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Consumption of palatable food (PF) can alleviate anxiety, and pain in humans. Contrary, spontaneous withdrawal of long-term PF intake produces anxiogenic-like behavior and abnormal pain sensation, causing challenges to weight-loss diet and anti-obesity agents. Thus, we examined α7-nicotinic acetylcholine receptors (α7nAChR) involvement since it plays essential role in nociception and psychological behaviors. METHODS: Adult male C57BL/6 mice were placed on a Standard Chow (SC) alone or with PF on intermittent or continuous regimen for 6 weeks. Then, mice were replaced with normal SC (spontaneous withdrawal). Body weight, food intake, and calories intake with and without the obesogenic diet were measured throughout the study. During PF withdrawal, anxiety-like behaviors and pain sensitivity were measured with PNU-282987 (α7nAChR agonist) administration. RESULTS: Six weeks of SC + PF-intermittent and continuous paradigms produced a significant weight gain. PF withdrawal displayed hyperalgesia and anxiety-like behaviors. During withdrawal, PNU-282987 significantly attenuated hyperalgesia and anxiety-like behaviors. CONCLUSION: The present study shows that a PF can increase food intake and body weight. Also, enhanced pain sensitivity and anxiety-like behavior were observed during PF withdrawal. α7nAChR activation attenuated anxiolytic-like behavior and hyperalgesia in PF abstinent mice. These data suggest potential therapeutic effects of targeting α7 nAChRs for obesity-withdrawal symptoms in obese subjects.
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Ansiedad , Benzamidas , Compuestos Bicíclicos con Puentes , Hiperalgesia , Ratones Endogámicos C57BL , Obesidad , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Masculino , Ansiedad/etiología , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Benzamidas/farmacología , Benzamidas/administración & dosificación , Obesidad/psicología , Obesidad/metabolismo , Compuestos Bicíclicos con Puentes/farmacología , Ratones , Ingestión de Alimentos/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Aumento de Peso/efectos de los fármacosRESUMEN
Type 2 Diabetes Mellitus (T2DM) is linked to multiple complications, including cognitive impairment, and the prevalence of memory-related neurodegenerative diseases is higher in T2DM patients. One possible theory is the alteration of the microvascular and macrovascular environment of the blood-brain barrier (BBB). In this study, we employed different approaches, including RT-PCR, functional pharmacokinetic studies using sodium fluorescein (NaFL), and confocal microscopy, to characterize the functional and molecular integrity of the BBB in a T2DM animal model, leptin receptor-deficient mutant mice (Leprdb/db mice). As a result, VCAM-1, ICAM-1, MMP-9, and S100b (BBB-related markers) dysregulation was observed in the Leprdb/db animal model compared to littermate wild-type mice. The brain concentration of sodium fluorescein (NaFL) increased significantly in Leprdb/db untreated mice compared to insulin-treated mice. Therefore, the permeability of NaFL was higher in Leprdb/db control mice than in all remaining groups. Identifying the factors that increase the BBB in Leprdb/db mice will provide a better understanding of the BBB microvasculature and present previously undescribed findings of T2DM-related brain illnesses, filling knowledge gaps in this emerging field of research.
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Barrera Hematoencefálica , Diabetes Mellitus Tipo 2 , Modelos Animales de Enfermedad , Receptores de Leptina , Animales , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Ratones , Receptores de Leptina/metabolismo , Receptores de Leptina/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Fluoresceína/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/genética , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Molécula 1 de Adhesión Celular Vascular/metabolismo , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Masculino , Diabetes Mellitus Experimental/metabolismo , Permeabilidad , Ratones Endogámicos C57BLRESUMEN
Background: The recent global increase in obesity rates, coupled with excessive palatable food (PF) consumption, has become a serious societal concern. Literature indicates that rewarding PF, especially upon cessation, can lead to overeating, binge eating, and compulsive eating, potentially resulting in obesity. Challenges in dietary paradigms, alongside limitations in approved treatments for eating disorders and anti-obesity medications, underscore the need to explore novel targets. In this context, α7nAChR (alpha-7 nicotinic acetylcholine receptor) may serve as a promising therapeutic target in combating food dependence and obesity. The present study aims to assess the role of α7nAChR in palatable food-induced dependence-like behaviors. Method: The study involved male C57BL/6J mice exposed to three different feeding paradigms over 6 weeks to induce obesity and food addiction. On day 43, palatable food was replaced with standard chow, and the mice received treatments (vehicle, PNU-282987 [α7nAChR agonist], or methyllycaconitine citrate [MLA; α7nAChR antagonist]). Addiction-like behaviors, including craving for palatable food, motivation-effort interaction tests, and compulsive eating-like behavior, were measured during abstinence with and without treatment. Results: The present study shows that chronic intermittent and continuous exposure to palatable food induces craving, motivation, and effort interaction behaviors as well as compulsive eating-like behaviors in palatable food-abstinent mice. Administration of the α7nAChR agonist, PNU-282987, significantly attenuated the craving behavior only in mice continuously fed palatable food (reduced calorie intake from 63.19 % to 48.21 %; p = 0.0053). Also, PNU-282987 suppressed the effort behaviors in either intermittently or continuously fed mice (significant reduction in the Δ number of active events per minute; p-values = 0.038 and 0.0098, respectively). However, it attenuated the compulsive-like eating behavior exclusively in the continuously fed group (p = 0.0433). Active and total interaction efforts were reversed by the MLA. These findings indicate the involvement of α7nAChR in dependence-like behaviors toward palatable food in mice. Conclusion: Our findings demonstrate that dependence-like behaviors toward palatable food can emerge after prolonged exposure. Mice fed on palatable food continuously exhibited more dependence-like behaviors toward palatable food, and activation of α7nAChR signaling attenuated the vulnerability to develop such behaviors.
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Chronic exposure to opioids can lead to downregulation of astrocytic glutamate transporter 1 (GLT-1), which regulates the majority of glutamate uptake. Studies from our lab revealed that beta-lactam antibiotic, ceftriaxone, attenuated hydrocodone-induced downregulation of GLT-1 as well as cystine/glutamate antiporter (xCT) expression in central reward brain regions. In this study, we investigated the effects of escalating doses of morphine and tested the efficacy of novel synthetic non-antibiotic drug, MC-100093, and ceftriaxone in attenuating the effects of morphine exposure in the expression of GLT-1, xCT, and neuroinflammatory factors (IL-6 and TGF-ß) in the nucleus accumbens (NAc). This study also investigated the effects of morphine and beta-lactams in locomotor activity, spontaneous alternation percentage (SAP) and number of entries in Y maze since opioids have effects in locomotor sensitization. Mice were exposed to moderate dose of morphine (20 mg/kg, i.p.) on days 1, 3, 5, 7, and a higher dose of morphine (150 mg/kg, i.p.) on day 9, and these mice were then behaviorally tested and euthanized on Day 10. Western blot analysis showed that exposure to morphine downregulated GLT-1 and xCT expression in the NAc, and both MC-100093 and ceftriaxone attenuated these effects. In addition, morphine exposure increased IL-6 mRNA and TGF-ß mRNA expression, and MC-100093 and ceftriaxone attenuated only the effect on IL-6 mRNA expression in the NAc. Furthermore, morphine exposure induced an increase in distance travelled, and MC-100093 and ceftriaxone attenuated this effect. In addition, morphine exposure decreased the SAP and increased the number of arm entries in Y maze, however, neither MC-100093 nor ceftriaxone showed any attenuating effect. Our findings demonstrated for the first time that MC-100093 and ceftriaxone attenuated morphine-induced downregulation of GLT-1 and xCT expression, and morphine-induced increase in neuroinflammatory factor, IL-6, as well as hyperactivity. These findings revealed the beneficial therapeutic effects of MC-100093 and ceftriaxone against the effects of exposure to escalated doses of morphine.
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Scientific evidences reported the deleterious effect of cigarette smoking or passive smoking on brain health particularly cognitive functions, blood-brain barrier (BBB) permeability, up-regulation of inflammatory cascades, and depletion of the antioxidant system. These combined effects become more progressive in the events of stroke, traumatic brain injury (TBI), and many other neurodegenerative diseases. In the current study, we investigated the long-term administered therapeutic potential of quercetin in ameliorating the deleterious neurobiological consequences of chronic tobacco smoke exposure in TBI mice. After exposure to 21 days of cigarette smoke and treatment with 50 mg/kg of quercetin, C57BL/6 mice were challenged for the induction of TBI by the weight drop method. Subsequently, a battery of behavioral tests and immunohistochemical analyses revealed the beneficial effect of quercetin on the locomotive and cognitive function of TBI + smoked group mice (p < 0.05 vs control sham). Immunohistochemistry analysis (Nrf2, HO-1, NFkB, caspase 3) demonstrated a marked protection after 21 days of quercetin treatment in the chronic tobacco smoking group possibly by up-regulation of antioxidant pathways, and decreased apoptosis. In conclusion, our findings support the therapeutic effectiveness of quercetin in partly protecting the central neurological functions that become aberrantly impaired in combined habitual cigarette-smoking individuals impacted with TBI.
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Khat (Catha edulis) is an evergreen shrub whose buds and leaves give a state of delight and euphoria when chewed. Cathinone, an amphetamine-like stimulant that is among the active ingredients in khat, is able to downregulate glutamate transporter subtype I (GLT-1). Neurobehavioral dysfunctions such as altered locomotor activity, anorexia, and nociception have been observed in animals exposed to cathinone. Interestingly, treatment with a ß-lactam antibiotic such as ceftriaxone, which upregulates GLT-1, normalizes cathinone-induced conditioned place preference, and alters repetitive movements in rats. However, little is known about the role of the glutamatergic system in memory dysfunction and anxiety-like behaviors in mice exposed to khat. We found here that clavulanic acid, a ß-lactam-containing compound and GLT-1 upregulator, would modulate the neurobehavioral changes, including memory impairment and anxiety-like behaviors, associated with repeated exposure of mice to khat. Our data supported that clavulanic acid could improve memory impairment and anxiety-like behaviors through upregulating GLT-1 in the nucleus accumbens (NAc), an effect abolished with a selective GLT-1 blocker. This upregulation was associated with restored glutamate/cystine antiporter expression in the NAc using a Western blotting assay. Cathine and cathinone were identified in khat extract using the gas chromatography technique. Our work provides preclinical insight into the efficacy of ß-lactam-containing compounds for the attenuation of neurobehavioral changes induced by khat exposure.
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Catha , Núcleo Accumbens , Ratones , Ratas , Animales , Ácido Clavulánico/farmacología , Núcleo Accumbens/metabolismo , Ansiedad/inducido químicamente , Ansiedad/tratamiento farmacológico , Trastornos de la Memoria/metabolismo , Anfetamina/metabolismoRESUMEN
NEW FINDINGS: What is the central question of this study? Is aortic dysfunction, a significant contributor to cardiovascular disease in metabolic syndrome, expressed uniformly across both the thoracic and abdominal aorta? What is the main finding and its importance? Our study shows that, in the setting of metabolic syndrome, functional and structural deficits in the aorta are differentially expressed along its length, with the abdominal portion displaying more extensive vascular abnormalities. It is, therefore, likely that early interventional strategies targeting the abdominal aorta might alleviate cardiovascular pathologies driven by the metabolic syndrome. ABSTRACT: The extent of vascular dysfunction associated with metabolic syndrome might vary along the length of the aorta. In this study, we investigated regional functional and structural changes in the thoracic and abdominal aorta of a rat model of metabolic syndrome, namely, high-fat diet (HFD) streptozotocin-induced diabetes mellitus (HFD-D). Four-week-old male Wistar albino rats were fed with either HFD or control diet (CD) for 10 weeks. At week 6, 40 mg/kg streptozotocin and its vehicle were injected i.p. into HFD and CD groups, respectively. At the end of the feeding period, rats were euthanised and aortic segments collected for assessment of vascular functional responses and histomorphometry. Tail-cuff systolic blood pressures (154 ± 6 vs. 110 ± 4 mmHg) and areas under the curve for oral glucose and i.p. insulin tolerance tests were greater in HFD-D versus CD rats. Abdominal aortic vasoconstriction in response to noradrenaline and KCl was greater in HFD-D compared with CD rats. Thoracic vasoconstrictor responses to noradrenaline, but not KCl, were greater in the HFD-D group. Abdominal, but not thoracic, endothelium-dependent vasorelaxation in response to acetylcholine was blunted in HFD-D relative to CD rats; however, nitric oxide-dependent vasorelaxation in HFD-D rats was impaired in both thoracic and abdominal segments. The abdominal aorta of HFD-D rats showed deranged interlamellar spacing and increased lipid plaque deposition. In conclusion, vascular dysfunction in metabolic syndrome is expressed differentially along the length of the aorta, with the abdominal aorta exhibiting increased susceptibility to vasoconstrictors and greater deficits in endothelium-dependent relaxation. These vascular functional abnormalities could potentially underlie the development of hypertensive cardiovascular disease associated with the metabolic syndrome.
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Síndrome Metabólico , Enfermedades Vasculares , Animales , Aorta Abdominal , Aorta Torácica/metabolismo , Endotelio Vascular , Masculino , Ratas , Ratas Wistar , Vasodilatación/fisiologíaRESUMEN
Research studies have indicated that the comorbidity burden of mood disorders and obesity is reasonably high. Insulin signaling has been shown to modulate multiple physiological functions in the brain, indicating its association with neuropsychiatric diseases, including mood disorders. Leptin is a hormone responsible for regulating body weight and insulin homeostasis. Previous studies on db/db mice (a mouse model that carries a spontaneous genetic mutation in leptin receptor Leprdb ) have shown that they exhibit inflammation as well as neurobehavioral traits associated with mood. Therefore, targeting inflammatory pathways such as TNF-α may be an effective strategy in the treatment of obesity-linked mood disorders. The objective of this study was to investigate the effect of long-term administration of etanercept (a TNF-α blocker) on anxiety and depressive-like behaviors in db/db mice. This was performed using light/dark box, forced swim, and open field tests with lean littermate wild type (WT) mice serving as a control group. Using flow cytometry in peripheral blood, we further examined the molecular effects of etanercept on NF-κB p65, TNF-α, IL-17A, and TLR-4 expressing CD4+, CD8+, and CD14+ cells in the peripheral blood. Our data show that peripheral administration of etanercept decreased these cells in db/db mice. Furthermore, our results indicated that peripheral administration of etanercept reduced anxiety and depressive-like behaviors. Therefore, targeting TNF-α signaling might be an effective strategy for modulating obesity-associated depression and anxiety.
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The 25-methoxy hispidol A (25-MHA) is a triterpenoid, isolated from the immature fruit of Poncirus trifoliata (Rutaceae). The pretreatment with 25-MHA markedly (p < 0.001) attenuated the formalin-induced biphasic responses as well as acetic acid-induced writhing responses. The intraperitoneal administration of 25-MHA significantly attenuated the mechanical hyperalgesia (p < 0.001) and allodynia (p < 0.05). Similarly, 25-MHA also significantly attenuated (p < 0.001) complete Freund's adjuvant (CFA)-induced paw edema in mice. The 25-MHA treatment significantly attenuated the production of nuclear kappa B (NF-κB) (p65 nuclear subunit). The cytokines are the important mediators of inflammation and pain; however, treatment with 25-MHA exhibited significant inhibition (p < 0.001) on the mRNA expression levels of various inflammatory mediators. The 25-MHA administration also significantly enhanced antioxidant enzymes (p < 0.001) and inhibited the oxidative stress markers. The current study indicates that 25-MHA significantly (p < 0.001) inhibited the nitric oxide (NO) in mice plasma. Similarly, the haematoxylin and eosin (H&E) staining shows that 25-MHA administration significantly inhibited the inflammatory process in the mice paw tissue compared with the CFA-treated group. The 25-MHA treatment did not exhibited any toxicity on the liver, kidney, muscles strength, and motor co-ordination in mice. The 25-MHA was coadministered with the various drugs such as tramadol, piroxicam, and gabapentin to observe the synergistic effect.
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Analgésicos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Dolor/tratamiento farmacológico , Poncirus/química , Triterpenos/uso terapéutico , Analgésicos/farmacología , Animales , Carragenina , Regulación hacia Abajo/efectos de los fármacos , Edema/inducido químicamente , Edema/tratamiento farmacológico , Adyuvante de Freund , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Masculino , Ratones , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Dolor/inducido químicamente , Dolor/metabolismo , Rutaceae/química , Transducción de Señal/efectos de los fármacos , Triterpenos/farmacologíaRESUMEN
In recent decades, there has been a gradual increase in the prevalence of asthma. Various factors including environmental pollutants have contributed to this phenomenon. Plasticizer, di(2-ethylhexyl)phthalate (DEHP) is one of the commonest environmental pollutants due to its association with plastic products. DEHP gets released from plastic products easily leading to respiratory exposure in humans. As a consequence, DEHP is associated with allergic asthma in humans and animals. DEHP is reported to act as an adjuvant in ovalbumin-induced mouse models of asthma at high doses. However, these studies mostly looked into the role of DEHP on Th2 cytokines/eosinophilic inflammation without investigating the role of airway epithelial cells (AECs)/dendritic cells (DCs)/Th17 cells. Its adjuvant activity with natural allergens such as cockroach allergens at tolerable daily intake needs to be explored. Cockroach allergens and DEHP may be inhaled together due to their coexistence in work place as well as household environments. Therefore, effect of DEHP was assessed in cockroach allergens extract (CE)-induced mouse model of asthma. Airway inflammation, histopathology, mucus secretion, and immune responses related to Th2/Th17/DCs and AECs were assessed in mice with DEHP exposure alone and in combination with CE. Our study shows that DEHP converts CE-induced eosinophilic inflammation into mixed granulocytic inflammation by promoting Th2 as well as Th17 immune responses. This was probably due to downregulation of E-cadherin in AECs, and enhancement of costimulatory molecules (MHCII/CD86/CD40)/pro-inflammatory cytokines (IL-6/MCP-1) in DCs by DEHP. This suggests that DEHP facilitates development of mixed granulocytic airway inflammation in the presence of a natural allergen.
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Alérgenos , Cucarachas , Dietilhexil Ftalato , Inflamación , Plastificantes , Alérgenos/toxicidad , Animales , Cucarachas/química , Citocinas , Dietilhexil Ftalato/uso terapéutico , Modelos Animales de Enfermedad , Humanos , Inflamación/inducido químicamente , Ratones , Ratones Endogámicos BALB C , Plastificantes/toxicidad , Sistema Respiratorio/efectos de los fármacos , Sistema Respiratorio/inmunologíaRESUMEN
INTRODUCTION: α7 nicotinic acetylcholine receptors (nAChRs) play an important role in vagus nerve-based cholinergic anti-inflammatory effects. This study was designed to assess the role of α7 nAChRs in dextran sodium sulfate (DSS)-induced colitis in male and female mouse. We first compared disease activity and pathogenesis of colitis in α7 knockout and wild-type mice. We then evaluated the effect of several α7 direct and indirect agonists on the severity of disease in the DSS-induced colitis. METHODS: Male and female adult mice were administered 2.5% DSS solution freely in the drinking water for 7 consecutive days and the colitis severity (disease activity index) was evaluated as well as colon length, colon histology, and levels of tumor necrosis factor-alpha colonic levels. RESULTS: Male, but not female, α7 knockout mice displayed a significantly increased colitis severity and higher tumor necrosis factor-alpha levels as compared with their littermate wild-type mice. Moreover, pretreatment with selective α7 ligands PHA-543613, choline, and PNU-120596 decreased colitis severity in male but not female mice. The anti-colitis effects of these α7 compounds dissipated when administered at higher doses. CONCLUSIONS: Our results suggest the presence of a α7-dependent anti-colitis endogenous tone in male mice. Finally, our results show for the first time that female mice are less sensitive to the anti-colitis activity of α7 agonists. Ovarian hormones may play a key role in the sex difference effect of α7 nAChRs modulation of colitis in the mouse. IMPLICATIONS: Our collective results suggest that targeting α7 nAChRs could represent a viable therapeutic approach for intestinal inflammation diseases such as ulcerative colitis with the consideration of sex differences.
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Antiinflamatorios , Colitis , Sulfato de Dextran/efectos adversos , Receptor Nicotínico de Acetilcolina alfa 7 , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Colitis/inducido químicamente , Colitis/genética , Colitis/metabolismo , Modelos Animales de Enfermedad , Femenino , Inflamación/genética , Isoxazoles/administración & dosificación , Isoxazoles/farmacología , Masculino , Ratones , Ratones Noqueados , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/farmacología , Quinuclidinas/administración & dosificación , Quinuclidinas/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/genética , Receptor Nicotínico de Acetilcolina alfa 7/metabolismoRESUMEN
OBJECTIVE: To evaluate the potential therapeutic value of telmisartan (TMT) against diabetic neuropathy (DN) and associated pain in Wistar rats. METHODS: Peripheral DN was induced by a single intraperitoneal streptozotocin injection (55 mg/kg), and 3 weeks later TMT treatment was started (5 and 10 mg/kg/day), and continued for 4 weeks. Mechanical nociceptive threshold, motor coordination, and thermal nociceptive threshold tests were performed before and after TMT treatment. In serum, glucose, pro-inflammatory cytokines including tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 were assessed. Nerve growth factor (NGF) levels and histopathological changes were estimated in the sciatic nerve. This study was conducted at the Experimental Animal Care Center, Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia between January 2013 and May 2014. RESULTS: We observed a significant reduction in mechanical nociceptive threshold, motor coordination, and thermal nociceptive threshold in diabetic animals. The TMT treatment significantly enhanced the reduced mechanical nociceptive threshold. The untreated diabetic animals revealed a significant decrease in sciatic NGF, which was markedly attenuated by TMT. The elevated serum levels of cytokines in diabetic animals were inhibited by the TMT treatments. Histopathological evaluation showed obvious nerve degeneration in the diabetic group that was eliminated in the TMT treated diabetic groups. CONCLUSION: Telmisartan has a potential neuro-protective effect on peripheral DN; this is mediated through its anti-inflammatory effects and its dual properties as an angiotensin receptor blocker, and a partial peroxisome proliferator activator receptor-gamma ligand.
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Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Bencimidazoles/uso terapéutico , Benzoatos/uso terapéutico , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Animales , Citocinas/sangre , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/patología , Neuropatías Diabéticas/patología , Hiperalgesia/patología , Inflamación/patología , Masculino , Actividad Motora/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Estimulación Física , Ratas , Ratas Wistar , Nervio Ciático/patología , TelmisartánRESUMEN
INTRODUCTION: The use of novel oral nicotine delivery devices and compositions for human consumption and for animal research studies has been increasing in the last several years. METHODS: Studies were undertaken to examine whether the systemic administration of methoxsalen, an inhibitor of human CYP2A6 and mouse CYP2A5, would modulate nicotine pharmacokinetics and pharmacological effects (antinociception in the tail-flick, and hot-plate tests, and hypothermia) in male ICR mouse after acute oral nicotine administration. RESULTS: Administration of intra peritoneal (ip) methoxsalen significantly increased nicotine's Cmax, prolonged the plasma half-life (fourfold decrease) of nicotine, and increased its area under the curve (AUC) compared with ip vehicle treatment. Methoxsalen pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (15mg/kg, po) for periods up to 6- and 24-hr postnicotine administration, respectively. Additionally, methoxsalen potentiated nicotine-induced antinociception and hypothermia as evidenced by leftward shifts in nicotine's dose-response curve. Furthermore, this prolongation of nicotine's effects after methoxsalen was associated with a parallel prolongation of nicotine plasma levels in mice. These data strongly suggest that variation in the rates of nicotine metabolic inactivation substantially alter pharmacological effects of nicotine given orally. CONCLUSION: We have shown that the pharmacological effects of inhibiting nicotine's metabolism after oral administration in mice are profound. Our results suggest that inhibiting nicotine metabolism can be used to dramatically enhance nicotine's bioavailability and its resulting pharmacology, which further supports this inhibitory approach for clinical development of an oral nicotine replacement therapy.
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Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Metoxaleno/farmacología , Nicotina/sangre , Nicotina/farmacocinética , Animales , Cromatografía Liquida , Cotinina/sangre , Cotinina/farmacocinética , Citocromo P-450 CYP2A6 , Familia 2 del Citocromo P450 , Interacciones Farmacológicas , Inyecciones Intraperitoneales , Masculino , Metoxaleno/administración & dosificación , Ratones , Espectrometría de Masas en TándemRESUMEN
Nicotine smoking contributes to many preventable disabilities, diseases and deaths. Targeting nicotine reward and withdrawal is a basis for the majority of smoking cessation pharmacotherapies. Due to the emergence of interest in 5-HT2A receptor modulators for numerous psychiatric disorders, we investigated the effect of nelotanserin, a 5-HT2A receptor inverse agonist, on nicotine reward and withdrawal in ICR mice. In nicotine-dependent mice, nelotanserin dose-dependently reduced somatic signs of nicotine withdrawal and thermal hyperalgesia as measured in the hot plate test. However, nelotanserin had no effect on anxiety-like behavior and failed to reduce nicotine reward as measured in the conditioned place preference test. Our results suggest that inverse agonism of the 5-HT2A receptor may be a feasible novel mechanism for smoking cessation by reducing both physical withdrawal and thermal hyperalgesia associated with nicotine abstinence but may require complementary pharmacotherapies targeting affective and reward-associated decrements to improve cessation outcomes.
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Ratones Endogámicos ICR , Nicotina , Recompensa , Agonistas del Receptor de Serotonina 5-HT2 , Síndrome de Abstinencia a Sustancias , Animales , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Nicotina/farmacología , Nicotina/administración & dosificación , Masculino , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Ratones , Relación Dosis-Respuesta a Droga , Tabaquismo/tratamiento farmacológico , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/inducido químicamente , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2A/efectos de los fármacos , Ansiedad/tratamiento farmacológico , Agonistas Nicotínicos/farmacología , Agonistas Nicotínicos/administración & dosificaciónRESUMEN
Opioid-related deaths are attributed to overdoses, and fentanyl overdose has been on the rise in many parts of the world, including the USA. Glutamate transporter 1 (GLT-1) has been identified as a therapeutic target in several preclinical models of substance use disorders, and ß-lactams effectively enhance its expression and function. In the current study, we characterized the metabolomic profile of the nucleus accumbens (NAc) in fentanyl-overdose mouse models, and we evaluated the protective effects of the functional enhancement of GLT-1 using ß-lactams, ceftriaxone, and MC-100093. BALB/c mice were divided into four groups: control, fentanyl, fentanyl/ceftriaxone, and fentanyl/MC-100093. While the control group was intraperitoneally (i.p.) injected with normal saline simultaneously with other groups, all fentanyl groups were i.p. injected with 1 mg/kg of fentanyl as an overdose after habituation with four repetitive non-consecutive moderate doses (0.05 mg/kg) of fentanyl for a period of seven days. MC-100093 (50 mg/kg) and ceftriaxone (200 mg/kg) were i.p. injected from days 5 to 9. Gas chromatography-mass spectrometry (GC-MS) was used for metabolomics, and Western blotting was performed to determine the expression of target proteins. Y-maze spontaneous alternation performance and the open field activity monitoring system were used to measure behavioral manifestations. Fentanyl overdose altered the abundance of about 30 metabolites, reduced the expression of GLT-1, and induced the expression of inflammatory mediators IL-6 and TLR-4 in the NAc. MC-100093 and ceftriaxone attenuated the effects of fentanyl-induced downregulation of GLT-1 and upregulation of IL-6; however, only ceftriaxone attenuated fentanyl-induced upregulation of TRL4 expression. Both of the ß-lactams attenuated the effects of fentanyl overdose on locomotor activities but did not induce significant changes in the overall metabolomic profile. Our findings revealed that the exposure to a high dose of fentanyl causes alterations in key metabolic pathways in the NAc. Pretreatment with ceftriaxone and MC-100093 normalized fentanyl-induced downregulation of GLT-1 expression with subsequent attenuation of neuroinflammation as well as the hyperactivity, indicating that ß-lactams may be promising drugs for treating fentanyl use disorder.
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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is marked by impaired social interactions, and increased repetitive behaviors. There is evidence of genetic changes in ASD, and several of these altered genes are linked to the process of DNA repair. Therefore, individuals with ASD must have improved DNA repair efficiency to mitigate risks associated with ASD. Despite numerous milestones in ASD research, the disease remains incurable, with a high occurrence rate and substantial financial burdens. This motivates scientists to search for new drugs to manage the disease. Disruption of glucagon-like peptide-1 (GLP-1) signaling, a regulator in neuronal development and maintains homeostasis, has been associated with the pathogenesis and progression of several neurological disorders, such as ASD. Our study aimed to assess the impact of semaglutide, a new GLP-1 analog antidiabetic medication, on behavioral phenotypes and DNA repair efficiency in the BTBR autistic mouse model. Furthermore, we elucidated the underlying mechanism(s) responsible for the ameliorative effects of semaglutide against behavioral problems and DNA repair deficiency in BTBR mice. The current results demonstrate that repeated treatment with semaglutide efficiently decreased autism-like behaviors in BTBR mice without affecting motor performance. Semaglutide also mitigated spontaneous DNA damage and enhanced DNA repair efficiency in the BTBR mice as determined by comet assay. Moreover, administering semaglutide recovered oxidant-antioxidant balance in BTBR mice. Semaglutide restored the disrupted DNA damage/repair pathways in the BTBR mice by reducing Gadd45a expression and increasing Ogg1 and Xrcc1 expression at both the mRNA and protein levels. This suggests that semaglutide holds great potential as a novel therapeutic candidate for treating ASD traits.
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Studies showed that nicotine has a positive influence on symptoms of ulcerative colitis. In the present study, we explored the effect of nicotine treatment using different routes of administration in the dextran sodium sulfate (DSS) colitis mouse model. We also investigated the effects of cotinine, a major metabolite of nicotine, in the model. C57BL6 adult male mice were given DSS solution freely in the drinking water for seven consecutive days, and tap water was given thereafter. Disease severity, length of the colon, colon tissue histology, and inflammatory markers, including colonic myeloperoxidase activity and colonic tumor necrosis factor-α levels, were evaluated. The effect of nicotine and cotinine treatments via various different routes of administration were examined the DSS model. In addition, we measured the plasma levels of nicotine and cotinine in our treatment protocols. Administration of low, but not high, doses of oral nicotine in DSS-treated mice resulted in a significant decrease in disease severity, histologic damage scores, as well as colonic level of tumor necrosis factor-α. However, the anti-inflammatory effect of nicotine was not seen after chronic s.c. or minipump infusion of the drug. Differences in plasma levels of nicotine and cotinine do not seem to account for this lack of effect. Finally, oral cotinine alone failed to show a significant effect in the DSS model of colitis. These results highlight that dose and route of administration play a critical role in the protective effect of nicotine in the DSS mouse colitis model.
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Colitis Ulcerosa/tratamiento farmacológico , Nicotina/uso terapéutico , Agonistas Nicotínicos/uso terapéutico , Animales , Cromatografía Líquida de Alta Presión , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/patología , Colon/patología , Cotinina/sangre , Cotinina/farmacología , Sulfato de Dextran , Relación Dosis-Respuesta a Droga , Inflamación/patología , Infusiones Intravenosas , Inyecciones Subcutáneas , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Nicotina/administración & dosificación , Nicotina/sangre , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/sangre , Peroxidasa/metabolismo , Fumar , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A substantial percentage of pregnant smokers stop using traditional cigarettes and switch to alternative nicotine-related products such as e-cigarettes. Prenatal exposure to tobacco increases the risk of psychiatric disorders in children. Adolescence is a complex phase in which higher cognitive and emotional processes undergo maturation and refinement. In this study, we examined the behavioral and molecular effects of first-trimester prenatal exposure to e-cigarettes. Adult female mice were divided into normal air, vehicle, and 2.5%-nicotine-exposed groups. Our analyses indicated that the adolescents in the 2.5%-nicotine-exposed group exhibited a significant lack of normal digging behavior, elevated initial sucrose intake, and reduced recognition memory. Importantly, we identified a substantial level of nicotine self-administration in the 2.5%-nicotine-exposed group. At a molecular level, the mRNAs of metabotropic glutamate receptors and transporters in the nucleus accumbens were not altered. This previously undescribed work indicates that prenatal exposure to e-cigarettes might increase the risk of nicotine addiction during adolescence, reduce cognitive capacity, and alter normal adolescent behavior. The outcome will aid in translating research and assist healthcare practitioners in tackling addiction and mental issues caused by toxicological exposure. Further, it will inform relevant policymaking, such as recommended taxation, labeling e-cigarette devices with more detailed neurotoxic effects, and preventing their sale to pregnant women and adolescents.
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Nicotinic agonists display a wide-range profile of antinociceptive activity in acute, tonic, and chronic pain models. However, their effectiveness is limited by their unacceptable side effects. We investigated the antinociceptive effects of two new α4ß2* nicotinic partial agonists, varenicline and sazetidine-A, in acute thermal and tonic pain mouse models. Both drugs failed to induce significant effects in the tail-flick and hot-plate tests after subcutaneous administration. However, they blocked nicotine's effects in these tests at very low doses. In contrast to acute pain tests, varenicline and sazetidine-A dose-dependently induced an analgesic effect in the mouse formalin test after systemic administration. Their antinociceptive effects were mediated, however, by different nicotinic acetylcholine receptor (nAChR) subtypes. Sazetidine-A effects were mediated by ß2* nAChR subtypes, whereas varenicline actions were attributed to α3ß4 nAChRs. Moreover, low inactive doses of varenicline blocked nicotine's actions in phase II of the formalin test. Overall, our results suggest that the antagonistic actions of varenicline at low doses are mediated by ß2*-nAChRs and at higher doses as an agonist by α3ß4*-nAChRs. In contrast, both actions of sazetidine-A are mediated by ß2*-nAChR subtypes. These results suggest that nicotinic partial agonists possess analgesic effects in a rodent tonic pain model and may provide a potential treatment for the treatment of chronic pain disorders.
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Analgésicos/farmacología , Azetidinas/farmacología , Benzazepinas/farmacología , Agonistas Nicotínicos/farmacología , Dolor/tratamiento farmacológico , Piridinas/farmacología , Quinoxalinas/farmacología , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Actividad Motora/efectos de los fármacos , Dolor/metabolismo , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Receptores Nicotínicos/metabolismo , VareniclinaRESUMEN
Nicotine-exposed animal models exhibit neurobehavioral changes linked to impaired synaptic plasticity. Previous studies highlighted alterations in neurotransmitter levels following nicotine exposure. Vesicular glutamate transporter (VGLUT1) and vesicular gamma-aminobutyric acid (GABA) transporter (VGAT) are essential for the transport and release of glutamate and GABA, respectively, from presynaptic neurons into synapses. In our work, an e-cigarette device was used to deliver vapor containing nicotine to C57BL/6J mice for four weeks. Novel object recognition, locomotion, and Y-maze tests were performed to investigate the behavioral parameters. Protein studies were conducted to study the hippocampal expression of VGLUT1, VGAT, and postsynaptic density protein 95 (PSD95) as well as brain cytokine markers. Long-term memory and locomotion tests revealed that e-cigarette aerosols containing nicotine modulated recognition memory and motor behaviors. We found that vapor exposure increased VGLUT1 expression and decreased VGAT expression in the hippocampus. No alterations were found in PSD95 expression. We observed that vapor-containing nicotine exposure altered certain brain cytokines such as IFNß-1 and MCP-5. Our work provides evidence of an association between neurobehavioral changes and altered hippocampal VGLUT1 and VGAT expression in mice exposed to e-cigarette vapors containing nicotine. Such exposure was also associated with altered neurobehaviors, which might affect neurodegenerative diseases.