , Leishmania , Leishmania braziliensis , Leishmania infantum , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/parasitologia , Leishmaniose Mucocutânea/imunologia , Leishmaniose Mucocutânea/parasitologia , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Micoses/epidemiologia , Psychodidae/parasitologia , Estudos Retrospectivos , Sífilis/epidemiologia , Toxoplasmose/epidemiologia , Tuberculose/epidemiologia , Adulto JovemRESUMO
Emerging evidence from case reports suggests that fentanyl may precipitate potentially life-threatening serotonin syndrome in patients taking serotonergic drugs. However, the underlying mechanism of the association between serotonin syndrome and fentanyl remains under investigation. We therefore investigated the pharmacological effects of an analgesic dose of fentanyl (0.2 mg/kg) injected subcutaneously (s.c.) on serotonergic toxicity-like responses in rats. Rats were s.c. injected with 0.75 mg/kg 8-OH-DPAT, a full 5-HT1A agonist, as an animal model of serotonin syndrome. The 8-OH-DPAT-treated rats showed well-characterized serotonin syndrome-like behaviors (low body posture, forepaw treading), hyperlocomotion, and decreased body temperature. Rats injected s.c. with fentanyl alone showed no significant changes in any of the parameters measured, while concomitant administration of fentanyl + 8-OH-DPAT resulted in exaggerated 8-OH-DPAT-induced serototoxic responses. A separate dose-response experiment showed that the serototoxic effect of fentanyl was dose-dependent. Pretreatment with naloxone [2.0 mg/kg, intraperitoneal (i.p.) injection], an opioid receptor antagonist, failed to antagonize the fentanyl-induced exaggerated serotonin syndrome-like behaviors. In contrast, pretreatment with WAY-100653, a serotonin 5-HT1A receptor antagonist (0.5 mg/kg, i.p. injection) completely inhibited all responses. Our findings provide preclinical proof-of-concept that an analgesic dose of fentanyl enhances serotonin toxicity, likely via its serotonin-reuptake inhibitory activity, independently of interaction with the opioid receptors.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Fentanila/farmacologia , Atividade Motora/efeitos dos fármacos , Síndrome da Serotonina/fisiopatologia , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Serotonina/metabolismo , Antagonistas da Serotonina/farmacologiaRESUMO
Leishmaniases comprise zoonotic diseases caused by protozoan flagellates of the Leishmania genus. They are endemic to South America, and the visceral form has been recently reported in Argentina. Dogs can play different roles in the Leishmania transmission cycles, depending mainly on the species of parasite involved. Here we focused on the clinical characterization of canine leishmaniasis (CanL) in Northeast Argentina and on the molecular typing of its etiological agent. The nested polymerase chain reaction and sequence analysis of the Leishmania cytochrome b (cyt b) gene was performed on DNA templates purified from lymph nodes, bone marrow or spleen aspirates obtained from 48 dogs previously diagnosed by the observation of Leishmania amastigotes on smears from these aspirates. Their clinical and epidemiological data were also recorded. Systemic abnormalities were observed in 46 subjects (95.8%), most frequently lymphadenopathy, and emaciation (89.6 and 75%). Furthermore, 87% also presented tegumentary abnormalities, such as alopecia (54.2%) or secondary skin lesions (47.9%), among others. Twenty three dogs were positive for cyt b amplification. The sequence analysis showed the presence of two genotypes, LiA1 and LiA2, assigned to Leishmania (Leishmania) infantum, with 99.9 and 100% homology with the reference strain MHOM/TN/80/IPT1 respectively. LiA1 was identified in 18 cases (78.3%) and LiA2 in five (21.7%). Two cyt b variants of L. (L.) infantum were incriminated as the causative agents of CanL cases from three cities: Posadas, Garupá, and Ituzaingó. All three cities are located in the northeastern area of the country, where these parasites seem to be spreading in urban areas.